Article

Coenzyme Q 10 improves the tolerance of the senescent myocardium to aerobic and ischemic stress: Studies in rats and in human atrial tissue

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Abstract

The inferior recovery of cardiac function after interventional cardiac procedures in elderly patients compared to younger patients suggests that the aged myocardium is more sensitive to stress. We report two studies that demonstrate an age-related deficit in myocardial performance after aerobic and ischemic stress and the capacity of CoQ10 treatment to correct age-specific diminished recovery of function. In Study 1 the functional recovery of young (4 mo) and senescent (35 mo) isolated working rat hearts after aerobic stress produced by rapid electrical pacing was examined. After pacing, the senescent hearts, compared to young, showed reduced recovery of pre-stress work performance. CoQ10 pretreatment (daily intraperitoneal injections of 4 mg/kg CoQ10 for 6 weeks) in senescent hearts improved their recovery to match that of young hearts. Study 2 tested whether the capacity of human atrial trabeculae (obtained during surgery) to recover contractile function, following ischemic stress in vitro (60 min), is decreased with age and whether this decrease can be reversed by CoQ10. Trabeculae from older individuals (> or = 70 yr) showed reduced recovery of developed force after simulated ischemia compared to younger counterparts (< 70 yr). Notably, this age-associated effect was prevented in trabeculae pretreated in vitro (30 min at 24 degrees C) with CoQ10 (400 MicroM). We measured significantly lower CoQ10 content in trabeculae from > or = 70 yr patients. In vitro pretreatment raised trabecular CoQ10 content to similar levels in all groups. We conclude that, compared to younger counterparts, the senescent myocardium of rats and humans has a reduced capacity to tolerate ischemic or aerobic stress and recover pre-stress contractile performance, however, this reduction is attenuated by CoQ10 pretreatment.

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... The researchers then measured the effect of CoQ10 pretreatment on the contractile function recovery, which was significantly different between older and younger individuals (favoring younger individuals). The pretreatment of CoQ10 attenuated the ischemia-induced decline of the contractile force in trabeculae from older patients [78], supporting the finding from Reference [77]. ...
... CABG [81][82][83][84] CAD [82] p.o. [82,83] nm [81] i.v. [84] ex vivo [78] 3 x 50 mg/day for 7 days [81] 1 x 50 mg/day for 7 days [82] 3 x 50 mg/day (< 60 kg) for 7 -10 days [83] 3 x 60 mg/day (> 60 kg) for 7 -10 days [83] 5 mg/kg/2hrs [84] 400 μM [78] anti-inflammatory effects reduced levels of conjugated dienes [81] reduced levels of MDA [81] organ function reduced levels of CK [81] less incidences of ventricular arrhythmias [81,83] reduced requirement of total inotropic [83] reduced mediastinal drainage [83] reduced blood requirement [83] decrease of myocardial cellular injury [84] prevention of left ventricular depression [84] no effect on infarct biomarkers CK-MB and troponin [82] decreased duration of hospital stays [83], no effect in [82] attenuated decline of contractile function [78] Curcumin Kidney Transplantation [94,95] p.o. [94,95] 400 mg curcumin, 100 mg quercetin, 10 mg bromelain/day [94] 480 mg curcumin, 20 mg quercetin for 1 month starting within 24 hrs after transplantation [95] organ function increased urine output [94] improved creatinine clearance [94,95] early graft function [95] fewer acute rejection events [95] anti-oxidative effects increased HO-1 expression [95] decreased level of iso-prostaglandins [94] Liver --- ...
... CABG [81][82][83][84] CAD [82] p.o. [82,83] nm [81] i.v. [84] ex vivo [78] 3 x 50 mg/day for 7 days [81] 1 x 50 mg/day for 7 days [82] 3 x 50 mg/day (< 60 kg) for 7 -10 days [83] 3 x 60 mg/day (> 60 kg) for 7 -10 days [83] 5 mg/kg/2hrs [84] 400 μM [78] anti-inflammatory effects reduced levels of conjugated dienes [81] reduced levels of MDA [81] organ function reduced levels of CK [81] less incidences of ventricular arrhythmias [81,83] reduced requirement of total inotropic [83] reduced mediastinal drainage [83] reduced blood requirement [83] decrease of myocardial cellular injury [84] prevention of left ventricular depression [84] no effect on infarct biomarkers CK-MB and troponin [82] decreased duration of hospital stays [83], no effect in [82] attenuated decline of contractile function [78] Curcumin Kidney Transplantation [94,95] p.o. [94,95] 400 mg curcumin, 100 mg quercetin, 10 mg bromelain/day [94] 480 mg curcumin, 20 mg quercetin for 1 month starting within 24 hrs after transplantation [95] organ function increased urine output [94] improved creatinine clearance [94,95] early graft function [95] fewer acute rejection events [95] anti-oxidative effects increased HO-1 expression [95] decreased level of iso-prostaglandins [94] Liver --- ...
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Although extended donor criteria grafts bear a higher risk of complications such as graft dysfunction, the exceeding demand requires to extent the pool of potential donors. The risk of complications is highly associated with ischemia-reperfusion injury, a condition characterized by high loads of oxidative stress exceeding antioxidative defense mechanisms. The antioxidative properties, along with other beneficial effects like anti-inflammatory, antiapoptotic or antiarrhythmic effects of several micronutrients and natural compounds, have recently emerged increasing research interest resulting in various preclinical and clinical studies. Preclinical studies reported about ameliorated oxidative stress and inflammatory status, resulting in improved graft survival. Although the majority of clinical studies confirmed these results, reporting about improved recovery and superior organ function, others failed to do so. Yet, only a limited number of micronutrients and natural compounds have been investigated in a (large) clinical trial. Despite some ambiguous clinical results and modest clinical data availability, the vast majority of convincing animal and in vitro data, along with low cost and easy availability, encourage the conductance of future clinical trials. These should implement insights gained from animal data.
... 4,5 Myocardial CoQ 10 content is reduced by cardiac failure and aging. [6][7][8] Further reductions can be caused by 3-hydroxy-3methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, which have been shown to lower plasma and myocardial levels of CoQ 10 . 9-12 Our previous experimental work has shown that CoQ 10 has the ability to protect the myocardium against ischemia-reperfusion injury 8 and against aerobic pacing stress, especially in elderly hearts. ...
... [6][7][8] Further reductions can be caused by 3-hydroxy-3methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, which have been shown to lower plasma and myocardial levels of CoQ 10 . 9-12 Our previous experimental work has shown that CoQ 10 has the ability to protect the myocardium against ischemia-reperfusion injury 8 and against aerobic pacing stress, especially in elderly hearts. 13 Previous clinical trials have suggested that treatment with CoQ 10 before cardiac surgery might improve postoperative cardiac function and reduce myocardial structural damage. ...
... 13 We have also shown that isolated human myocardial trabeculae obtained from patients aged 34 to 89 years are also protected against ischemia-reperfusion injury when pre-exposed to CoQ 10 suspension in vitro. 8 Moreover, in this previous study myocardial tissue from elderly individuals showed increased susceptibility to injury, and the protective effect of CoQ 10 was greatest in these elderly tissues. These in vitro effects of CoQ 10 followed rapid uptake of CoQ 10 into sarcolemmal and mitochondrial membranes. ...
... This breach has consequences for a variety of related mitochondrial effects, many of which are facilitated and enhanced by advanced age: reduced efficiency of Ca M handling, increased permeability of the inner mitochondrial membrane to solutes occurs causing mitochondrial swelling, 'proton leak', decreased ADP-induced oxygen consumption, prolonged conversion of ADP to ATP, reduced oxidative phosphorylation rates and a degree of uncoupling between respiration and ATP synthesis (Ferrari, 1996; Di Lisa et al., 1998; Halestrap et al., 1998; Pepe et al., 1999; Jahangir et al., 2001). Such uncoupling causes reduced efficiency of oxygen utilisation and augmented free radical production (Nohl et al., 1978; Sawada and Carlson, 1987; Sohal et al., 1990; Papa and Skulachev, 1997; Rosenfeldt et al., 1999; Ambrosio et al., 1993; Droge, 2002a,b; Turrens, 2003). Besides Ca 2C -overload, post-ischemic appearance of markers predictive of irreversible cell injury include: increased acidosis and P i ; decreased superoxide dismutase activity; accumulation of free radicals; activation of phospholipases; accumulation of long-chain acyl CoA and toxic products of membrane lipid peroxidation; and formation of protein adducts (Ferrari, 1996; Di Lisa et al., 1998; Halestrap et al., 1998; Pepe et al., 1999; Jahangir et al., 2001; Esterbauer et al., 1991; Lapidus and Sokolov, 1994; Blasig et al., 1995; Szweda, 1998, 1999; Droge, 2002b ). ...
... Such HNE reactions that form protein adducts may adversely modify adenine nucleotide translocase and cyclophilin-D to interfere with DJ m and ultimately contribute to MPT. Mitochondrial ROS in the heart has been reported to increase with age (Nohl et al., 1978; Sawada and Carlson, 1987; Sohal et al., 1990; Papa and Skulachev, 1997; Lucas and Szweda, 1998; Rosenfeldt et al., 1999; Ambrosio et al., 1993; Droge, 2002a; Terrens, 2003). A number of endogenous mitochondrial antioxidant defenses may also diminish with age and thus reduce the capacity for efficient management of ROS (Sohal et al., 1990; Papa and Skulachev, 1997; Rosenfeldt et al., 1999). ...
... Mitochondrial ROS in the heart has been reported to increase with age (Nohl et al., 1978; Sawada and Carlson, 1987; Sohal et al., 1990; Papa and Skulachev, 1997; Lucas and Szweda, 1998; Rosenfeldt et al., 1999; Ambrosio et al., 1993; Droge, 2002a; Terrens, 2003). A number of endogenous mitochondrial antioxidant defenses may also diminish with age and thus reduce the capacity for efficient management of ROS (Sohal et al., 1990; Papa and Skulachev, 1997; Rosenfeldt et al., 1999). Oxidative stress occurs due to an imbalance between the formation of ROS and antioxidant defenses. ...
Article
Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca2+ buffering during events that stimulate increased myocardial Ca2+, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca2+, intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca2+ homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e. arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.
... Ischemic heart disease (IHD) and associated stroke are the lead causes of mortality globally (Fuster & Kelly, 2010), with age a major risk factor in their development. While aged myocardium is most likely to suffer I-R insult (~75% of infarcts occur in those >65 yrs of age), it may possess reduced resistance to I-R injury (Headrick, 1998;Rosenfeldt et al., 1999;Mariani et al., 2000;Headrick et al., 2003;Lesnefsky et al., 2006) compounded by refractoriness to protective intervention (Ferdinandy et al., 2007;Boengler et al., 2009;Peart & Headrick, 2009). These clinically relevant changes could reflect mechanistic determinants of the poorly understood aging process itself: in the 'green hypothesis' the expression/functionality of intrinsic 'detoxification' systems eliminating molecular damage and governing cellular stress-resistance is forwarded as a primary determinant of aging and longevity (Gems & McElwee, 2005). ...
... Right atrial myocardium was sampled from middle-aged and aged cardiac patients with mean ages of 55±2 (n=10) and 75±2 (n=10) yrs, respectively, and functionally assessed for I-R tolerance as detailed by us previously (Rosenfeldt et al., 1999;Mariani et al., 2000). Resected atrial appendage was acquired from patients undergoing elective coronary artery bypass graft or valve operations with cardiopulmonary bypass at the Alfred Hospital in Melbourne, under approval of the Human Research Ethics Committee for Discarded Tissue. ...
... Given prevalence of heart disease in older individuals, it is critical we understand the influence of age on myocardial responses to injurious insult and protective therapies (and unravel poorly understood mechanisms of cell aging). Myocardial I-R tolerance was markedly reduced in older rodent and human tissue, in agreement with reports of age-related changes in stress-resistance in animal (Headrick, 1998;Headrick et al., 2003;Lesnefsky et al., 2006) and human tissue (Rosenfeldt et al., 1999;Mariani et al., 2000). This is consistent with the view of declining stress-resistance as a hallmark of cellular aging, however the genesis of this decline remains obscure. ...
Article
Changes in cytoprotective signaling may influence cardiac aging, and underpin sensitization to ischemic insult and desensitization to 'anti-ischemic' therapies. We tested whether age-dependent shifts in ischemia-reperfusion (I-R) tolerance in murine and human myocardium are associated with reduced efficacies and coupling of membrane, cytoplasmic and mitochondrial survival-signaling. Hormesis (exemplified in ischemic preconditioning; IPC) and expression of proteins influencing signaling/stress-resistance were also assessed in mice. Mouse hearts (18 vs. 2-4 mo) and human atrial tissue (75±2 vs. 55±2yr) exhibited profound age-dependent reductions in I-R tolerance. In mice aging negated cardioprotection via IPC, G-protein coupled receptor (GPCR) agonism (opioid, A1 and A3 adenosine receptors) and distal protein kinase C (PKC) activation (4 nM phorbol 12-myristate 13-acetate; PMA). In contrast, p38-mitogen activated protein kinase (p38-MAPK) activation (1μM anisomycin), mitochondrial ATP-sensitive K(+) channel (mKATP) opening (50μM diazoxide) and permeability transition pore (mPTP) inhibition (0.2μM cyclosporin A) retained protective efficacies in older hearts (though failed to eliminate I-R tolerance differences). A similar pattern of change in protective efficacies was observed in human tissue. Murine hearts exhibited molecular changes consistent with altered membrane control (reduced caveolin-3, cholesterol and caveolae), kinase signaling (reduced p70 ribosomal s6 kinase; p70s6K) and stress-resistance (increased G-protein receptor kinase 2, GRK2; glycogen synthase kinase 3ß, GSK3ß; and cytosolic cytochrome c). In summary, myocardial I-R tolerance declines with age in association with dysfunctional hormesis and transduction of survival signals from GPCRs/PKC to mitochondrial effectors. Differential changes in proteins governing caveolar and mitochondrial function may contribute to signal dysfunction and stress-intolerance.
... In a more recent paper, the same group showed that supplementation of mice with CoQ 10 significantly increased CoQ 9 and CoQ 10 content in homogenates and mitochondria of liver, heart, kidney, skeletal muscle and brain [19]. This issue was also addressed by Rosenfeldt et al. in rats and in human myocardial tissue [20]. Hearts isolated from senescent (35 months) rats were tested in vitro in a model, where they were subjected to rapid electrical pacing. ...
... CoQ 10 pre-treatment of rats from which the senescent hearts were isolated improved the heart recovery of the aged myocardial muscle. In another experiment [20], the same authors showed that trabeculae isolated from older patients (>70 years of age) during heart surgery showed reduced recovery of developed force after simulated ischemia compared to younger counterparts (<70 years). CoQ 10 content was decreased in the myocardium from aged patients. ...
Article
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For a number of years, coenzyme Q (CoQ10 in humans) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and extensively investigated its antioxidant role. These two functions constitute the basis on which research supporting the clinical use of CoQ10 is founded. Also at the inner mitochondrial membrane level, coenzyme Q is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the transition pore. Furthermore, recent data reveal that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of exogenously administered CoQ10 may be due to this property. Coenzyme Q is the only lipid soluble antioxidant synthesized endogenously. In its reduced form, CoQH2, ubiquinol, inhibits protein and DNA oxidation but it is the effect on lipid peroxidation that has been most deeply studied. Ubiquinol inhibits the peroxidation of cell membrane lipids and also that of lipoprotein lipids present in the circulation. Dietary supplementation with CoQ10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoproteins to the initiation of lipid peroxidation. Moreover, CoQ10 has a direct anti-atherogenic effect, which has been demonstrated in apolipoprotein E-deficient mice fed with a high-fat diet. In this model, supplementation with CoQ10 at pharmacological doses was capable of decreasing the absolute concentration of lipid hydroperoxides in atherosclerotic lesions and of minimizing the size of atherosclerotic lesions in the whole aorta. Whether these protective effects are only due to the antioxidant properties of coenzyme Q remains to be established; recent data point out that CoQ10 could have a direct effect on endothelial function. In patients with stable moderate CHF, oral CoQ10 supplementation was shown to ameliorate cardiac contractility and endothelial dysfunction. Recent data from our laboratory showed a strong correlation between endothelium bound extra cellular SOD (ecSOD) and flow-dependent endothelial-mediated dilation, a functional parameter commonly used as a biomarker of vascular function. The study also highlighted that supplementation with CoQ10 that significantly affects endothelium-bound ecSOD activity. Furthermore, we showed a significant correlation between increase in endothelial bound ecSOD activity and improvement in FMD after CoQ10 supplementation. The effect was more pronounced in patients with low basal values of ecSOD. Finally, we summarize the findings, also from our laboratory, on the implications of CoQ10 in seminal fluid integrity and sperm cell motility.
... Проведенный ими анализ показал, что систолическое АД в этих исследованиях в среднем снизилось на 16 мм pт.cт., а диастолическое -на 10 мм рт.ст. С учетом отсутствия у КоQ 10 побочных эффектов авторы полагают, что этот препарат может служить альтернативой гипотензивным лекарственным средствам или может быть использован для усиления их гипотензивного эффекта [15][16][17][18]. ...
... Одним из препаратов коэнзима Q 10 является Кудесан, созданный по технологии микрокапсулирования, содержащий солюбилизированную форму коэнзима Q 10 . Биодоступность солюбили-зированной формы коэнзима Q 10 в 2,6 раза больше биодоступности жирорастворимой формы Q 10 [13][14][15][16][17][18][19][20][21][22][23][24][25][26]. ...
Article
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Increasing incidence of arterial hypertension (AH) justifies the need for more effective AH treatment and prevention. Pharmaceutical therapy remains the basis of AH management. The most modern and effective variant of pharmaceutical AH management is combination treatment, as confirmed by the data from multiple clinical trials. Antihypertensive agents could be combined with metabolic medications, in particular, ubiquinone – coenzyme Q10 (Kudesan). This agent optimises electron transport in the cytochrome chain, improves tissue energy balance, and demonstrates antioxidant activity. Moreover, several studies have shown antihypertensive effects of this medication. In addition, coenzyme Q10 is virtually free from adverse effects. The available evidence supports the clinical use of coenzyme Q10 (Kudesan) for AH treatment.
... Only four cases are reported with genetic based failure of synthesis [49]. Low levels of coenzyme Q are found in disease or ageing [21,50,51,52]. It is not clear how the distribution of coenzyme Q in tissue is controlled. ...
... This is especially true in young, healthy animals. In older animals with decreased coenzyme Q, in some tissue, supplemental coenzyme Q can restore normal levels [50,53,54]. In addition to decrease in biosynthesis, other factors may affect levels or function of coenzyme Q. ...
Article
Full-text available
Coenzyme Q is well defined as a crucial component of the oxidative phosphorylation process in mitochondria which converts the energy in carbohydrates and fatty acids into ATP to drive cellular machinery and synthesis. New roles for coenzyme Q in other cellular functions are only becoming recognized. The new aspects have developed from the recognition that coenzyme Q can undergo oxidation/reduction reactions in other cell membranes such as lysosomes. Golgi or plasma membranes. In mitochondria and lysosomes, coenzyme Q undergoes reduction/oxidation cycles during which it transfers protons across the membrane to form a proton gradient. The presence of high concentrations of quinol in all membranes provides a basis for antioxidant action either by direct reaction with radicals or by regeneration of tocopherol and ascorbate. Evidence for a function in redox control of cell signaling and gene expression is developing from studies on coenzyme Q stimulation of cell growth, inhibition of apoptosis, control of thiol groups, formation of hydrogen peroxide and control of membrane channels. Deficiency of coenzyme Q has been described based on failure of biosynthesis caused by gene mutation, inhibition of biosynthesis by HMG coA reductase inhibitors (statins) or for unknown reasons in ageing and cancer. Correction of deficiency requires supplementation with higher levels of coenzyme Q than are available in the diet.
... This lower coenzyme Q10 content of the tissue was associated with a significantly reduced contractile performance in vitro, which was reversed by pretreatment with coenzyme Q10. 11 Differences in the contractile strength between young and senescent myocardial tissue from rats were similar. 11 The study concluded that pretreatment with coenzyme Q10 improved the tolerance of the senescent myocardium to aerobic stress by improving ATP generation within the affected mitochondria as well as through its antioxidant role as a free radical scavenger. ...
... 11 Differences in the contractile strength between young and senescent myocardial tissue from rats were similar. 11 The study concluded that pretreatment with coenzyme Q10 improved the tolerance of the senescent myocardium to aerobic stress by improving ATP generation within the affected mitochondria as well as through its antioxidant role as a free radical scavenger. ...
Article
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Coenzyme Q10 is an important factor in mitochondrial respiration. Primary and secondary deficiencies of coenzyme Q10 result in a number of neurologic and myopathic syndromes. Hydroxyl-methylglutaryl coenzyme A reductase inhibitors or statins interfere with the production of mevalonic acid, which is a precursor in the synthesis of coenzyme Q10. The statin medications routinely result in lower coenzyme Q10 levels in the serum. Some studies have also shown reduction of coenzyme Q10 in muscle tissue. Such coenzyme Q10 deficiency may be one mechanism for statin-induced myopathies. However, coenzyme Q10 supplements have not been shown to routinely improve muscle function. Additional research in this area is warranted and discussed in this review.
... Indeed, aging causes significant reduction in the heart's ability to endure damage from ischemia and reperfusion injury.[4],[7] While aging is associated with increased oxidative stress, further increase in stress caused by injury makes the aged heart more vulnerable.[2],[3],[5],[6],[8],[9] Elderly patients often present at a clinic in an atypical manner, indicative of other diseases and complicating factors, which not only impedes diagnosis and treatment but increases susceptibility of the aged heart to more injury.[10] ...
... Evidence from animal models and humans indicate a decreased ability of the aged heart to tolerate stress compared to young counterparts.[2]–[6] Differences in how an aged heart responds to a specific disease, type of injury or individual drug therapy compared to young heart imposes an added complication. ...
Article
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The average human life span has markedly increased in modern society largely attributed to advances in medical and therapeutic sciences that have successfully reduced important health risks. However, advanced age results in numerous alterations to cellular and subcellular components that can impact the overall health and function of an individual. Not surprisingly, advanced age is a major risk factor for the development of heart disease in which elderly populations observe increased morbidity and mortality. Even healthy individuals that appear to have normal heart function under resting conditions, actually have an increased susceptibility and vulnerability to stress. This is confounded by the impact that stress and disease can have over time to both the heart and vessels. Although, there is a rapidly growing body of literature investigating the effects of aging on the heart and how age-related alterations affect cardiac function, the biology of aging and underlying mechanisms remain unclear. In this review, we summarize effects of aging on the heart and discuss potential theories of cellular aging with special emphasis on mitochondrial dysfunction.
... A lower EOF reflects the protection of the structure and extensibility of erythrocyte membrane and cell geometry, which may be attributed to ubiquinol (CoQ 10 H 2 ), the reduced form of ubiquinone (CoQ 10 ), which exists mostly in blood and serves as an antioxidant. The reduction of EOF seems more prominent before 29 d of dietary CoQ 10 administration, which may be related to absorption of CoQ 10 , the tissue level, or the age of the birds, as described in other studies (Zhang et al., 1995Zhang et al., , 1996 Rosenfeldt et al., 1999; Ibrahim et al., 2000 ). The absorption of CoQ 10 in broilers is yet to be in- vestigated. ...
Article
Full-text available
Effects of coenzyme Q10 (CoQ10) supplementation on growth performance and ascites were studied in broilers. One hundred eighty 1-d-old Arbor Acre male broiler chicks were randomly allocated into 3 groups with 6 replicates each. From d 8, the diets were supplemented with CoQ10 at levels of 0, 20, and 40 mg/kg, respectively. From d 15 to 21, all the chicks were exposed to low ambient temperature (15 to 18 °C) to induce ascites. Average feed intake, BW gain, and feed conversion ratio of the broilers during 0 to 3 wk, 3 to 6 wk, and 0 to 6 wk were measured. The results showed that there were no influences observed on broilers' growth performance, but the mortality due to ascites was reduced by CoQ10 supplementation (P < or = 0.05). Erythrocyte osmotic fragility (EOF) was significantly decreased by 40 mg/kg CoQ10 compared with the control, but no significant changes were observed on blood packed cell volume (PCV) among the treatments. Pulmonary arterial diastolic pressure was significantly decreased on d 36, but no significant changes were observed on right ventricular pressure (RVP), pulmonary arterial systolic pressure, and the maximum change ratio of right intraventricular pressure (+/- dp/ dtmax). Ascites heart index (AHI) was significantly decreased by 40 mg/kg CoQ10 supplementation (P < or = 0.05). The results of this study suggested that CoQ10 has a beneficial effect in reducing ascites mortality in broilers, and 40 mg/kg CoQ10 seems to be more effective than 20 mg/ kg CoQ10.
... An Australian group of cardiovascular surgeons has recently documented impairment in myocardial function secondary to age-related CoQ 10 deficiency in patients undergoing coronary artery bypass surgery (CABG). That impairment was completely eliminated with incubation of the atrial myocardium with CoQ 10 [57]. Later these researchers performed a trial of preoperative supplemental CoQ 10 therapy and found improved outcomes in coronary artery bypass surgery [58]. ...
Article
The depletion of the essential nutrient CoQ10 by the increasingly popular cholesterol lowering drugs, HMG CoA reductase inhibitors (statins), has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably. An estimated 36 million Americans are now candidates for statin drug therapy. Statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials. This drug-induced nutrient deficiency is dose related and more notable in settings of pre-existing CoQ10 deficiency such as in the elderly and in heart failure. Statin-induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti-inflammatory properties of the statin drugs. We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide-spread deficiency of a nutrient critically important for normal heart function.
... 4 In the second study, human atrial tissue was obtained at the time of open heart surgery and subjected to simulated ischemia in the organ bath after incubation with CoQ 10 . 5 In the third study, a clinical trial of CoQ 10 was performed in patients undergoing cardiac surgery. ...
Article
With aging of the population, increasing numbers of elderly patients are presenting for cardiac surgery. However, the results in the elderly are inferior to those in the young. A likely contributing factor is an age-related reduction in cellular energy production in the myocardium during surgery, which is known to induce aerobic and ischemic stress. The lipophilic antioxidant and mitochondrial respiratory chain redox coupler, coenzyme Q10 (CoQ10), has the potential to improve energy production in mitochondria by bypassing defective components in the respiratory chain as well as by reducing the effects of oxidative stress. We hypothesized that CoQ10 pretreatment prior to stress could improve the recovery of the myocardium after stress.
... In healthy tissues, ubiquinones are synthesized from phenylalanine and mevalonate (Schultz and Clarke, 1999), and it appears that CoQ 10 reaches saturation level in cell membranes (Beal, 1999). However, low levels of cellular CoQ 10 have been reported in disease state and ageing (Reahal and Wriggleworth, 1992;Rosenfeldt et al., 1999;Willis et al., 1999). The autooxidation of CoQ 10 has been shown to produce hydrogen peroxide that activates transcription factors such as NFkB (Kaltschimdt et al., 1999;McLennan and Degli Esposti, 2000). ...
... 15 Similar differences have also been observed between young and senescent myocardial tissue from rats. 15 CoQ 10 may also help to improve myocardial performance in older individuals during cardiac surgery and in times of aerobic or ischemic stress. 6,16 A number of studies have shown that CoQ 10 improves various parameters related to exercise and athletic performance as well as subjective sensations of fatigue and physical performance during fatigue-inducing workload trials. ...
Article
Many older athletes take statins, which are known to have potential for muscle toxicity. The adverse effects of statins on muscles and the influence thereof on athletic performance remain uncertain. Coenzyme Q-10 (CoQ10) may improve performance and reduce muscle toxicity in older athletes taking statins. This trial was designed to evaluate the benefits of CoQ10 administration for mitochondrial function in this population. Twenty athletes aged ≥ 50 years who were taking stable doses of statins were randomized to receive either CoQ10 (200 mg daily) or placebo for 6 weeks in a double-blind, placebo-controlled, crossover study to evaluate the impact of CoQ10 on the anaerobic threshold (AT). Several secondary endpoints, including muscle function, cardiopulmonary exercise function, and subjective feelings of fitness, were also assessed. The mean (SD) change in AT from baseline was -0.59 (1.2) mL/kg/min during placebo treatment and 2.34 (0.8) mL/kg/min during CoQ10 treatment (P = 0.116). The mean change in time to AT from baseline was significantly greater during CoQ10 treatment than during placebo treatment (40.26 s vs 0.58 s, P = 0.038). Furthermore, muscle strength as measured by leg extension repetitions (reps) increased significantly during CoQ10 treatment, with a mean (SD) increase from baseline of 1.73 (2.9) reps during placebo treatment versus 3.78 (5.0) reps during CoQ10 treatment (P = 0.031). Many other parameters also tended to improve in response to CoQ10 treatment. Treatment with CoQ10 improved AT in comparison with baseline values in 11 of 19 (58%) subjects and in comparison with placebo treatment values in 10 of 19 (53%) subjects. Treatment with CoQ10 (200 mg daily) did not significantly improve AT in older athletes taking statins. However, it did improve muscle performance as measured by time to AT and leg strength (quadriceps muscle reps). Many other measures of mitochondrial function also tended to improve during CoQ10 treatment.
... Likewise, a decrease in coenzyme Q~o was shown in rat heart and other tissues (26,27). The aged myocardium is clearly more sensitive to aerobic and ischemic stress in humans and in animals, and coenzyme Q~o treatment before ischemia markedly improves recovery (28,29). Also, a diet rich in coenzyme Qlo can slow down the decline in mitochondrial respiratory function normally observed in rat skeletal muscle (30). ...
Article
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The influence of diagnostic categories, age, and gender on parameters of oxidative stress measured in 102 patients with neuromuscular diseases and 11 control subjects was assessed using a stepwise multiple linear regression model. Antioxidative enzyme activities, lipophilic antioxidants, and lipid peroxidation were analyzed in muscle biopsies. Mitochondrial myopathies and amyotrophic lateral sclerosis (ALS) are thought to be particularly susceptible to increased oxidative stress. In our study, mitochondrial myopathies emerged as a positive predictor of malondialdehyde (p < 0.05) and ALS as a negative predictor of alpha-tocopherol (p < 0.05). Although the primary atrophic process in ALS is not in muscle but in motoneurons, this finding could have therapeutic implications, as such patients might benefit from antioxidant supplementation. In our study age emerged as a negative predictor of the coenzyme Q10 concentration (p < 0.003), whereas the percentage of reduced coenzyme Q10 remained unchanged. Age emerged as a positive predictor of the activities of catalase (p < 0.01) and superoxide dismutase (p < 0.002), probably reflecting an enzymatic upregulation that compensates for the loss of coenzyme Q10. The increased activities of catalase and superoxide dismutase in females compared to males indicate a higher antioxidative potential in female muscle. Whether this increase contributes to a higher life expectancy of women remains to be investigated.
... As individuals live longer and chronic diseases such as cardiovascular disease become more prevalent, cardiac surgeons are called upon to operate on older and older patients (Rosenfeldt et al., 1999). As a consequence, the oxidative stress response is augmented and increased rates of post-operative complications and mortality are observed. ...
Article
Reactive oxygen species (ROS) play an important role in the regulation of normal cellular function. When ROS are produced in excess they can have detrimental effects, a state known as oxidative stress. Thus ROS play both physiological and pathophysiological roles in the body. In clinical practice oxidative stress and its counterpart, antioxidant capacity can be measured and can guide remedial therapy. Oxidative stress can have a negative impact in all forms of major surgery including cardiac surgery, general surgery, trauma surgery, orthopedic surgery and plastic surgery; this is particularly marked in an ageing population. Many different therapies to reduce oxidative stress in surgery have been tried with variable results. We conclude that in surgical patients the assessment of oxidative stress, improvement of the understanding of its role, both positive and negative, and devising appropriate therapies represent fruitful fields for future research.
... 8,9 Previous experimental work has shown that CoQ10 has the ability to protect the myocardium against I/R injury and against aerobic pacing stress, especially in elderly hearts. 10,11 Preoperative oral coenzyme CoQ10 therapy in patients undergoing cardiac surgery increases myocardial and cardiac mitochondrial coenzyme CoQ10 levels, improves mitochondrial efficiency, and increases myocardial tolerance to in vitro hypoxia-reoxygenation stress. 12 ...
Article
To determine the efficacy of coenzyme Q10 (CoQ10) and alpha-lipoic acid (alpha-LA), either alone or in combination, to protect the contractile responses of the rabbit urinary bladder from damage caused by repetitive stimulation in the presence or absence of in vitro ischemia. Four groups of New Zealand white rabbits (4 per group) were treated with vehicle (group 1), CoQ10 (group 2), alpha-LA (group 3), or CoQ10 plus alpha-LA (group 4) for 2 weeks. At the end of the treatment period, eight longitudinal strips from each rabbit bladder body were placed in oxygenated Tyrode's solution with glucose (normal physiologic medium). The strips were stimulated by field stimulation, carbachol, and KCl, and the responses were recorded. One half of the strips were switched for 1 hour to Tyrode's solution with no glucose equilibrated with nitrogen (ischemia medium). Simultaneously, all strips were subjected to 1 h of repetitive field stimulation followed by 1 hour of recovery in normal physiologic medium, and the responses to all stimuli were recorded again. CoQ10 showed no protective effect. Alpha-LA resulted in increased contractile responses of the control bladder and showed a moderate protective effect for all forms of stimulation. The combination, however, showed a significantly greater increase in the contraction of the control bladder and a greater protective effect than alpha-LA alone. The combination of alpha-LA and CoQ10 treatment enhanced the contractile response in normal medium and diminished the contractile dysfunction induced by repetitive field stimulation and ischemia.
... In young and healthy individuals CoQ 10 supplementation does not increase tissue levels above normal (except in liver and spleen) but, in older animals with decreased CoQ 10 levels supplemental CoQ 10 can restore normal levels (Beal, 1999;Rosenfeldt et al., 1999). Low levels of CoQ 10 have been related to the higher oxidative stress produced during aging and in the course of different related diseases. ...
Article
Coenzyme Q10 (CoQ10) is a ubiquitous molecule present in all eukaryotic organisms whose principal role in the cell is related to its participation in the electron transport chain in the inner mitochondrial membrane. CoQ10 plays a major role in the control of cell redox status, and both the amount and functionality of this molecule have been related to the regulation of reactive oxygen species generation. Numerous reports can be found discussing the implications of CoQ10 supplementation in human studies and clinical trials related to aging. However, few reviews have made an updating through the translational point of view to integrate both basic and clinical aspects. The aim of this paper is to review our current knowledge from CoQ10 implications at biochemical and physiological level, in order to unravel the molecular mechanisms involved in its application in clinical practice. Although the importance of CoQ10 has been mainly attributed to its role as an agent for energy transduction in mitochondria, new functions for CoQ10 have been described in the recent past years, including anti-inflammatory effects, gene expression regulation and lipid bilayer membranes stabilization, which explain its involvement in aging and age-related diseases such as cardiovascular diseases, renal failure and neurodegenerative diseases.
... Supplementation with CoQ9 and CoQ10 both in vitro and as a nutritional supplement has been shown to reverse the consequences of mitochondrial dysfunction, particularly deficits in complex ll-lll activity (Rahman et al., 2001;Hodgson et al., 2002;Quiles et al., 2006), and to augment mitochondrial specific antioxidant defence (Saretzki et al., 2003;Adlam et al., 2005). It has now been shown in several studies that administration of CoQ9 and 10 can reverse affects of aging (Rosenfeldt et al., 1999;Rowland et al., 1998). It would therefore be of interest to determine whether dietary supplementation with CoQ9 can reverse telomere shortening and premature aging in these 'catch-up' animals. ...
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We have recently reported that maternal dietary imbalance during pregnancy and lactation can reduce the lifespan of offspring. Rats that were growth restricted in utero by maternal protein restriction and underwent rapid weight gain when suckled by control fed dams died earlier than animals whose mothers were fed a control diet throughout pregnancy and lactation. We demonstrate here that mitochondrial abnormalities and DNA damage occur in the kidney of offspring who die prematurely. We have established by direct measurement and by in vitro supplementation that mitochondrial abnormalities occur because of a functional deficit of the mitochondrial cofactor coenzyme Q9 (CoQ9). These data provide molecular insight into the association between maternal nutrition and determination of offspring lifespan, and identify, a potential dietary intervention to prevent detrimental consequences of imbalanced maternal nutrition.
... Blood and cardiac muscle CoQ10 deficiencies have been well documented in heart failure (19,20). The role of CoQ10 as a protector of the cardiac cell has also been well demonstrated in high-risk patients in heart surgery (21,22). Patients with age related low plasma CoQ10 levels are at risk when sent to coronary artery bypass surgery (CABG). ...
Article
Frequently, dietary supplements, vitamins and nutraceuticals are studied and recommended as sole sources of therapy, based upon their individual activities. Scientifically, studies of multiple agents, especially in humans, are infrequent because of the difficulty in asserting mechanisms of action. However, foods are complex mixtures of water- and fat-soluble antioxidants, providing key functions in health promotion and interacting to maintain antioxidant homeostasis. In prevention and treatment of disease mixtures, two or more dietary supplements should be more effective than each individual one. Therefore, we evaluated the published literature and some initial research suggesting that Pycnogenol® and coenzyme Q10, water- and lipid-soluble antioxidants respectively, may have synergies to promote heart health.
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Unlabelled: With ageing of the general population, increasing numbers of elderly patients are presenting for interventional cardiac treatment such as cardiac surgery, angioplasty and thrombolysis. However, the results of these interventions in the elderly are inferior to those in the young. A likely contributing factor is an age-related reduction in cellular energy production in the myocardium during interventions that induce aerobic or ischaemic stress. Coenzyme Q10 (CoQ10) has the potential to improve the efficiency of energy production in mitochondria by bypassing defective components in the respiratory chain as well as reducing the effects of oxidative stress. We hypothesised that CoQ10 pretreatment prior to stress could improve the post-stress recovery of the myocardium. We investigated this hypothesis in three studies. In Study 1, isolated hearts taken from senescent or mature rats, pre-treated with CoQ10 were subjected to rapid electrical pacing and the recovery of work after pacing as a percentage of pre-pacing level was measured. In Study 2, human atrial tissue obtained at the time of open heart surgery was subjected to simulated ischaemia in the organ bath after incubation with CoQ10 or vehicle and recovery measured. Study 3 was a clinical trial of oral CoQ10 therapy for 2 weeks pre-operatively in patients undergoing elective cardiac surgery. Study 1. CoQ10 treatment in senescent rat hearts improved recovery of work after rapid pacing (48.1+/-4.1 vs 16.8+/-4.3%; P < 0.0001) and MVO2 (82.1+/-2.8 vs 61.3+/-4.0%; P < 0.01) in treated versus untreated hearts respectively. Study 2. Post-ischaemic human trabeculae from the > or =70 years old group displayed less contractile recovery compared to the <70 years old group, but this difference was abolished by CoQ10 pre-incubation. Study 3: respiration by mitochondria isolated from trabeculae was more efficient after CoQ10 pretreatment than placebo. Compared to placebo, CoQ10 patients had a lower release of Troponin I, improved cardiac pump function and a shorter length of stay in hospital. In conclusion: 1) Senescent hearts have reduced baseline function and reduced tolerance to aerobic stress compared to young hearts. 2) Pre-treatment with oral CoQ10 improves baseline function of the senescent myocardium and its tolerance to aerobic stress. 3) CoQ10 pre-treatment in vitro overcomes the reduced capacity of aged human heart muscle to recover contractile function after ischaemia compared to younger muscle. 4) Oral CoQ10 therapy before cardiac surgery improves efficiency of mitochondrial energy production, improves post-operative heart function, reduces intra-operative myocardial damage and shortens hospital stay.
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Metabolic therapy involves the administration of a substance normally found in the body to enhance a metabolic reaction within the cell. This may be achieved in two ways. Firstly, for some systems a substance can be given to achieve greater than normal levels in the body so as to drive an enzymic reaction in a preferred direction. Secondly, metabolic therapy may be used to correct an absolute or relative deficiency of a cellular component. Thus, metabolic therapy differs greatly from most standard cardiovascular pharmacologic therapies such as the use of ACE Inhibitors, beta-blockers, statins and calcium channel antagonists that are given to block rather than enhance cellular processes.
Article
Metabolic therapy involves the administration of a substance normally found in the body to enhance a metabolic reaction within the cell. This may be achieved in two ways. First, for some systems, a substance can be given to achieve greater than normal levels in the body so as to drive an enzymic reaction in a preferred direction. Second, metabolic therapy may be used to correct an absolute or relative deficiency of a cellular component. Thus, metabolic therapy differs greatly from most standard cardiovascular pharmacologic therapy such as the use of ACE Inhibitors b-blockers, statins and calcium channel antagonists that are given to block rather than enhance cellular processes. In this review we highlight some metabolic substances that have potential benefit in treating heart disease or improving outcomes after cardiovascular interventions. Glucose-insulin-potassium therapy is protective against myocardial ischaemia by elevating myocardial glycogen levels. Coenzyme Q(10) is a lipid-soluble antioxidant that plays a crucial role in cellular ATP production. Magnesium orotate, a key intermediate in the biosynthetic pathway of glycogen, has been shown to improve the energy status of the cell and improve recovery from cardioplegic arrest. The amino acid aspartate plays an important role in providing energy substrates for oxidative phosphorylation in the myocyte. By improving cellular energy production, metabolic therapy has the potential to benefit cardiac function during the stress of cardiac surgery, myocardial infarction and cardiac failure.
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Coxibs, such as rofecoxib, celecoxib, and valdecoxib, selectively inhibit cyclooxygenase (COX)-2, the mainly inducible, pro-inflammatory COX isoform. Unlike traditional non-steroidal anti-inflammatory drugs (NSAIDs) most coxibs do not significantly inhibit COX-1 and are therefore less toxic to the gastrointestinal tract. Hence, coxibs widely replaced traditional NSAIDs for treatment of arthritis and other painful inflammatory conditions. In many, but not all, clinical studies, coxibs became associated with higher risks of myocardial infarction (MI) and stroke. Several mechanisms may be involved in the pathogenesis of such complications. First, selective inhibition of COX-1 lowers platelet synthesis of thromboxane (TXA(2)), a thrombogenic and atherogenic eicosanoid. Selective inhibition of COX-2 limits endothelial cell synthesis of prostacyclin (PGI(2)), an arachidonic acid product that opposes the effects of thromboxane. In apoE-/- mice, interruption of TXA(2) signaling by deletion of its receptor (TP) limits atherogenesis, whereas interruption of PGI2 signaling by deletion of its receptor (IP) accelerates atherogenesis. This suggests that selective inhibition of COX-2 can disrupt the physiological balance between thromboxane and prostacyclin and thus increase atherosclerosis, thrombogenesis, and the risk of cardiovascular complications. Second, COX inhibition can raise levels of arachidonic acid, which can inhibit mitochondrial oxidative phosphorylation (OXPHOS) and increase OXPHOS generation of reactive oxygen species. Several NSAIDs, including coxibs and meloxicam, directly uncouple or inhibit OXPHOS. Studies of apoE-/- mice indicate that mitochondrial dysfunction plays an early role in atherogenesis. Third, many NSAIDs exhibit COX-independent properties. For example, in animal models, short-term treatment with celecoxib reduces monocyte chemotaxis by reducing expression of monocyte chemoattractant protein (MCP)-1. However, long-term treatment results in the opposite effect and accelerates atherogenesis. In conclusion, to reduce the risk of cardiovascular complications during long-term coxib therapy, low-dose aspirin supplementation should be considered. An alternative is to use a less COX-2-selective inhibitor such as meloxicam. Genotyping of -765 alleles of the COX-2 gene promoter and examining the polymorphism of other genes involved in eicosanoid metabolism or NSAID degradation may become helpful in predicting patients who are at higher risk of cardiovascular complications during selective COX-2 inhibitor therapy.
Article
Objectives: Previous clinical trials suggest that coenzyme Q(10) might afford myocardial protection during cardiac surgery. We sought to measure the effect of coenzyme Q(10) therapy on coenzyme Q(10) levels in serum, atrial trabeculae, and mitochondria; to assess the effect of coenzyme Q(10) on mitochondrial function; to test the effect of coenzyme Q(10) in protecting cardiac myocardium against a standard hypoxia-reoxygentation stress in vitro; and to determine whether coenzyme Q(10) therapy improves recovery of the heart after cardiac surgery. Methods: Patients undergoing elective cardiac surgery were randomized to receive oral coenzyme Q(10) (300 mg/d) or placebo for 2 weeks preoperatively. Pectinate trabeculae from right atrial appendages were excised, and mitochondria were isolated and studied. Trabeculae were subjected to 30 minutes of hypoxia, and contractile recovery was measured. Postoperative cardiac function and troponin I release were assessed. Results: Patients receiving coenzyme Q(10) (n = 62) had increased coenzyme Q(10) levels in serum (P = .001), atrial trabeculae (P = .0001), and isolated mitochondria (P = .0002) compared with levels seen in patients receiving placebo (n = 59). Mitochondrial respiration (adenosine diphosphate/oxygen ratio) was more efficient (P = .012), and mitochondrial malondialdehyde content was lower (P = .002) with coenzyme Q(10) than with placebo. After 30 minutes of hypoxia in vitro, pectinate trabeculae isolated from patients receiving coenzyme Q(10) exhibited a greater recovery of developed force compared with those in patients receiving placebo (46.3% +/- 4.3% vs 64.0% +/- 2.9%, P = .001). There was no between-treatment difference in preoperative or postoperative hemodynamics or in release of troponin I. Conclusions: Preoperative oral coenzyme Q(10) therapy in patients undergoing cardiac surgery increases myocardial and cardiac mitochondrial coenzyme Q(10) levels, improves mitochondrial efficiency, and increases myocardial tolerance to in vitro hypoxia-reoxygenation stress.
Chapter
A key feature of advanced age is a reduced threshold for excess Ca2+ loading during events that stimulate increased Ca2+ entry, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Remodeling of myocardial cell membranes is a major factor underlying the relative Ca2+ intolerance in senescence and greater vulnerability to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca2+ homeostasis. Age-associated membrane changes, that may also be influenced by diet, include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA, cardiolipin. These alterations have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3: omega-6 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.
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Full-text available
Reactive oxygen species (ROS) play both physiological and pathophysiological roles in the body. In clinical practice, oxidative stress and its counterpart, antioxidant capacity, can be measured and can guide remedial therapy. Oxidative stress can make a negative impact in all forms of major surgery including cardiac surgery, general surgery, trauma surgery, orthopedic surgery, and plastic surgery. Many and various therapies aimed at reducing oxidative stress in surgery have been tried with variable results. We conclude that in surgical patients, the assessment of oxidative stress, improving understanding of its role, both positive and negative, and devising appropriate therapies are of great clinical importance and represent fruitful fields for further research. © Springer-Verlag Berlin Heidelberg 2014. All rights are reserved.
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Recently there has been recognition in Australia of the importance of experimental gerontological research. To date, the major areas of research into the biology of ageing have been oxidative stress and mitochondrial dysfunction. Future directions for gerontological research in Australia are likely to place more emphasis on comprehensive studies that integrate basic biological research, with clinical studies and the behavioural and social domains of ageing. Priority will be given to studies incorporating biological markers that are population based and longitudinal. The growing interest in experimental gerontological research complements Australian research strengths in other domains such as disease-based research, social gerontology, population studies and health policy research.
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A hypothesis as to the nature of the ageing process is presented. Our studies lead us to emphasise that ageing is a stochastic process; it is individualistic, it is species specific, it is different for individuals within a species, it is organ and tissue specific as well as varying among individual cells of a tissue. Human ageing is a slow process which takes place over decades; it is a cellular process in a dynamic equilibrium of continuing damage and repair. Tissues are damage mosaics. We hypothesise that the characteristic of ageing post-mitotic tissues is the progressive, slow loss of cells; those cells which no longer adequately function are removed by an apoptotic or non-inflammatory necrotic process. A case is made for an encompassing role for coenzyme Q10 in the regulation of systemic disease, cellular metabolism and ageing.
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: With aging of the population, increasing numbers of elderly patients are presenting for cardiac surgery. However, the results in the elderly are inferior to those in the young. A likely contributing factor is an age-related reduction in cellular energy production in the myocardium during surgery, which is known to induce aerobic and ischemic stress. The lipophilic antioxidant and mitochondrial respiratory chain redox coupler, coenzyme Q10 (CoQ10), has the potential to improve energy production in mitochondria by bypassing defective components in the respiratory chain as well as by reducing the effects of oxidative stress. We hypothesized that CoQ10 pretreatment prior to stress could improve the recovery of the myocardium after stress.
Article
Coenzyme Q (CoQ) is an essential lipid of cells present in all cellular compartments. The functions of CoQ in mitochondrial respiration and as an antioxidant are established, although the lipid likely has additional, presently unknown, roles. While the therapeutic utility of CoQ10 supplements is recognized in the rare cases of primary CoQ10 deficiencies, a potential role for CoQ10 supplements in cardiovascular disease, particularly heart failure, has also been studied for over 40 years. This review summarizes our current knowledge in these areas derived from animal studies and human trials. Current evidence for a benefit of CoQ10 supplements in diseases other than primary CoQ10 deficiencies is insufficient. Expected final online publication date for the Annual Review of Nutrition Volume 35 is July 17, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Mitochondrial dysfunction causes or exacerbates a number of diseases. These include genetic disorders such as Friedreich's ataxia where the primary lesion is a defect in a nuclear gene and those diseases caused by mutations to mitochondrial DNA. Mitochondrial damage also contributes to neurodegenerative diseases, diabetes and ischaemia-reperfusion injury. Drug therapies to prevent or alleviate mitochondrial dysfunction use redox active compounds, anti-oxidants or mitochondrial co-factors, however, their effectiveness is limited. A promising approach to increase the selectivity and potency of these compounds is to modify them so that they concentrate within mitochondria. This can be done by incorporating a lipophilic cation which causes the molecules to concentrate several hundred-fold in mitochondria, driven by the membrane potential across the inner membrane. As lipophilic cations cross biological membranes easily, they can be delivered to mitochondria of the heart, brain and skeletal muscle, the organs most affected by mitochondrial damage. Mitochondria-targeted lipophilic cations may lead to improved therapies for diseases involving mitochondrial dysfunction.
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Short duration exposure to cellular stresses have been shown to activate p38 mitogen-activated protein kinase (MAPK) in cultured rat ventricular cardiomyocytes and isolated perfused hearts; however, effects of chronic stress on p38 MAPK are not well understood. This study determined whether alterations in the p38 MAPK pathway occurred prior to end-stage human heart failure. The p38 MAPK alpha isoform was detectable in human cardiac tissue. However, carefully controlled analysis of protein and message in this study demonstrated an absence of the p38 MAPK beta -isoform. Low levels of message for the non-SB203580 sensitive p38 MAPK gamma and delta isoforms were also detected in both normal and failing human myocardium. Ischemic and idiopathic end-stage failing human hearts were compared to non-failing hearts for both p38 alpha MAPK protein level and total p38 MAPK activity. Western blotting techniques demonstrated no significant changes in total p38 alpha MAPK content. However, approximately 75% decreases in active/phosphorylated p38 MAPK (P<0.005) were observed in both ischemic and idiopathic failing hearts compared to non-failing hearts. In-gel kinase assays confirmed that activated p38 MAPK, detected by Western blotting, phosphorylated its potential downstream targets. When compared to non-failing hearts, approximately 46% decreases in p38 MAPK phosphorylation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK-2) were observed in ischemic and idiopathic failing hearts (P=0.03 and P=0.04 respectively). Active p38 MAPK was localized to sarcomeric structures in the cytosol of myocytes by confocal immunofluorescence microscopy. The correlation between decreased MAPKAPK-2 phosphorylation and loss of active p38 MAPK in failing human myocytes suggests that decreases in the activation of p38 MAPK alpha, the predominant cardiac isoform, occur prior to end-stage heart failure.
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The In-Training Examination in Internal Medicine (ITE-IM) has been offered to internal medicine trainees annually since 1988 as an instrument for self-assessment. This report outlines the manner in which the test is prepared, reviews the results of annual examinations, and analyzes trends during the past 6 years. Results of each examination were reviewed with regard to the demographic characteristics of persons taking the test, their previous medical training, and their present program affiliations. Then number of residents participating in the ITE-IM has increased steadily over the past 6 years. In 1993, more than 12,000 residents from more than 90% of internal medicine training programs in the United States participated in the examination; the percentage of international medical school graduates taking the examination increased from 27% in 1988 to 47% in 1993. Statistical analyses of each examination have shown it to be reliable, internally consistent, and discriminating. Over the past 6 years, graduates of U.S. medical schools have scored consistently higher than those of international medical schools and schools of osteopathic medicine on all annual examinations. However, in 1993, for residents at all levels of training, the differences in scores between graduates of U.S. medical schools and graduates of international medical schools narrowed substantially. From 1988 to 1993, there has been a trend toward lower scores by every cohort on each subsequent examination. The decreases in scores are most pronounced for graduates of U.S. medical school and those of schools of osteopathic medicine. The lower scores may be caused by either an increased level of difficulty in the examination or decreased knowledge among examinees. The ITE-IM is a useful instrument to assess the knowledge base of residents and program directors with a reliable evaluation of themselves and their programs in comparison to their national peer groups. It also provides objective data to monitor trends over time in residents' scores and relates them to the changing demographic characteristics of trainees and to innovations in the clinical curricula of internal medicine training programs.
Chapter
Oxidative stress is produced by an increased production of reactive oxygen species (ROS) or a decrease in the antioxidant defenses, causing damage to all components of the cell, including proteins, lipids, and DNA. Coenzyme Q10 (CoQ10) shows unique biochemical characteristics as a lipid-soluble antioxidant; it is synthesized endogenously, is present in all membranes, and exceeds other antioxidants in both amount and efficiency. CoQ10 can neutralize ROS and may decrease or even help to prevent some of the damage they cause.Genetic mutations can reduce CoQ10 biosynthesis, and many neurodegenerative disorders, as well as diabetes and renal and cardiovascular diseases, have been associated with low CoQ10 levels, as has aging. Because dietary uptake of this lipid is limited, CoQ10 supplementation is causing considerable clinical interest as a therapeutic tool in the treatment of these human diseases and for use in the elderly. More research is needed to determine the appropriate dose, effectiveness, and bioavailability of orally administered CoQ10, especially in the elderly. There may even be the possibility of designing therapeutic agents that increase the endogenous synthesis of CoQ10..
Chapter
Coenzyme Q10 (CoQ10) is an essential component of the electron transport system and the only lipid-soluble compound synthesized endogenously present in all cell membranes with bioenergetics and antioxidant properties. AgingAging, neurodegenerative disorders, cardiovascular disease and other aged-related diseases, as well as genetic mutations, have been associated with CoQ10 deficiency. Since both limited uptake and low bioavailability of dietary CoQ10 might influence in this deficiency, supplementation with CoQ10 must be considered in those cases as therapeutic solution. However, more research is needed in order to identify the appropriate dose, the effectiveness and the bioavailability of orally-administered CoQ10. Furthermore research must be developed in order to design therapeutic agents to induce the endogenous synthesis CoQ10 specially in elderly people. This review will focus in the most relevant biochemical characteristics of this important antioxidantAntioxidants, including its main functions, levels and distribution in human organism and the therapeutic potential of CoQ10, especially, during agingAging and the associated diseases.
Chapter
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For a number of years, coenzyme Q (CoQ10 in humans), was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and also extensively investigated its antioxidant role. This chapter discusses the relationship between the acknowledged bioenergetic role of CoQ10 and some clinical effects. The antioxidant properties of CoQ10 are then analyzed especially for their consequences on protection of circulating human low-density lipoproteins and prevention of atherogenesis. The relationship between CoQ10 and statins is also discussed in the light of possible involvement of CoQ10 deficiency in the issue of statin side effects. New aspects of the antioxidant involvement of coenzyme Q are also discussed together with their relevance in cardiovascular disease. Data are reported on the efficacy of CoQ10 in ameliorating endothelial dysfunction in patients affected by ischemic heart disease. Many of the effects of CoQ10, which were classically ascribed to its bioenergetic properties, are now considered as the result of its biochemical interaction with nitric oxide (NO), NO synthase and reactive oxygen species capable of inactivating NO. Clinical studies are reported highlighting the effect of CoQ10 on extracellular SOD, which is deeply involved in endothelial dysfunction. Previous studies have shown decreased levels of CoQ10 in the seminal plasma and sperm cells of infertile men with different kinds of asthenospermia. Research has been extended to supplementation with CoQ10 of infertile men affected by idiopathic asthenozoospermia. CoQ10 levels increased significantly in seminal plasma and sperm cells after 6 months of treatment with concomitant improvement of sperm cell motility.
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1. In addition to Ca²⁺-dependent mediation of excitation– contraction coupling during cardiac work and ATP hydrolysis, Ca²⁺ also stimulates the Krebs’ cycle and mitochondrial matrix dehydrogenases to maintain the nicotinamide adenine dinucleotide redox potential and ATP synthesis. Thus, the balance between energy demand and supply is maintained during increases in cardiac work by elevated cytosolic Ca²⁺ that is transmitted to the mitochondrial matrix via regulation of uniporter and antiporter pathways across the inner mitochondrial membrane.
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In this paper, we review two parts of our recent work on human skeletal muscle. The first part mainly describes changes occurring during aging, whereas the second part discusses the functions of coenzyme Q10 (CoQ10), particularly in relation to the aging process. During the lifetime of an individual, mtDNA undergoes a variety of mutation events and rearrangements. These mutations and their consequent bioenergenic decline, together with nuclear DNA damage, contribute to the reduced function of cells and organs, especially in postmitotic tissues. In skeletal muscle, this functional decline can be observed by means of changes with age in fiber type profile and the reduction in the number and size of the muscle fibers. In addition to the functions of coenzyme Q10 as an electron carrier in the respiratory chain and as an antioxidant, CoQ10 has been shown to regulate global gene expression in skeletal muscle. We hypothesize that this regulation is achieved via superoxide formation with H2O2 as a second messenger to the nucleus.
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1. An improved perfusion system for the isolated rat heart is described. It is based on the isolated working heart of Neely, Liebermeister, Battersby & Morgan (1967) (Am. J. Physiol. 212, 804-814) and allows the measurement of metabolic rates and cardiac performance at a near-physiological workload. The main improvements concern better oxygenation of the perfusion medium and greater versatility of the apparatus. Near-physiological performance (cardiac output and aortic pressure) was maintained for nearly 2 h as compared with 30 min or less in the preparations of earlier work. 2. The rates of energy release (O2 uptake and substrate utilization) were 40-100% higher than those obtained by previous investigators, who used hearts at subphysiological workloads. 3. Values are given for the rates of utilization of glucose, lactate, oleate, acetate and ketone bodies, for O2 consumption and for the relative contributions of various fuels to the energy supply of the heart. Glucose can be replaced to a large extent by lactate, oleate or acetate, but not by ketone bodies. 4. Apart from quantitative differences there were also major qualitative differences between the present and previous preparations. Thus insulin was not required for maximal rates of glucose consumption at near-physiological, in contrast with subphysiological, workloads when glucose was the sole added substrate. When glucose oxidation was suppressed by the addition of other oxidizable substrates (lactate, acetate or acetoacetate), insulin increased the contribution of glucose as fuel for cardiac energy production at high workload. 5. In view of the major effects of workload on cardiac metabolism, experimentation on hearts performing subphysiologically or unphysiologically is of limited value to the situation in vivo.
Article
, AlbertoAlbanesea , MohammedAmrania , Giuseppe Biondi-Zoccaib and Giacomo Fratib,c a Department of Cardiac Surgery, Harefield Hospital, London, UK b Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy c Department of AngioCardio Neurology, IRCCS NeuroMed, Pozzilli, Italy * Corresponding author. Department of Cardiac Surgery, Harefield Hospital, London, UK. Tel: +44-1895-828550; fax: +44-1895-828992; e-mail: umberto.benedetto@hotmail.com (U. Benedetto). Received 25 September 2013; received in revised form 18 November 2013; accepted 17 December 2013
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Summary Digitalis, diuretics, and vasodilators are considered standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure, which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2500 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing drug surveillance study in 173 Italian centers. The daily dose of CoQ10 was 50–150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two- to seven-point scales. Preliminary results on 1113 patients (mean age 69.5 years) show a low incidence of side effects: 10 adverse reactions were reported in 8 (0.8%) patients, of which only 5 reactions were considered as correlated to the test treatment. After 3 months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 81%, edema 76.9%, pulmonary rales 78.4%, enlargement of the liver area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations 75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo 73%, and nocturia 50.7%. Moreover, we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.
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The need for accurate risk assessment has become an indispensable element in the practice of cardiac surgery. The Society of Thoracic Surgeons National Cardiac Surgery Database allows subscribing institutions to perform sophisticated patient risk assessment using traditional statistical tools and a newly developed risk model of operative mortality. The database experience with isolated coronary artery bypass grafting has been studied most closely at this point and serves as the basis for this report. The approach to operative risk assessment is presented along with an analysis of important risk factors in the practice of coronary artery surgery from 1980 through 1990. The database contains records of 80,881 patients undergoing coronary artery bypass grafting in numerous institutions from 1980 through 1990. These records were used to conduct a detailed analysis of risk factors associated with coronary operations in this time interval and to present statistical methods used to formulate a risk equation that allows one to predict the probability of operative death. In the course of this decade, there were clearly defined trends showing a statistically significant increase in adverse patient risk factors. The risk model has proven to be a reliable tool for predicting the probability of operative death in an individual patient and may be valuable in both patient counseling and medical decision making. Large multiinstitutional databases of this type are key ingredients of modern operative risk assessment. A database containing a broad national experience of this type can represent an aggregate experience that may well approximate a universally accepted standard of care.
Article
1Heart mitochondria from rats at 3 months and 23 months of age were investigated for their capacity to generate oxygen radicals and hydrogen peroxide.2Highest values for O2+-formation were obtained with submitochondrial particles freed from superoxide dismutase after the addition of succinate and antimycin A to start the reaction. Under these conditions superoxide-radical formation with mitochondria from old rats (2.54 nmol × min−1× mg−1) exceeded formation rates in the young controls (1.9 nmol × min−1× mg−1) by 25%.3A constant fraction of 20% of the radicals produced escaped quenching by intramitochondrial superoxide dismutase. This fraction was independent of the rate of radical formation; its magnitude was deduced from generation rates of hydrogen peroxide in the presence and absence of exogenous superoxide dismutase.4Free oxygen radicals could be obtained with intact rat-heart mitochondria as well following the addition of ATP, a system which is closer to physiological states. Formation rates of oxygen radicals observed under these conditions were similar to those seen in the particulate fractions which escaped quenching by mitochondrial superoxide dismutase.5Peroxidative degradation of membrane lipids was found to parallel steady-state concentrations of free oxygen radicals.6The results are discusssed in terms of a radical-generating mechanism which functions in vivo at the level of the mitochondrial electron-transferring system.
Article
To investigate the effect of aging on myocardial ischemic and reperfusion injury, cytosolic calcium (Ca2+), intracellular pH (pHi), and mechanical performance were measured in isolated perfused rabbit hearts. Hearts of mature (4-5-month-old) and aged (28-38-month-old) rabbits were loaded with 10 microM of fura-2 or 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and subjected to 30 minutes of normothermic ischemia and reperfusion. Cytosolic Ca2+ levels ([Ca2+]) during the nonbeating ischemic period and end-diastolic Ca2+ levels ([EDCa2+]) during reperfusion were determined from the fura-2 fluorescence ratio of emission at 510 nm during excitation at 340 and 380 nm. pHi was obtained from the ratio of emission at 530 nm during excitation at 450 and 490 nm. [Ca2+] of the mature group (n = 8) increased from 188 +/- 19 nM (mean +/- SEM) to 373 +/- 32 nM during ischemia, and that of the aged group (n = 7) increased from 242 +/- 17 to 465 +/- 20 nM. The rise of [Ca2+] of the aged group was significantly greater (p < 0.05) than that of the mature group. Immediately after reperfusion, [EDCa2+] in both groups returned to the preischemic level. pHi decreased to the same extent (from 7.2 to 6.7) during ischemia and returned to preischemic values during reperfusion. The mature group recovered 84 +/- 3% of left ventricular peak pressure after ischemia, whereas the aged group recovered only 55 +/- 3% (p < 0.005). Functional recovery was inversely correlated to the increase of [Ca2+] during ischemia (r = 0.66). Aged hearts exhibit greater accumulation of [Ca2+] during ischemia and less functional recovery after ischemia than mature hearts. The greater rise of [Ca2+] in aged hearts is not a result of the difference of buffering capacity for ischemia-induced acidosis.
Article
Six young, sexually mature sheep and seven senescent sheep (aged 0.75 +/- 0.11 years and 7.1 +/- 0.45 years) were instrumented with sonomicrometric crystals and micromanometers to assess global left ventricular mechanics while preload was varied during right heart bypass both before and 30 minutes after 15 minutes of global normothermic ischemia. Left ventricular weight and end-diastolic volume were not significantly different between age groups when indexed to body weight. Contractility was quantitated by the slope of the linear preload-recruitable stroke work relationship and diastolic mechanics by an exponential end-diastolic pressure versus volume function generated over physiologic cardiac workloads. Postischemic systolic functional recovery was markedly worse in the older group (22.7% +/- 10.7% versus 54.2% +/- 9.5%, old versus young, p less than 0.05). However, diastolic stiffness was not changed in either group postischemically. These data demonstrate that the senescent myocardium is less tolerant of ischemia and may require specific intraoperative myocardial management strategies to preserve global pump function.
Article
Previous reports of elderly patients undergoing coronary artery bypass grafting have not addressed the current era of aggressive percutaneous angioplasty and frequent urgent or emergent operation. To investigate this important subgroup of patients, we analyzed our recent coronary artery bypass grafting experience with patients 70 years of age or older. From January 1984 to January 1989, 121 consecutive patients in this age range underwent surgical revascularization at our institution. Overall inhospital operative mortality (OM) was 7.4% ( ), with 77.8% ( ) of deaths due to cardiac causes. Serious postoperative morbidity occurred in 71.1% ( ). Surgical priority was significantly correlated with operative mortality: for elective cases, the OM was 2.9% ( ), but it was 8.6% ( ) for urgent cases (p < 0.05) and 22.2% ( ) for emergency cases (p < 0.05). Univariate analysis isolated the need for inotropic support, intraaortic balloon pump, reoperation, cardiopulmonary resuscitation, and emergency status as significant risk factors for OM (p < 0.05). Multivariate stepwise logistic regression analysis identified the need for inotropic support, intravenous nitroglycerin, reoperative coronary artery bypass grafting, and hypertension as independently significant risk factors. A logistic risk equation developed from this population accurately modeled OM at the extremes of operative risk. Three (3.1%) of the 97 patients predicted to have less than 5% OM died, whereas all patients predicted by the model to have greater than 90% OM died. These results indicate that in spite of relatively high morbidity and mortality rates, elderly patients have a very acceptable operative risk in the current era of high-risk coronary artery bypass grafting. This is particularly true if elective revascularization is possible.
Article
The human atrial trabecular preparation is an in vitro model which has been used to evaluate drugs and conditions to which cardiac muscle is exposed perioperatively. During its development, modifications have been made to this preparation. Two important components affecting myocardial muscle contraction are temperature and calcium concentration of the muscle bath medium. Previously, these parameters were determined independently of one another and found to be 34 degrees C and 2.5 mM calcium in a minimal Tyrode's buffer with glucose. This study was undertaken to define the optimal temperature and calcium concentration which would result in the highest yield of muscles that satisfied rigorous criteria for acceptability: developed force (DF) greater than 0.8 g, resting force (RF) less than 0.7 g, cross-sectional area less than or equal to 1.0 mm2). A total of 134 trabeculae were tested using a modified Krebs-Henseleit buffer, enriched with Eagles' medium and containing either 1.25 or 2.5 mM calcium at 34 or 37 degrees C. The trabeculae contracting in 2.5 mM calcium at 37 degrees C resulted in the highest yield of 26% while those maintained at 34 degrees C in either 1.25 or 2.5 mM calcium led to 20 and 15% useful preparations respectively (P = N.S.). Trabeculae contracting at 37 degrees C in 1.25 mM calcium resulted in the poorest yield of 8% (P = 0.002). There is a small (5 to 7%), but significant (P = 0.02), decrease in DF in 1 h when all groups were analyzed together. The exclusion criteria which are applied eliminate variability due to disease and/or treatment, therefore only 20 to 25% are acceptable for study. In summary, with well-defined and stringently applied criteria, the human right atrial trabecular preparation can be a reliable and reproducible model functioning at 37 degrees C and 2.5 mM calcium for a variety of studies.
Article
The human mitochondrial genome is very small and economically packed; the expression of the whole genome is essential for the maintenance of mitochondrial bioenergetic function. Mutation occurs at a much higher rate in the mitochondrial DNA (mtDNA) than in chromosomal DNA. Transient heteroplasmy of mtDNA occurs after a mutational event; the random pattern of cytoplasmic segregation that occurs during subsequent growth gives rise to a mosaic of cells. The variable proportion of mutant mitochondrial genomes per cell results in cells with a range of bioenergetic capacities. It is proposed that the accumulation of mitochondrial mutations and the subsequent cytoplasmic segregation of these mutations during life is an important contributor both to the ageing process and to several human degenerative diseases. Replacement therapy and pharmacological support may be possible for the amelioration of such disorders by means of appropriate redox compounds. Moreover, new compounds with desired redox potentials can be rationally designed for clinical use.
Article
Recent advances in interventional cardiology have altered the profile of patients referred for coronary artery bypass surgery. In recent years, the proportion of high-risk patients has increased dramatically. To evaluate the impact of the changing pattern of surgical patients, we prospectively followed up 7,334 patients who had coronary artery bypass surgery between 1982 and 1986. Multivariate analysis identified the following risk factors for operative mortality: urgency of surgery, left ventricular ejection fraction, age, female sex, previous bypass surgery, and left main coronary artery stenosis. Perioperative mortality has remained stable despite an increasing incidence of high-risk patients. However, perioperative morbidity has increased, due to the large number of high-risk patients. A multivariate analysis was performed by year to identify temporal trends in risk factors. Urgency of surgery, age, and previous bypass surgery have become more significant predictors of mortality with respect to time, whereas female sex, left ventricular ejection fraction, and left main coronary artery stenosis have become less significant determinants of mortality. Our results demonstrate the critical dependence of mortality and morbidity rates on the case mix, and further improvements in the results of coronary artery bypass surgery will require better strategies for the increasing number of high-risk patients.
Article
Elective coronary artery bypass surgery can be performed with an expected operative mortality of 1-3%. However, the effects of age on morbidity and mortality in patients undergoing this procedure remain controversial. To analyze morbidity and mortality in septuagenarians undergoing isolated coronary artery bypass surgery, we compared the results in 685 septuagenarians with those in 3,142 patients under the age of 70 years, all of whom underwent this procedure from January 1981 to December 1986. A larger percentage of elderly patients had triple-vessel disease (89% vs. 71%), left main coronary artery obstruction (34% vs. 16%), and ejection fractions less than 45% (68% vs. 41%). A larger percentage of septuagenarians had perioperative myocardial infarction (8% vs. 2%), required prolonged ventilatory support (10% vs. 3%), and had major neurological complications (4% vs. 1%). Mortality rates were significantly higher in elderly patients (7% vs. 2%) but did not correlate with the severity of coronary artery disease, the anginal pattern, or the diminishment of ventricular function. Major causes of mortality were pulmonary failure, renal failure, or both, sepsis, and neurological complications. These data suggest that elderly patients have an increased risk of cardiac and noncardiac morbidity and mortality after coronary artery bypass surgery. Higher mortality rates in this age group appear attributable to noncardiac organ failure. Late follow-up studies failed to show any significant difference among patients based on age alone.
Article
Studies that have examined the effect of age on the myocardium do not support the notion that a generalized decline in myocardial function occurs with adult aging but, rather, that certain specific changes in cardiac biochemistry and function occur. Although in many instances the molecular bases for these changes have not been precisely defined, sufficient clues regarding their nature are at hand to provide at least the first step toward an understanding of the dramatic effects of aging or time on the myocardium. A fundamental understanding of the effects of aging will provide an additional dimension to studies of myocardial biochemistry and function and may be useful in elucidating mechanisms of excitation-contraction coupling in the heart.
Article
Accumulating evidence has emphasized the role of genetic factors in the development of aging and degenerative diseases. Mitochondrial DNA (mtDNA), that codes for protein subunits essential for the maintenance of mitochondrial ATP synthesis, acquires mutations at a much higher rate than that of nuclear DNA. Recent studies have shown that somatically acquired mutations such as deletions in mtDNA are caused by oxygen damage during the life of an individual. Accumulation of these somatic mutations in postmitotic neuromuscular cells causes bioenergetic deficiency leading to age-associated dysfunction of cells and organs. The base sequencing of the entire mtDNA from individuals revealed that inherited germ-line point mutations accelerate the somatic oxygen damage, and the fragmentation in mtDNA leads to phenotypic expression such as premature aging and degenerative diseases. This article reviews the concept, molecular genetics, pathology, clinical symptoms, diagnosis, and therapy of mitochondrial aging and related diseases.
Article
Mitochondrial DNA (mtDNA) that codes protein subunits essential for the maintenance of mitochondrial ATP synthesis system acquires mutations at a much higher rate than that in nuclear DNA. Recent study has revealed that somatically acquired mutations such as deletions in mtDNA are caused mainly by oxygen free-radical damage. Cumulative accumulation of these somatic mutations during the life of an individual causes bioenergetic deficit leading to cell death and normal ageing. The base-sequencing of the entire mtDNA from 48 individuals revealed that germ-line point mutations accelerate extensively the somatic oxygen free-radical damage and the deletions leading to generation of more than a hundred kinds of mtDNA minicircle. These accelerated somatic mutations are expressed as premature ageing of the patients with degenerative diseases. Comprehensive analyses of the entire mtDNA, including the total base-sequencing and the total deletion correlating with oxygen free-radical damage, has revealed a clear relationship between the genotype and its phenotype, such as the severity of clinical symptoms and the survival time of the patients. Extensive generation of mtDNA minicircles caused by the oxygen free radical implies a close relations between the redox mechanism of ageing and the programmed cell-death machinery.
Article
Previous studies have shown that acute exogenous administration of coenzyme ubiquinone (CoQ10) can protect the heart against oxidant-mediated injury. The aim of this study was to investigate whether protection against cardiac oxidative stress could be obtained by increasing tissue levels of CoQ10, as achieved by chronic CoQ10 supplementation. Wistar rats were randomly divided into two groups: a control group given standard diet and a test group receiving diet supplemented with CoQ10 (5 mg/kg/day) for 4 weeks. Functional and metabolic changes induced by oxidative stress were investigated in isolated perfused hearts and in papillary muscles. Tissue concentrations of ubiquinones were significantly higher in the left ventricle of treated rats than in controls. H2O2 infusion (60 microM for 60 min) induced marked alterations of both developed pressure, which decreased to -58.8 +/- 16.8% of base line and end-diastolic pressure which increased almost 13-fold. These effects were reduced significantly (P < .05) in hearts from CoQ10-supplemented rats (-13.8 +/- 2.3 and +375.0 +/- 42.5%, respectively). In the same hearts, cumulative release of oxidized glutathione (a specific marker of oxidative stress) was 450.2 +/- 69.2 nmol/g of wet weight in the control group and only 89.6 +/- 22.3 nmol/g of wet weight in treated hearts (P < .01). In papillary muscles, after 60 min of perfusion with H2O2, active tension decreased, largely in controls whereas it was almost unchanged in the treated group (-34.4 +/- 7.5% of baseline vs. -0.1 +/- 0.05%, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Digitalis, diuretics and vasodilators are considered the standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of Coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2664 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing study in 173 Italian centers. The daily dosage of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two-to seven-point scales. The results show a low incidence of side effects: 38 adverse effects were reported in 36 patients (1.5%) of which 22 events were considered as correlated to the test treatment. After three months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 78.1%, oedema 78.6%, pulmonary rales 77.8%, enlargement of liver area 49.3%, jugular reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating 79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo 73.1% and nocturia 53.6%. Moreover we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.
Article
Survival after acute myocardial infarction is decreased in elderly patients as compared with the overall adult population. Although several cardiac and noncardiac causes could contribute to the increased mortality rate, little is known regarding the relative susceptibility of aging myocardium to injury during ischemia and reperfusion. We hypothesized that the elderly heart is intrinsically more susceptible to damage than the adult heart. The recovery of isolated, buffer-perfused rat hearts from elderly animals (Fischer 344 rats, 24 months of age) was compared with that of adult hearts (6 months of age) obtained from the same strain. Hearts underwent 25 minutes of ischemia followed by 30 minutes of reperfusion. Hemodynamic recovery was decreased in elderly (n = 5) as compared with adult (n = 5) hearts, including developed pressure (% of preischemic baseline: elderly 31% +/- 4% vs adult 57% +/- 4%, p < 0.01). Elderly hearts also sustained greater tissue damage, with a markedly increased release of creatine kinase (elderly 2950 +/- 500 U vs adult 860 +/- 345 U, p < 0.01) during the 30-minute reperfusion period. The release of total protein and lactate dehydrogenase, other markers of myocyte injury, was also increased. Thus the elderly rat heart is more susceptible than the adult rat heart to ischemia-reperfusion injury. Greater injury during ischemia and reperfusion in an experimental model of aged myocardium raises the possibility of a more rapid progression of ischemic damage in elderly patients suffering acute myocardial infarction.
Article
In this study, 70 patients > or = 70 years of age admitted to the coronary care unit with non-Q-wave acute myocardial infarction (AMI) were followed prospectively for 1 year, and the clinical course in these patients was compared with that in 61 patients < 70 years with non-Q-wave AMI and 56 patients > or = 70 years with Q-wave AMI. Compared with the younger patients with non-Q-wave AMI, older patients were more likely to develop atrial fibrillation (23% vs 8%; p < 0.05) and congestive heart failure (53% vs 30%; p < 0.01), and less likely to receive thrombolytic therapy (9% vs 28%; p < 0.01), cardiac catheterization (41% vs 72%; p < 0.01), and coronary angioplasty (20% vs 39%; p < 0.05). Hospital mortality did not differ significantly between older and younger non-Q-wave AMI patients (10% vs 3%), but 1-year mortality was higher in the elderly (36% vs 16%; p = 0.02). Elderly patients with Q-wave AMI had more in-hospital complications, including death (25% vs 10%; p < 0.05), than elderly patients with non-Q-wave AMI. In contrast, postdischarge mortality was higher in elderly patients with non-Q-wave AMI, so that total mortality at 1 year was similar in the 2 groups. Overall, elderly patients with non-Q-wave AMI accounted for 62% of all deaths occurring during the first year after discharge (relative risk 2.6 compared with other groups; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
This study examined the predictors of in-hospital and 6-month outcome after different reperfusion strategies in acute myocardial infarction. Thrombolytic therapy and primary angioplasty are both widely applied as reperfusion modalities in patients with myocardial infarction. Although it is accepted that restoration of early patency of the infarct-related artery can reduce mortality and salvage myocardium, the optimal reperfusion strategy remains controversial, and the predictors of outcome in the reperfusion era have been incompletely characterized. At 12 centers, 395 patients presenting within 12 h of onset of acute transmural myocardial infarction were prospectively randomized to receive tissue-type plasminogen activator (t-PA) or undergo primary angioplasty without antecedent thrombolysis. Sixteen clinical variables were examined with univariate and multiple logistic regression analysis to identify the predictors of clinical outcome. By univariate analysis, in-hospital mortality was increased in the elderly, women, patients with diabetes and in patients treated with t-PA as opposed to angioplasty. Only advanced age and treatment by t-PA versus angioplasty independently correlated with increased in-hospital mortality (6.5% vs. 2.6%, respectively, p = 0.039 by multiple logistic regression analysis). Similarly, the only variables independently related to in-hospital death or nonfatal reinfarction were advanced age and treatment by t-PA versus angioplasty (12.0% vs. 5.1%, p = 0.02). The reduction in in-hospital death or reinfarction with angioplasty versus t-PA was particularly marked in patients > or = 65 years of age (8.6% vs. 20.0%, p = 0.048). Furthermore, primary management with angioplasty versus t-PA was the most powerful multivariate correlate of freedom from recurrent ischemic events (10.3% vs. 28.0%, p = 0.0001). The independent beneficial effect of angioplasty on freedom from death or reinfarction was maintained at 6-month follow-up (8.2% vs. 17.0%, p = 0.02). In the reperfusion era, the two most powerful determinants of freedom from death, reinfarction and recurrent ischemia after myocardial infarction are young age and treatment by primary angioplasty.
Article
As an increasingly aged population undergoes cardiac surgery, myocardial protective strategies must address the fundamental differences between adult and senescent myocardium. In a test of the hypothesis that senescent myocardium is less tolerant of cardioplegic arrest, adult (0.5 to 1.0 years) and senescent (6 to 9 years) sheep underwent 55 minutes of hypothermic blood cardioplegic arrest. A 5-minute dose of terminal warm blood cardioplegic solution was administered followed by 30 minutes of vented reperfusion. Left ventricular volume was monitored by means of sonomicrometric crystals in three orthogonal planes. Myocardial function was assessed with the preload recruitable stroke work relationship. Diastolic function was assessed with two techniques: the "stiffness" coefficient (beta), derived from the exponential end-diastolic pressure-volume relationship, and the time constant of isovolumic left ventricular pressure decay (tau). Data were acquired before arrest and after the reperfusion period. Contractility in the adult hearts was well preserved (preload recruitable stroke work: 63.7 +/- 6.1 versus 56.8 +/- 4.1 mJ/beat per milliliter per 100 gm, prearrest versus postarrest, p = not significant). In contrast, senescent heart contractility was poorly preserved (56.8 +/- 4.1 versus 35.4 +/- 4.2 mJ/beat per milliliter per 100 gm, p < 0.025). Early diastolic relaxation (tau) was prolonged in the adult hearts (42.5 +/- 3.3 versus 48.8 +/- 3.5 msec prearrest versus postarrest, p < 0.05), whereas the senescent hearts were essentially unchanged (49.3 +/- 3.1 versus 52.3 +/- 4.5 msec. p = 0.35). Myocardial stiffness (beta) was unchanged in both groups. When compared with adult hearts, contractility in senescent hearts is poorly preserved after cold blood cardioplegic arrest. Active diastolic relaxation, however, is more prolonged in adult hearts. Passive diastolic properties are unchanged in both groups. Because there are specific age-related differences in tolerance to cardioplegic arrest, extrapolation of myocardial protective strategies from studies in adult hearts to elderly patients may not be appropriate.
Article
Although successful dilatation of a target lesion by means of percutaneous transluminal coronary angioplasty (PTCA) can be attained as frequently in elderly as in younger patients, elderly patients have a higher risk of complications. Furthermore, cohorts of patients older than 75 years and undergoing PTCA include more women and more cases of unstable angina, factors that increase the risk of complications. Included in this analysis of 3199 PTCAs performed between January 1991 and September 1992 were 474 (14.8%) patients who were > or = 75 years old. Age was an independent risk factor for death, acute myocardial infarction, need for transfusion, and need for arterial repair after PTCA. The frequency of successful dilatation of individual lesions, emergency coronary bypass surgery, or repeated PTCA of the same lesion was not related to age. In previous studies no association has been demonstrated between age and increased risk of in-hospital reclosure. The presence of more severe coronary disease and of the greater frequency of coexisting morbid conditions makes elderly patients less able to tolerate unsuccessful or complicated PTCA.
Article
Cytosolic calcium in the myocardium is rapidly accumulated during ischemia and has been correlated with the attenuation of functional recovery in the myocardium. The aged myocardium is more sensitive to ischemia and accumulates significantly more cytosolic calcium than either the newborn or the mature myocardium. Modification of the age-related propensity to increased cytosolic calcium accumulation may be achieved through the use of magnesium or potassium/magnesium cardioplegia. Improved postischemic ventricular function obtained with magnesium or potassium/magnesium cardioplegia may have important implications in the reduction of myocardial morbidity and mortality.
Article
To determine the results of cardiac surgery in the very elderly. A retrospective study of 56 very elderly patients (mean age 82 years, range 79-89 years) undergoing open heart surgery between 1988 and 1991. Thirty-three patients had coronary artery bypass grafting, 12 had valve replacement alone and 11 had valve replacement with an associated procedure. St Francis Xavier Cabrini Hospital, Melbourne--a large private hospital. There were four in-hospital deaths (7%). The one-year actuarial survival rate was 88%. Of the 49 survivors, 92% were in New York Heart Association (NYHA) Class III or IV before operation, whereas 96% were in NYHA Class I or II a mean of 15 months after operation. In very elderly patients with medically refractory cardiac symptoms, cardiac surgery has a tolerable mortality and provides excellent relief of symptoms.
Article
Digitalis, diuretics, and vasodilators are considered standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure, which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2500 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing drug surveillance study in 173 Italian centers. The daily dose of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two- to seven-point scales. Preliminary results on 1113 patients (mean age 69.5 years) show a low incidence of side effects: 10 adverse reactions were reported in 8 (0.8%) patients, of which only 5 reactions were considered as correlated to the test treatment. After 3 months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 81%, edema 76.9%, pulmonary rales 78.4%, enlargement of the liver area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations 75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo 73%, and nocturia 50.7%.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Preclinical atherosclerosis is associated with increased endothelial cell (EC) expression of leukocyte adhesion molecules (LAMs), which mediate monocyte adhesion during atherogenesis. Identification of cell-surface LAMs may uniquely allow assessment of endothelial function, but there are no in vivo methods for detecting LAMs. We tested a new microbubble designed to bind to and allow specific ultrasound detection of intercellular adhesion molecule-1 (ICAM-1). A perfluorobutane gas-filled lipid-derived microsphere with monoclonal antibody to ICAM-1 covalently bound to the bubble shell was synthesized. Bubbles with either nonspecific IgG or no protein on the shell were synthesized as controls. Coverslips of cultured human coronary artery ECs were placed in a parallel-plate perfusion chamber and exposed to 1 of the 3 microbubble species, followed by perfusion with culture medium. Experiments were performed with either normal or interleukin-1beta-activated ECs overexpressing ICAM-1, and bubble adherence was quantified with epifluorescent videomicroscopy. There was limited adherence of control bubbles to normal or activated ECs, whereas a 40-fold increase in adhesion occurred when anti-ICAM-1-conjugated bubbles were exposed to activated ECs compared with normal ECs (8.1+/-3.5 versus 0.21+/-0.09 bubbles per cell, respectively, P<0.001). Although diminished, this difference persisted even after perfusion at higher wall shear rates. A gas-filled microbubble with anti-ICAM-1 antibody on its shell specifically binds to activated ECs overexpressing ICAM-1. Diagnostic ultrasound in conjunction with targeted contrast agents has the unique potential to characterize cell phenotype in vivo.
Article
In elderly patients the results of cardiac interventions are inferior to those in the young. A possible contributing factor is an age-related reduction in cellular energy transduction during the intervention which may induce aerobic or ischemic stress. To investigate whether coenzyme Q10 (CoQ10) improves the response to aerobic stress, functional recoveries of senescent and young rat hearts after rapid pacing were compared with or without CoQ10. Young (4.8 +/- 0.1 months) and senescent (35.3 +/- 0.2 months) rats were given daily intraperitoneal injections of CoQ10 (4 mg/kg) or vehicle for 6 weeks. Their isolated hearts were rapidly paced at 510 beats per minute for 120 min to induce aerobic stress without ischemia. In senescent hearts pre-pacing cardiac work was 74% and oxygen consumption (MVO2) 66% of that in young hearts. CoQ10 treatment abolished these differences. After pacing, the untreated senescent hearts, compared to young, showed reduced recovery of pre-pacing work, (16.8 +/- 4.3 vs. 44.5 +/- 7.4%; P < 0.01). CoQ10 treatment in senescent hearts improved recovery of work, (48.1 +/- 4.1 vs. 16.8 +/- 4.3%; P < 0.0001) and MVO2 (82.1 +/- 2.8 vs. 61.3 +/- 4.0%; P < 0.01) in treated versus untreated hearts respectively. Post-pacing levels of these parameters in CoQ10 treated senescent hearts were as high as in young hearts. (1) Senescent rat hearts have reduced baseline function and reduced tolerance to aerobic stress compared to young hearts. (2) Pre-treatment with CoQ10 improves baseline function of the senescent myocardium and its tolerance to aerobic stress.
Mitochondrial oxidative phosphorylation changes in the life span Molecular aspects and physiopathological implications Coenzyme Q10 normalizes impaired post-ischemic contractile recovery of aged human myocardium in vitro
  • S Papa
  • S Pepe
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  • R Lew
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S. Papa, Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications, Biochimica Biophysica Acta 1276 (1996), 87–105. [21] S. Pepe, R. Ou, R. Lew, J. Mariani, P. Nagley, A.W. Linnane and F.L. Rosenfeldt, Coenzyme Q10 normalizes impaired post-ischemic contractile recovery of aged human myocardium in vitro, Circulation 98(Suppl. I) (1998), 1–685.
Predictors of in hospital and 6 month outcome after acute myocardial infarction (PAMI) trial
  • G Stone
  • C Grines
  • K Browne
  • J Marco
  • D Rothbaum
  • G Keefe
  • P Hartzler
  • B Overlie
  • N Donohue
  • G Chelliah
  • R Timmis
  • M Vlietstra
  • S Strzelecki
  • W Puchrowicz-Ochocki
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G. Stone, C. Grines, K. Browne, J. Marco, D. Rothbaum, J. O'Keefe, G. Hartzler, P. Overlie, B. Donohue, N. Chelliah, G. Timmis, R. Vlietstra, M. Strzelecki, S. Puchrowicz-Ochocki and W. O'Neill, Predictors of in hospital and 6 month outcome after acute myocardial infarction (PAMI) trial, Journal of American College of Cardiology 25 (1995), 370–377.
Coenzyme Q10 normalizes impaired post-ischemic contractile recovery of aged human myocardium in vitro
  • S Pepe
  • R Ou
  • R Lew
  • J Mariani
  • P Nagley
  • A W Linnane
S. Pepe, R. Ou, R. Lew, J. Mariani, P. Nagley, A.W. Linnane and F.L. Rosenfeldt, Coenzyme Q10 normalizes impaired post-ischemic contractile recovery of aged human myocardium in vitro, Circulation 98(Suppl. I) (1998), 1–685.
Mitochondrial DNA mutation and human aging: molec-ular biology, bioenergetics and redox therapy
  • P Nagley
  • C Zhang
  • R D Martinus
  • F Vaillant
  • A W Linnane
P. Nagley, C. Zhang, R.D. Martinus, F. Vaillant and A.W. Linnane, Mitochondrial DNA mutation and human aging: molec-ular biology, bioenergetics and redox therapy, in: Mitochondrial DNA in Human Pathology, S. Mauro and D.C. Wallace, eds, Raven Press Ltd., New York, 1993, p. 137.
  • G Stone
  • C Grines
  • K Browne
  • J Marco
  • D Rothbaum
  • J O 'keefe
  • G Hartzler
  • P Overlie
  • B Donohue
  • N Chelliah
  • G Timmis
  • R Vlietstra
  • M Strzelecki
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