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Preventing and arresting coronary atherosclerosis
Abstract
The good news about coronary atherosclerosis is that it takes an awful lot of plaque before symptoms of myocardial ischemia occur. The bad news is that despite the need for large quantities of plaque for symptoms to occur, nevertheless nearly half of us in the United States eventually have the necessary quantity. Atherosclerosis is infrequently hereditary in origin. Most of us get atherosclerosis because we consume too much fat, cholesterol, and calories. The consequence is an elevated ( > 150 mg/dl) serum total cholesterol level, and the higher the number is above 150, the greater is the quantity of plaque deposited in our arteries. If the serum total cholesterol level can be prevented from rising to more than 150 mg/dl, plaques are not laid down; if elevated levels are lowered to 150 mg/dl, further plaque does not form, and parts of those present may vanish. A fruit-vegetarian-starch diet is necessary as a rule to achieve the 150 mg/dl level in most adults. Lipid-lowering drugs are required in the patients with familial hypercholesterolemia and in most patients with atherosclerotic events. The best news about atherosclerosis is that it can be prevented in those without the hereditary form, and it can be arrested by lowering elevated serum total (and LDL) cholesterol to the 150 mg/dl level.
... An elevated level of total cholesterol is the strongest risk factor for CAD [5] . ~ 147 ~ The mean level of total cholesterol in cord blood of newborns worldwide is 75 mg/dL, which rises to 120 mg/dL in two weeks and remains at that level until approximately 20 years of age, when it starts to gradually rise again [6] . Total cholesterol levels among Asian Indians are similar or lower than in Europids [7] . ...
... A high cholesterol concentration can easily lead to hypercholesterolemia, a risk factor for coronary occlusion [1,2]. It is also associated with various cardiovascular diseases [3]. ...
This research focuses on the proteolytic capacity of sea bass byproduct (SB) and their hypocholesterolemic activity via the cholesterol micelle formation (CMF) inhibition. SB was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. The lactic fermented SB was hydrolyzed with Protease N for 6 h under HHP to obtain the SB hydrolysates (HHP-assisted Protease N hydrolysis after fermentation, F-HHP-PN6). The supernatant was separated from the SB hydrolysate and freeze-dried. As the hydrolysis time extended to 6 h, soluble protein content increased from 187.1 to 565.8 mg/g, and peptide content increased from 112.8 to 421.9 mg/g, while inhibition of CMF increased from 75.0% to 88.4%. Decreasing the CMF inhibitory activity from 88.4% to 42.1% by simulated gastrointestinal digestion (FHHP-PN6 was further hydrolyzed by gastrointestinal enzymes, F-HHP-PN6-PP) reduced the CMF inhibitory activity of F-HHP-PN6. Using gel filtration chromatography, the F-HHP-PN6-PP was fractioned into six fractions. The molecular weight of the fifth fraction from F-HHP-PN6-PP was between 340 and 290 Da, and the highest inhibitory efficiency ratio (IER) on CMF was 238.9%/mg/mL. Further purification and identification of new peptides with CMF inhibitory activity presented the peptide sequences in Ser-Ala-Gln, Pro-Trp, and Val-Gly-Gly-Thr; the IERs were 361.7, 3230.0, and 302.9%/mg/mL, respectively.
... An elevated level of total cholesterol is the strongest risk factor for CAD [1] . The mean level of total cholesterol in cord blood of newborns worldwide is 75 mg/dL, which rises to 120 mg/dL in two weeks and remains at that level until approximately 20 years of age, when it starts to gradually rise again [2] . Total cholesterol levels among Asian Indians are similar or lower than in Europids [3] . ...
... Dyslipidemia have been demonstrated as a major risk factor in cardiovascular and cerebrovascular complications (Roberts, 1995;Tunstall, 1994). It has been reported that dyslipidemias also induce liver damage and kidney dysfunction (Bugianesi and Leone, 2002). ...
The aim of this study was designed to evaluate the activity of the Kigelia Pinnata ethanolic leaf extract on the serum lipid profile of male albino Wistar rats exposed to a fat diet. Kigelia Pinnata leaves were obtained, air dried, powdered and extracted in a Soxhlet apparatusin 400ml ethanol solution. Hypolipidaemic activity studies on rat models fed with palm oil and coconut milk was conducted. The acute toxicity test of the extract was carried out by the lorke's method. Results showed that Kigelia Pinnata ethanolic leaf extract significantly lowered (P<0.05) plasma Total Cholesterol (TC), Low Density Lipoprotein (LDL)-Cholesterol and Triacylglycerol (TG) and significantly (P<0.05) increased plasma High Density Lipoprotein (HDL)-Cholesterol. Toxicity studies suggested that, the extract was safe at the doze 2000mg/kg. Overall findings from this study showed that the ethanolic extract exhibited hypolipidaemic activity and may possess cardio-protective properties.
... The lipids contained within the core of the lipoproteins are principally either triglycerides or cholesterol. It has been reported that atherosclerosis is a major cause of coronary heart disease (CHD) [10]. Several forms of elevated lipoproteins are inherited. ...
This study was designed to find out the effect of non-hypertensive and hypertensive type 2 diabetes on lipid profile to determine whether these biochemical parameters were affected in individuals associated with these disease conditions. A total of one hundred and fifty one (151) individuals were subjected for the study. Of these thirty seven (37) were established hypertensive diabetics and thirty four (34) are established non-hypertensive diabetics. The established hypertensive non-diabetics were thirty eight (38) while forty two (42) were normal healthy individuals. The results showed that there was no significant differences (P>0.05) in the mean concentrations of cholesterol, triglycerides (TG), HDL-cholesterol, LDL-cholesterol and glucose between hypertensive diabetics and non-hypertensive diabetics studied. The study also demonstrated that, there were no significant differences (P>0.05) in the mean levels of all the parameters measured between hypertensive diabetics and hypertensive non-diabetics subjects studied, except for serum glucose that significantly higher (P<0.05) in hypertensive diabetics. It was observed that, mean concentrations of cholesterol, triglycerides (TG), LDC-cholesterol, as well as systolic blood pressure were significantly higher (P<0.05) in hypertensive diabetics compared with normal healthy individuals. The results also show that the mean HDL-cholesterol level was significantly lower (P>0.05) in hypertensive diabetics compared with normal healthy individuals. It was also illustrated that the concentrations of cholesterol, triglycerides, LDL-cholesterol systolic and diastolic blood pressure were significantly higher (P>0.05) in hypertensive non diabetics individuals compared with normal healthy individuals studied. However, the glucose and pulse rate mean levels showed no significant difference (P >0.05) between hypertensive non-diabetics and normal healthy individuals.
... Although some investigators have considered cholesterol the cause of atherosclerosis for several decades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), 26 authors, mainly from Europe, in April 2017 published an article titled "Lowdensity lipoproteins cause atherosclerotic cardiovascular disease," a consensus statement from the European Atherosclerosis Society Consensus Panel (16). I was glad to see the article that soundly supports the view that cholesterol is the cause of atherosclerosis. ...
... Although some investigators have considered cholesterol the cause of atherosclerosis for several decades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), 26 authors, mainly from Europe, in April 2017 published an article titled "Lowdensity lipoproteins cause atherosclerotic cardiovascular disease," a consensus statement from the European Atherosclerosis Society Consensus Panel (16). I was glad to see the article that soundly supports the view that cholesterol is the cause of atherosclerosis. ...
... Leukocyte activation can subsequently obstruct capillary networks and thus reduce pumping [46] i.e. atherosclerosis ( Figure 2). In hyperlipidemia/atherosclerotic patients, adaptation to oxidative stress is poor; this is due to the impairment in the endogenous mechanisms against myocardial stress [47]. The role of cholesterol in the interruption and alteration of vascular structure and function as it builds within the lining of the vascular wall leading to lesions, plagues, occlusion, reduction in healing, recovery and appropriate management of ischemia/reperfusion injury has been described [9,48]. ...
Cardiovascular disease is a compound name for clusters of disorders afflicting the heart and blood vessels; it is assuming an increasing role as a major cause of morbidity and mortality. Unhealthy practices such as smoking, high intake of saturated fat and cholesterol, diabetes and physical inactivity are predisposing factors. The risk factors cause alteration in vascular integrity, compromised membrane integrity, increase free radical generation and reduced endogenous antioxidant system resulting in oxidative stress. Substance with ability to maintain vascular integrity, prevent, or reduce radical formation are able to treat cardiovascular disease. Conventional drugs in use to this effect are with side effect and as alternative, medicinal plants are increasingly gaining acceptance from the public and medical professionals. Reports have shown that bioactive compounds in plants with antioxidant, anti-inflammatory, ability to protect vascular endothelium, prevent lipid oxidation, and augment endogenous antioxidant system are cardioprotective. Phenolics and flavonoids in medicinal plants have been widely reported to play these major roles. This study reviewed the role of bioactive compounds in medicinal plants using a wide range database search.
... The lipids contained within the core of the lipoproteins are principally either triglycerides or cholesterol. It has been reported that atherosclerosis is a major cause of coronary heart disease (CHD) [10]. ...
Studies on the effect of non-hypertensive and hypertensive type 2 diabetes on lipid profile was performed to determine whether these biochemical parameters were affected in individuals associated with these disease conditions. A total of one hundred and thirty-three (133) individuals were used for these studies. Of these thirty-five (35) were established hypertensive diabetics and thirty (30) are established non-hypertensive diabetics. The established hypertensive non-diabetics were thirty-three (33) while thirty-five (35) were normal healthy individuals. The results showed that there was no significant differences (P>0.05) in the mean concentrations of cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and glucose between hypertensive diabetics and non-hypertensive diabetics studied. The study also showed that there were no significance differences (P>0.05) in the mean levels of all the parameters measured between hypertensive diabetics and hypertensive non-diabetics subjects studied, except for serum glucose that significantly higher (P<0.05) in hypertensive diabetics. It was observed that mean concentrations of cholesterol, triglycerides, LDC-cholesterol, as well as systolic blood pressure were significantly higher (P<0.05) in hypertensive diabetics compared with normal healthy individuals. The results also show that the mean HDL-cholesterol level was significantly lower (P>0.05) in hypertensive diabetics compared with normal healthy individuals. It was also observed that the concentrations of cholesterol, triglycerides, LDL-cholesterol systolic and diastolic blood pressure were significantly higher (P>0.05) in hypertensive non diabetics individuals compared with normal healthy individuals studied. However, the glucose and pulse rate mean levels showed no significant difference (P>0.05) between hypertensive non-diabetics and normal healthy individuals.
... Hypertension is the most important known risk factor for coronary artery disease. Despite the fact that systemic arterial hypertension is an accelerator of atherosclerosis pathogenically dependent on cholesterol, it is also an independent risk factor for ischemic heart disease (18). Hypertension is responsible for 35% of all atherosclerotic cardiovascular events. ...
INTRODUCTION: In this study, epidemiologic investigation of clinical features and risk factors of the patients diagnosed as acute ST elevation myocardial infarction (STEMI).
METHODS: The study designed as retrospective, descriptive, cross-sectional. 229 patients admitted to the training and research hospital emergency department with a yearly admission of 252677 in 2010, were included the study.
RESULTS: A total of 77.7% of the patients was male. Patient admission was the most in February (11.8%), and the least in August (5.2%). The most effected part of the heart was anterior (48.5%). 55.4% of the patients had smoking and 2.8% had alcohol usage history; 23.3% had hypertension, 20.0% hyperlipidemia, 18.3% diabetes mellitus, 11.7% family history of coronary artery disease.
DISCUSSION AND CONCLUSION: By the prevention from the modifiable risk factors for acute coronary diseases can reduce the frequency of coronary artery diseases.
... High cholesterol diet is regarded as an important factor in the development of cardiac diseases as it leads to development of hyperlipidaemia, atherosclerosis and ischaemic heart disease. [23] Lowering elevated plasma lipid levels is highly effective in reducing coronary artery disease (CAD) mortality and other cardiovascular system (CVS) events. Diet and drug therapy for hypercholesterolaemia is clearly indicated for individuals with existing CAD, as well as for individuals with multiple risk factors for cardiovascular diseases. ...
... High cholesterol diet is regarded as an important factor in the development of cardiac diseases as it leads to development of hyperlipidaemia, atherosclerosis and ischaemic heart disease. [23] Lowering elevated plasma lipid levels is highly effective in reducing coronary artery disease (CAD) mortality and other cardiovascular system (CVS) events. Diet and drug therapy for hypercholesterolaemia is clearly indicated for individuals with existing CAD, as well as for individuals with multiple risk factors for cardiovascular diseases. ...
Objective: Guggulu (Commiphora wightii (Arn.) Bhandari) belong to family Burseraceae is a well‑known anti‑hyperlipidaemic drug. An
Ayurvedic classic attributes brihmana (weight increasing) effect to fresh Guggulu, while lekhana (weight reducing) effect to the old one.
Though anti‑hyperlipidaemic activity of Guggulu has been studied, the actual differentiation in efficacy of Guggulu samples during storage
period has not yet attempted in experimental animals. This prompted us to initiate a comparative anti‑hyperlipidaemic activity of fresh Guggulu
and one‑year old Guggulu samples against cholesterol diet induced hyperlipidaemia in rats. Materials and Methods: Hyperlipidaemia
was induced by cholesterol (0.5 ml/kg, 20% suspension in coconut oil) and hydrogenated vegetable oil (5 ml/kg). The effects of drugs were
assessed on body weight, serum biochemical parameters and histological parameters. Results: Both drugs produced significant attenuation
of relative weight of liver in cholesterol‑fed animals. Fresh sample of Guggulu provided better effect in lowering serum cholesterol
(15.34%), triglyceride (34.72%), very low density lipoprotein (34.7%) and low density lipoprotein (18.66%) and non‑significant increase
in serum HDL‑cholesterol while old sample of Guggulu provided mild effect in lowering serum triglyceride (6.47%), VLDL (6.49%) and
LDL (29.50%) and non‑significant increase in serum HDL‑cholesterol in comparison with control group. Conclusion: From the present
study, it is concluded that fresh Guggulu produced pronounced hyperlipidaemic effect than the old one in experimental animals, which
may be due the presence of higher concentration of Z‑guggulsterone and E‑guggulsterone.
... We disease. There is a linear relationship between elevation of serum total cholesterol concentration and the incidence of myocardial infarction; furthermore, the heart of hyperlipidemic/atherosclerotic patients is hardly capable of adapting to physical exercise or other kinds of stress (86,87). This has been attributed solely to the development of atherosclerosis, and the possibility of the deterioration of endogenous adaptive mechanisms against myocardial ischemia, ie, preconditioning, has not been considered in hypercholesterolemic patients. ...
... ROS are known to be associated with the formation of oxidized LDL that, in turn, stimulates the release of ROS and enhanced adhesion molecule expression as well as platelet activity with pro-atherogenic effects in the vasculature [99]. Hyperlipidaemia is characterized by increased LDL and triglyceride concentrations, which is often accompanied by decreased HDL [100]. Type-II hyper-cholesterolemia causes changes in the structure and fluidity of erythrocyte plasma membranes since the excess cholesterol affects the normal rheology of blood through its interaction with erythrocytes. ...
During the past few decades, there have been numerous studies related field of free radical chemistry. Free radicals including reactive oxygen species and reactive nitrogen species are generated by the human body by various endogenous systems, exposure to different physiochemical conditions, or pathological states; and thus, they participate in the pathogenesis of increasing numbers of diseases. These free radicals are also the common by-products of many oxidative biochemical reactions in cells. In the past few years, there have been more attention and focus towards the field of free radical chemistry. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Thus, they adversely alter lipids, proteins and DNA, which triggers a number of human diseases. In a number of pathophysiological conditions, the delicate equilibrium between free radical production and antioxidant capability is distorted leading to oxidative stress and increased tissue injury. Reactive oxygen species which are mainly produced by vascular cells are implicated as possible underlying pathogenic mechanisms in a progression of cardiovascular diseases including ischemic heart disease, atherosclerosis, cardiac arrhythmia, hypertension, and diabetes. This review summarizes the key roles played by free radicals in the pathogenesis of atherosclerosis, diabetes and dyslipidemia. Although not comprehensive, this review will also provide a brief perspective on some of the current research being conducted in this area for a better understanding of the role free radicals play in the pathogenesis of atherosclerosis, diabetes and dyslipidemia. This article is protected by copyright. All rights reserved.
... The treatment of CHD has evolved from simple lifestyle modification in the mid-to-late 1960s, largely focused on early ambulation, exercise training, and a prudent diet, to an array of costly and palliative coronary revascularization procedures that, unfortunately, fail to address the foundational factors for atherosclerosis, that is, the most proximal risk factors for CHD, including poor dietary habits, physical inactivity, and cigarette smoking (Fig. 1). However, contemporary studies now suggest that behavior change and multifactorial risk factor modificationespecially smoking cessation and more intensive measures to control hyperlipidemia with diet, drugs, and exercisemay slow, halt, or even reverse (albeit modestly) the otherwise inexorable progression of atherosclerotic CHD [90,91]. Other investigations have now shown that combining dietary therapy with drug treatment is more effective than drug treatment alone in improving brachial artery flow-mediated vasodilation [92], in correcting dyslipidemia [42,93], in reducing ambulatory blood pressure [94], and the risk of acute coronary syndromes [95]. ...
... More importantly, even amongst those studies, the conclusions have been conflicting. Clinical studies identify a number of conditions that increase mortality from myocardial infarction; these include heart failure, diabetes, hypertension, aging and hypercholesterolemia (8,9). It is plausible that these conditions interfere with the biochemical pathways underlying the PC response. ...
Objectives:
We investigated the effects of ischemic preconditioning (PC) on diabetic and failing human myocardium and the role of mitochondrial KATP channels on the response in these diseased tissues.
Background:
There is conflicting evidence to suggest that PC is a healthy heart phenomenon.
Methods:
Right atrial appendages were obtained from seven different groups of patients: nondiabetics, diet-controlled diabetics, noninsulin-dependent diabetics (NIDD) receiving KATP channel blockers, insulin-dependent diabetics (IDD), and patients with left ventricular ejection fraction (LVEF) >50%, LVEF between 30% and 50% and LVEF <30%. After stabilization, the muscle slices were randomized into five experimental groups (n = 6/group): 1) aerobic control-incubated in oxygenated buffer for 210 min, 2) ischemia alone-90 min ischemia followed by 120 min reoxygenation, 3) preconditioning by 5 min ischemia/5 min reoxygenation before 90 min ischemia/120 min reoxygenation, 4) diazoxide (Mito KATP opener, 0.1 mm)-for 10 min before the 90 min ischemia/120 min reoxygenation and 5) glibenclamide (10 microm)-10 min exposure prior to PC (only in the diabetic patient groups). Creatine kinase leakage into the medium (CK, U/g wet wt) and MTT reduction (OD/mg wet wt), an index of cell viability, were assessed at the end of the experiment.
Results:
Ischemia caused similar injury in both normal and diseased tissue. Preconditioning prevented the effects of ischemia in all groups except NIDD, IDD and poor cardiac function (<30%). In the diazoxide-treated groups, protection was mimicked in all groups except the NIDD and IDD groups. Interestingly, glybenclamide abolished protection in nondiabetic and diet-controlled NIDD groups and did not affect NIDD groups receiving KATP channel blockers or IDD groups.
Conclusions:
These results show that failure to precondition the diabetic heart is due to dysfunction of the mitochondrial KATP channels and that the mechanism of failure in the diabetic heart lies in elements of the signal transduction pathway different from the mitochondrial KATP channels.
Introduction: Hyperlipidemia associated with increase of atherosclerosis and heart, blood vessels diseases.the present study was discuss of potentials effect of bay leave extract (BLE) and atorvastatin drug at dietwith high fat, feeding rat types. Material and Methods: The Rats were randomly classificationfor 4 groupseach group have 10 rats. control feed standard diet, group two rats feed HFD, group three rats feed HFD +( BLE 250mg/kg ) and group four rats feed HFD + Atorvastatin 20 mg/kg in the experiment, the treatmentdone by gavage and treated with 4 weeks daily. Results and Conclusion: The results show increasedsignificantly at the end body weights also the weight gain at group two by treated (HFD) , while hepaticlevels was inhibited for the cholesterol, and also triglycerides, also the low-density lipoprotein cholesterol;While the hepatic levels and serum of high-density lipoprotein cholesterol may be increased when theanimal treated 250 mg/kg BLE and 20mg/kg atorvastatin , also the result showed increased significantlyin serum AST ,ALT, ALP, urea and creatinine in group of animals treated HFD , and caused decreasedsignificantly in the value of above parameters when the animals treated 250 mg/kg BLE and 20mg/kgatorvastatin ,it reach the control. In conclusion, bay leave exerts and atorvastatin have amelioration effectagainst hyperlipidemia in HFD-fed rats.
In the interview, Prof. Barry A. Franklin discussed his perspectives on physical activity, cardiorespiratory fitness, and cardiovascular health. He also unraveled how soft skills can empower superachievers. His major viewpoints are: (a) exercise benefits cardiac patients; yet, too much exercise may be risky, (b) exercise prescription should be scientifically based and varies by different objectives for each individual, (c) patients' motivation to change their behaviors matters during cardiac rehabilitation, (d) physical activities could play a protective role for dementia prevention, (e) technology and virtual approaches enable more patients to participate in cardiac rehab programs, (f) patients with heart failure may benefit even more from exercise training than other patient populations, (g) psychosocial stressors may partially explain some cardiac events, (h) novel risk factors help identify people at increased risk of cardiovascular disease, such as genetics, coronary calcium score, air pollution, and inflammation, and (i) soft skills are needed by all people, regardless of their field.
As doenças coronarianas, entre elas a aterosclerose, tornaram-se a principal causa de morte. Esse problema é decorrente de aspectos do estilo de vida moderno, entre eles alimentação irregular, tabagismo, ingestão de bebidas alcoólicas, estresse e o sedentarismo. Nosso estudo tem por objetivo avaliar a importância do exercício físico como recurso terapêutico no tratamento de pacientes com doença arterial coronariana, correlacionando os benefícios do mesmo na diminuição dos marcadores inflamatórios assim como no controle dos fatores de risco e na morbidade cardiovascular. Os dados deste estudo demonstram a importância dos marcadores inflamatórios como preditores de risco para doença cardiovascular. A efetividade do exercício físico no controle dos fatores de risco de doença cardiovascular, tendo como parâmetro os marcadores inflamatórios, atinge múltiplos benefícios, que podem ser alcançados com alto grau de segurança.Palavras-chave: aterosclerose, marcadores inflamatórios, exercício físico, reabilitação.
Treatment of dyslipidemia patients with lipid-lowering drugs leads to a significant reduction in low-density lipoproteins (LDL) level and a low to moderate level of increase in high-density lipoprotein (HDL) cholesterol in plasma. However, a possible role of these drugs in altering morphology and distribution of cholesterol particles is poorly understood. Here, we describe the in vitro evaluation of lipid-lowering drug effects in modulating morphological features of cholesterol particles using the plaque array method in combination with imaging flow cytometry. Image analyses of the cholesterol particles indicated that lovastatin, simvastatin, ezetimibe, and atorvastatin induce the formation of both globular and linear strand-shaped particles, whereas niacin, fibrates, fluvastatin, and rosuvastatin induce the formation of only globular-shaped particles. Next, purified very low-density lipoprotein (VLDL) and LDL particles incubated with these drugs showed changes in the morphology and image texture of cholesterol particles subpopulations. Furthermore, screening of 50 serum samples revealed the presence of a higher level of linear shaped HDL cholesterol particles in subjects with dyslipidemia (mean of 18.3%) compared to the age-matched normal (mean of 11.1%) samples. We also observed considerable variations in lipid-lowering drug effects on reducing linear shaped LDL and HDL cholesterol particles formation in serum samples. These findings indicate that lipid-lowering drugs, in addition to their cell-mediated hypolipidemic effects, may directly modulate morphology of cholesterol particles by a non-enzymatic mechanism of action. The outcomes of these results have potential to inform diagnosis of atherosclerosis and predict optimal lipid-lowering therapy. © 2017, Journal of Visualized Experiments. All rights reserved.
Objective
Ischemic postconditioning (IPOC) is an endogenous cardioprotective phenomenon, which gets attenuated during the hyperlipidemia. It has been documented that erythropoietin (EPO), a glycoprotein, produces IPOC-like cardioprotection through common signaling pathway such as PI-3K pathway. The aim of this study has been designed to investigate the role of EPO in IPOC induced cardioprotection in hyperlipidemic rat heart.
Materials and methods
Heart was isolated from hyperlipidemic rat and mounted on Langendorff's apparatus, subjected to 30 min ischemia and 120 min reperfusion. IPOC was mediated by four cycles of 5 min reperfusion and 5 min ischemia. The infarct size was estimated using TTC stain and coronary effluent was analyzed for LDH and CK-MB release to assess the degree of myocardial injury.
Results
Four cycles of IPOC produces cardioprotection noted in terms of decrease in infarct size and decrease in the release of LDH and CK-MB in normal rat heart. However, IPOC-induced cardioprotection was completely attenuated in isolated heart obtained from hyperlipidemic rat. Perfusion of EPO (1 U/ml) significantly restored the attenuated cardioprotection in hyperlipidemic rat heart, which was completely blocked by perfusion of LY294002 (10 μM), a selective inhibitor of PI-3K.
Conclusion
Thus, it is suggested that EPO restores the attenuated cardioprotective effect of IPOC in hyperlipidemic rat heart by the activation of PI-3K signaling pathway.
Historical Notes: Genesis and Progress in Concepts of Preventive Cardiology: A Historical Overview
Der Begriff „Sekundärprävention“ im Rahmen der koronaren Herzkrankheit (KHK) umschreibt Maßnahmen zur Senkung von Risikofaktoren bei Patienten, die bereits ein klinisches Ereignis wie Angina pectoris, einen Herzinfarkt, eine PTCA (perkutane transluminal Koronarangiographie) oder eine aortokoronare Bypassoperation (CABG) erlebt haben. Der epidemiologische Ausdruck „Prävention“ ist irreführend, vielmehr handelt es sich um ein generelles Management von Patienten mit bereits dokumentierter KHK. Maßnahmen zur Sekundärprävention werden auch bei der Rehabilitation subsumiert, welche der umfassendere Begriff ist und welche aufgrund des zeitlichen Zusammenhanges mit dem Ereignis, (s. Kap. 11.1) in verschiedene Stufen eingeteilt wird [76, 78, 89].
Atherosclerosis is a diffuse disease of the endothelium, with an uneven distribution of plaque formation. Therefore, anatomical interventions such as coronary artery bypass surgery(CABG), which attack single plaques, may be of only limited value. Effective therapies should include aggressive cholesterol lowering as well as management of other risk factors such as blood pressure, cigarette smoking, obesity and sedentary living. Studies have shown that at least two-thirds of coronary patients suffer recurrent cardiovascular events regardless of cholesterol intervention. Possible reasons include (1) the presence of other coronary risk factors, e.g. triglycerides, which can promote atherogenesis even after cholesterol reduction; (2) the need for more aggressive cholesterol lowering - this is currently being addressed in the Treating to New Targets (TNT) study in which patients are treated for 5 years with either the starting (10 mg) or maximum (80 mg) dose of atrovastatin; and (3) the burden of atherosclerosis,,which may be too great to be eliminated by cholesterol-lowering interventions,Primary prevention measures should include changes in diet and the use of cholesterol-lowering drugs. Results from the post-CABG study indicate that over 50% of new coronary lesions can be prevented from developing by cholesterol-lowering interventions. In both Europe and the U.S.A., there is a disquietingly low level,of prescription of cholesterol-lowering diets and drugs. Moreover, data from a recent study indicate that even when cholesterol-lowering drugs are prescribed, 60% of the prescriptions are not refilled. Such poor compliance is an issue that must be addressed.
The serum total and LDL cholesterol levels of long-term vegans tend to be very low. The characteristically low ratio of saturated to unsaturated fat in vegan diets, and the absence of cholesterol in such diets, clearly contribute to this effect. But there is reason to suspect that the quantity and composition of dietary protein also play a role in this regard. Vegan diets of moderate protein intake tend to be relatively low in certain essential amino acids, and as a result may increase hepatic activity of the kinase GCN2, which functions as a gauge of amino acid status. GCN2 activation boosts the liver's production of fibroblast growth factor 21 (FGF21), a factor which favorably affects serum lipids and metabolic syndrome. The ability of FGF21 to decrease LDL cholesterol has now been traced to at least two mechanisms: a suppression of hepatocyte expression of sterol response element-binding protein-2 (SREBP-2), which in turn leads to a reduction in cholesterol synthesis; and up-regulated expression of hepatocyte LDL receptors, reflecting inhibition of a mechanism that promotes proteasomal degradation of these receptors. In mice, the vascular benefits of FGF21 are also mediated by favorable effects on adipocyte function - most notably, increased adipocyte secretion of adiponectin, which directly exerts anti-inflammatory effects on the vasculature which complement the concurrent reduction in LDL particles in preventing or reversing atherosclerosis. If, as has been proposed, plant proteins preferentially stimulate glucagon secretion owing to their amino acid composition, this would represent an additional mechanism whereby plant protein promotes FGF21 activity, as glucagon acts on the liver to boost transcription of the FGF21 gene.
The present study was undertaken to evaluate cardioprotective activity of Makandi (Coleus forskohli Willd.) Churna and Ghanavati on the basis of electrocardiographic, biochemical, cardiac output and histopathological parameters against isoproterenol (ISO) induced myocardial infarction in diet induced hyperlipidaemic rats. The drug treatment and hyperlipidaemic diets were administered for 20 consecutive days. Myocardial injury was induced by injecting ISO (85 mg/kg) to rats at an interval of 24 h for two days. Forty eight hours after the first dose of ISO injection, parameters like ECG, cardiac output, biochemical and histological observations of the heart tissues were performed. Hyperlipidaemic diet followed by ISO significantly increased heart weight, altered serum lipid profiles, SGPT and ALP activity, caused ST segment elevation, prolonged QT interval and QTc in ECG, increased blood pressure and decreased cardiac output. Histopathologically also, heart showed severe cytoarchitectural disturbances like myonecrosis, fatty changes and endocardial oedema. When administered orally, both the formulations of Makandi decreased atherogenic index, almost normalized ST segment elevation, QT interval prolongation and cardiac output. Histopathologically also remarkable protection was observed. Analysis of the results showed that Makandi in Churna form has both anti-atherogenic potentia l and cardioprotective activity, while Ghanavti has only weak cardioprotective activity.
Asian Indians around the globe have the highest rates of coronary artery disease (CAD), even though almost half of them are life-long vegetarians. When compared to Whites, Blacks, Hispanics and other Asians, the CAD rates in Asian Indians worldwide are 2-4 times higher at all ages and 5-10 times higher in those under 40 years of age. The prevalence of CAD in New Delhi is 4-fold higher than in Framingham (US). The unifying hypothesis, considering all the data available today, suggests the combined role of nature and nurture in the development of malignant atherosclerosis in young Asian Indians. Nature is provided by elevated levels of lipoprotcin(a), the levels of which are genetically determined. Urbanization, affluence, and mechanization provide nurture. Since conventional risk factors do not explain this excess burden of CAD in Asian Indians, conventional approaches to prevention and treatment may also be insufficient. Asian Indian physicians in the US have made maximum modification of lifestyle and yet their CAD rates are 4-fold higher than White Americans and 6-fold higher than Chinese Americans. Dyslipidemia characterized by the 'Lipid tetrad' appears to offer the best plausible explanation. Therefore, an aggressive approach to treatment of dyslipidemia seems not only justified, but warranted in this population. The overall risk of CAD in Asian Indians appears to be similar to that of other populations with known CAD. Therefore, high-risk Asian Indians should be treated for an low density lipoprotein (LDL) goal < 100 mg/dl, the level recommended for patients with CAD, if maximum modification of lifestyle fails to achieve this goal.
Hyperlipidemia was induced in rats by administering 2% cholesterol, 20% coconut oil and 0.125% cholic acid for 10 weeks. Atorvastatin (0.8 mg/kg b.w.) was administered orally to rats together with high fat diet for ten weeks. At the end of the experimental period, the circadian characteristics (acrophase, amplitude and mesor) of liver marker enzymes (aspartate aminotransferase (AST) and alanine transferase (ALT)), lipid peroxidation products (thiobarbituric acid reactive substances (TBARS) and antioxidants (superoxide dismutase (SOD), catalase, reduced glutathione (GSH), and glutathione peroxidase (GPX)) were analyzed. Circadian characteristics (mesor, amplitude and acrophase) of liver marker enzymes, TBARS and antioxidants were altered in high fat diet induced rats and the diminished amplitude along with decreased mesor levels of antioxidants were observed in high fat diet induced rats. Further, oral administration of atorvastatin to high fat diet induced rats showed the normalized mesor, amplitude and acrophase. These findings suggest that the antihyperlipidemic potential of atorvastatin could modulate the circadian patterns of liver marker enzymes and redox status in hyperlipidemic rats.
A doença cardiovascular ocorre em conseqüência de uma série complexa de eventos que começa com desequilíbrio homeostático causado por interações anormais do ambiente com alterações genéticas. Atualmente, entende-se o processo aterosclerótico não apenas como decorrência do acúmulo de lípides nas paredes dos vasos, mas também como conseqüência da disfunção endotelial e da ativação do sistema inflamatório. A associação da aterosclerose com inflamação nos leva a procurar marcadores envolvidos no processo inflamatório que possam predizer o risco de doença arterial coronariana (DAC). Um marcador pode refletir a fisiopatologia subjacente à doença, predizer eventos futuros, indicar a presença da afecção ou danos a um órgão, além de avaliar o progresso do tratamento. Evidência recente indica que os níveis sangüíneos da proteína C reativa (PCR) podem predizer doença cardiovascular futura. À exceção da PCR de alta sensibilidade e da Interleucina- 6 (IL-6), outros marcadores inflamatórios, como moléculas de adesão intercelular (ICAM-1 e ICAM-2) e a molécula de adesão da célula vascular (VCAM-1), outras citocinas como o fator de necrose tumoral alfa (TNF-?), o “Cluster of Differentiation” 40 (CD 40) e proteínas de fase aguda (Fibrinogênio, Soro Amilóide A) não acrescentam valor preditivo maior ou igual que os fatores de risco pela Tabela de Framingham para desenvolvimento de doença cardiovascular. Tal fato pode ser justificado por não existirem ainda exames laboratoriais, de fácil aplicabilidade e baixo custo, que determinem com exatidão níveis apropriados para o uso clínico. Entretanto, muitos destes biomarcadores são importantes na fisiopatologia da aterosclerose e servem como ferramentas fundamentais para a pesquisa.
Die Kranzarterien und viele ihrer großen Äste verlaufen vollständig oder weitgehend im epikardialen Binde- und Fettgewebe.
Hier sind sie während der Systole nicht einer Kompression durch die Herzmuskulatur ausgesetzt, und hier sind ihre Längenänderungen
während des Herzzyklus am geringsten, weil sich aus geometrischen Gründen bei der Kontraktion eines Hohlkörpers die äußeren
Wandschichten geringer als die inneren verkleinern. Die während des Herzzyklus auftretenden Längenänderungen der epikardialen
Kranzarterien entsprechen denen der benachbarten Herzoberfläche. Sie sind im Bereich des Sulcus interventricularis recht ausgeprägt,
in der Atrioventrikularfurche aber wesentlich geringer (GEROVA 1993).
Cardiovascular disease (CVD) rates have been reported in several parts of the world and have been found to be unusually high in people originating from the Indian subcontinent. High coronary disease rates appear to be common to South Asian groups of different geographic origin, religion, and language. This presents a challenge for understanding the development of coronary heart disease. The high rates in Asian Indians are only partly explained with respect to elevated serum cholesterol, smoking, or hypertension. Low plasma high-density lipoprotein cholesterol, high plasma triacylglycerols, and high prevalence of type 2 diabetes mellitus have been consistently found in Asian Indians suggesting a state of insulin resistance. This review examines published data on the risk factors and prevalence of CVD in Indiana populations. Further studies are needed to determine if metabolic disturbances related to insulin can account for the high rates of CVD in Asian Indians and to identify possibilities for prevention.
Several recent studies demonstrate that dietary Cr intake in humans and farm animals may be suboptimal. Recent advances in Cr nutrition include the following: 1) Triglycerides of subjects with noninsulin-dependent diabetes (NIDDM) decreased following daily supplementation of 200 μg of Cr. Glucose and cholesterol values were not affected. 2) HDL cholesterol of subjects taking beta-blockers for the control of hypertension improved following supplementation with 600 μg of Cr per day. 3) Chromium prevented sucrose-induced hypertension in spontaneously hypertensive rats but did not alter genetic hypertension. 4) The pig was shown to be a good experimental model for human Cr nutrition studies. Supplemental Cr (300 μg/Kg diet) improved glucose, insulin, HDL, and related parameters in pigs, similar to effects reported previously for humans. 5) Lean body mass increased and percent fat decreased in pigs receiving supplemental Cr, supporting earlier human studies suggesting that Cr effects body composition. 6) Litter size of pigs increased from the lowest 10th percentile to the highest 10th percentile following Cr supplementation. 7) Immune function improved in Cr-supplemented cattle. Improvements in immune function were only present in the stressed animals. These recent advances document the nutritional role of Cr and demonstrate that the normal nutritional status of humans and farm animals may be suboptimal. J. Trace Elem. Exp. Med. 11:241–250, 1998. Published 1998 Wiley-Liss, Inc.†
The aim of this study was to assess the impact of hypertension on angiographic results in Iraqi patients with coronary artery disease. Six hundred and ifty seven patients with coronary artery disease (CAD) were submitted to routine coronary angiography in the period from January 2008 to December 2010. A comparison and evaluation have been divided into 2 stages. There was no signiicant association between patients with CAD who had a history of hypertension only with the number and distribution of coronary artery vessels involvement, as well as with morphological severity of coronary lesions. But, there was a statistically signiicant association between hypertension associated with other cardiac risk factors with multiple coronary lesions. Hypertension was signiicantly associated with multiple coronary artery lesions when combined with other cardiac risk factors.
Vegetarianism continues to gain prominence in contemporary society. This research uses a two-phase approach to further the understanding of this phenomenon. In the first phase, a phenomenological perspective is utilized to provide a deeper understanding of the motivations, tensions, and coping mechanisms underlying vegetarianism. The second phase builds upon this understanding and broadens the scope of the research by introducing the concept of vegetarian orientation. Here, survey methodology is employed to investigate the manner in which a person's demographic, attitudinal, and personality characteristics influence his/her vegetarian-oriented attitudes and behaviors. Findings and their marketing implications are discussed. © 2001 John Wiley & Sons, Inc.
Risk stratification is a key component to recently developed consensus statements and guidelines for the prevention of cardiovascular
disease (CVD), including the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and American College
of Cardiology/American Heart Association (AHA) guidelines. In an effort to provide clinicians with guidance regarding the
primary prevention of CVD and the identification of high-risk individuals, various organizations have developed consensus
statements and clinical guidelines. Each stresses the centrality of risk stratification in tailoring individualized therapy
and identifies high-risk individuals through categorical risk factor counting (categorical method) or continuous risk thresholds
(continuous variables method). The NCEP ATP III, for example, varies the cholesterol thresholds for initiation of treatment
and goals of therapy based on the presence of vascular disease or coexistent risk factors. Other consensus groups, including
the Joint European Societies Expert Panel, recommend that pharmacological therapy be based on assessment of absolute risk.
To compare the acceptability, compliance, and effectiveness of two forms of cholestyramine resin in the treatment of hypercholesterolemia in children.
Patients aged 10 to 18 years with familial hypercholesterolemia were enrolled in a randomized, crossover trial of two 8-week periods of either a pill or powder form of cholestyramine at a dose of 8 gm/day.
Of 40 children enrolled, 38 completed both medication periods, with a median age of 13 years (range, 10 to 18). At the end of the study, 82% preferred the pill form, 16% the powder form and 2% neither form. Mean (+/-SD) compliance as assessed by the amount of medication taken was significantly greater for pills (61% +/- 31%) than powder (50% +/- 30%, p = 0.01). The form of the medication increased compliance by at least 25% for 16 patients (42%), 13 in favor of pills and 3 in favor of powder. Compliance was not associated with patient attitudes and perceptions of hypercholesterolemia, demographics, family history, previous experience with lipid-lowering medication, or lipid profile parameters. Significant mean reductions in low-density lipoprotein cholesterol concentrations were noted for both pills (-10% +/- 20%, p = 0.006) and powder (-15% +/- 17%, p = 0.0001), with no significant difference between forms (p = 0.16).
A change in bile acid-binding resin formulation from powder to pills significantly increases acceptability and compliance in some children with hypercholesterolemia.
We examined whether the inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine (lNNA) abolished pacing-induced preconditioning, and if prolonged exposure to cholesterol-enriched diet led to the loss of preconditioning due to decreased cardiac NO formation. Therefore, Wistar rats fed 2% cholesterol-enriched diet or standard diet for 24 weeks were treated with a single dose of 1 mg/kg lNNA or its solvent at the end of the week 24, respectively. Isolated hearts from all groups were subjected to either preconditioning induced by three consecutive periods of pacing at 600 beats/min for 5 min, with 5-min interpacing periods, or time-matched non-preconditioning perfusion, followed by a 10-min coronary occlusion, respectively. In the control group, coronary occlusion after a non-preconditioning protocol decreased aortic flow (AF) from 45.4+/-2.4 to 15.6+/-1.5 ml/min, and resulted in a lactate dehydrogenase (LDH) release of 219+/-55 mU/min/g, however, preconditioning attenuated the consequences of coronary occlusion [AF: 27.3+/-1.7 ml/min (P<0.05); LDH: 44+/-14 mU/min/g (P<0.05)]. Preconditioning did not confer protection in the lNNA-treated (AF: 17.4+/-1.5 ml/min; LDH: 151+/-21 mU/min/g), and/or in the high-cholesterol-fed groups (AF: 15.7+/-1.2 ml/min; LDH: 168+/-22 mU/min/g). Preconditioning was preserved however, when hearts were treated with lNNA after the preconditioning protocol [AF: 29.6+/-2.2 ml/min (P<0.05); LDH: 48+/-17 mU/min/g (P<0.05)]. Both lNNA treatment and cholesterol-enriched diet markedly decreased cardiac NO content assayed by electron spin resonance spectroscopy. We conclude that NO may be involved in the triggering mechanism of pacing-induced preconditioning, the protective effect of which is blocked by sustained exposure to dietary cholesterol, possibly by influencing cardiac metabolism of NO.
This model for risk stratification includes variables that classify patients for Risk of Event similar to current models of risk stratification, as well as variables that stratify patients for Risk of Progression of Atherosclerosis by established risk factors. Categories of risk are established using accepted data from the literature for each risk factor that targets regression or plaque stabilization as the goal for Low Risk. A case-rate charging system and the proposed removal of time restrictions for length of cardiovascular rehabilitation fit neatly into the present climate for health care. Health maintenance organizations will be seeking programs that use similar models to address cost issues inherent in cardiovascular rehabilitation programs under current fee-for-service models. Improved outcomes will also be targets for these programs and case-management lends itself to disease management, thus, improved outcomes. Tracking outcomes becomes even more important to both the provider and the insurer because results drive referrals. Likewise, removal of the time restriction for cardiovascular rehabilitation allows programs to individualize care and to target risk factors that are not only most deleterious, but also where patients show readiness for change. The changing environment of health care virtually mandates change in cardiovascular rehabilitation. It is imperative that programs manage the disease process, are effective in achieving outcomes that affect both patient function and the disease process, and are cost effective. This model for risk stratification and delivery of services addresses these requirements and provides a beginning for implementing these changes in cardiovascular rehabilitation.
Effective therapeutic strategies for protecting the ischaemic myocardium are much sought after. Ischaemic heart disease in humans is a complex disorder, often associated with other systemic diseases such as dyslipidaemia, hypertension and diabetes that exert multiple biochemical effects on the heart, independently of ischaemia. Ischaemic preconditioning of myocardium is a well-described adaptive response in which brief exposure to ischaemia markedly enhances the ability of the heart to withstand a subsequent ischaemic insult. The underlying molecular mechanisms of this phenomenon have been extensively investigated in the hope of identifying new rational approaches to therapeutic protection of the ischaemic myocardium. However, most studies have been undertaken in animal models in which ischaemia is imposed in the absence of other disease processes. In this article, Peter Ferdinandy, Zoltan Szilvassy and Gary Baxter review the ways in which systemic diseases might modify the preconditioning response and they emphasize the importance of further preclinical studies that specifically examine preconditioning in relation to complicating disease states.
We have previously shown that hypercholesterolemia leads to the loss of pacing-induced preconditioning (PC), possibly due to the impairment of cardiac nitric oxide (NO) synthesis. It has been shown that excess exogenous cholesterol inhibits formation of several polyprenyl derivatives involved in signal transduction. In the present study, we examined whether PC and cardiac NO synthesis are restored by treatment with the key polyprenyl product, farnesol, in cholesterol-fed rats. Rats fed 2% cholesterol-enriched/control diet for 24 weeks were given i.p. 5 microM/kg farnesol/vehicle, respectively. An hour later, hearts were isolated and prepared for 'working' perfusion, then subjected to PC/non-PC protocols of 3 intermittent periods of pacing of 5 min duration at 10 Hz, followed by a 10 min coronary occlusion to test the effect of PC. PC increased ischemic aortic flow (AF) from its control value of 15.6+/-1.5 to 27.3+/-1.7 mL/min (p < 0.05). PC was not observed in hearts obtained from hypercholesterolemic rats (AF: 15.7+/-1.2 mL/min), however, it reappeared in the farnesol-treated hypercholesterolemic group (AF: 31.8+/-3.4 mL/ min, p < 0.05). In tissue samples from the left ventricle, cholesterol-diet markedly decreased the intensity of the electron spin resonance spectra of NO obtained after in vivo spin trapping with Fe2+-diethyl-dithio-carbamate complex. Farnesol-treatment did not influence cardiac NO content in the cholesterol-fed or in the control group. These results show that the lost PC can be recaptured by farnesol-treatment in hypercholesterolemia, however, farnesol-treatment does not restore cardiac NO synthesis.
HMG reductase inhibitors have significant desirable effects on patients with dyslipidemia. Multiple factors are involved in these desirable effects. Other factors that might play a role in the risk of coronary artery disease are fibrinogen concentration, homocysteine, Lp (a), small dense LDL, insulin resistance, and infection with chlamydia.
High-dose reductase inhibitors may be indicated in select patients. The ideal end point may be 150 mg/dL for adults.
Coronary atherosclerosis begins to develop in late adolescence and early adulthood. If intervention in coronary risk factors is delayed until middle-age, it is likely that a considerable number of patients will be lost to irreversible disease. Even with the dramatic cholesterol lowering that can be induced by statin drugs, coronary events can be reduced by only 25% to 40%, leaving most at-risk patients unprotected. Diet, exercise, and other nonpharmacological interventions have a role in the age of statins, not only to augment the effects of these drugs in high-risk patients, but also, by preventing atherogenesis in the first place, to reduce the number of at-risk patients.
This report describes the design of the Coronary Primary Prevention Trial (CPPT), a clinical trial sponsored by the National Heart, Lung and Blood Institute (NHLBI). The primary objective of the trial is to test the hypothesis that long-term reduction of serum cholesterol in hypercholesterolemic men initially free of clinical coronary heart disease (CHD) will lead to a lowered incidence of CHD. A total of 3810 men with primary Type II hyperlipoproteinemia were enrolled at 12 North American clinical centers. At the time of entry, these men were 35-59 yr old, in good general health and free of any overt symptoms of CHD. All participants were prescribed a standard diet allowing daily intake of approx 400 mg of cholesterol with a polyunsaturated-to-saturated fat ratio of approx 0.8. In addition, 24 g/day of a bile acid sequestrant, cholestyramine, was prescribed to half the men; the other half received a placebo. The assignment of participants to drug or placebo groups was done randomly within eight welldefined prognostic strata at each clinic and in a double-blind manner. Participants are being followed for a minimum of 7 yr. The primary end points are coronary death and non-fatal myocardial infarction. The CPPT data are reviewed periodically by a Safety and Data Monitoring Board for evidence of adverse and/or beneficial treatment effects.
This report describes the status of the coronary arteries in nine patients (average age, 29 years) with juvenile onset diabetes mellitus (average age at onset, nine years), and compares the clinical and morphologic observations in them to those in nine control subjects (average age, 29 years). The nine patients with juvenile diabetes had significantly more extramural coronary luminal narrowing by atherosclerotic plaques than did the control subjects. The lumens of one or more of the four major epicardial coronary arteries were narrowed more than 75 per cent in cross-sectioned area in six of the diabetic patients and in none of the control subjects. This difference in degree of narrowing of the epicardial coronary arteries was even more striking when the per cent of narrowing of the entire lengths of the four major coronary arteries was examined: of the 191 cm of major coronary artery examined in the nine diabetic patients, the lumen in 90.5 cm (47 per cent) was narrowed more than 50 per cent in cross-sectioned area, whereas of 155 cm of coronary artery examined in the nine control subjects, the lumen of only 2 cm (1 per cent) was narrowed to this degree.
The first report from the Framingham Study that demonstrated an inverse relationship between high-density lipoprotein cholesterol (HDL-C) and the incidence of coronary heart disease (CHD) was based on four years of surveillance. These participants, aged 49 to 82 years, have now been followed up for 12 years, and this report shows that the relationship between the fasting HDL-C level and subsequent incidence of CHD does not diminish appreciably with time. Since a second measurement of HDL-C is available eight years after the initial determination, the relationship of HDL-C measurements on the same subjects at two points in time is examined. This second HDL-C measurement is also used in a multivariate model that includes cigarette smoking, relative weight, alcohol consumption, casual blood glucose, total cholesterol, and blood pressure. It is concluded that even after these adjustments, nonfasting HDL-C and total cholesterol levels are related to development of CHD in both men and women aged 49 years and older. Study participants at the 80th percentile of HDL-C were found to have half the risk of CHD developing when compared with subjects at the 20th percentile of HDL-C.
The 356 222 men aged 35 to 57 years, who were free of a history of hospitalization for myocardial infarction, screened by the Multiple Risk Factor Intervention Trial (MRFIT) in its recruitment effort, constitute the largest cohort with standardized serum cholesterol measurements and long-term mortality follow-up. For each five-year age group, the relationship between serum cholesterol and coronary heart disease (CHD) death rate was continuous, gradecf, and strong. For the entire group aged 35 to 57 years at entry, the age-adjusted risks of CHD death in cholesterol quintiles 2 through 5 (182 to 202, 203 to 220, 221 to 244, and ≥245 mg/dL [4.71 to 5.22, 5.25 to 5.69, 5.72 to 6.31, and ≥6.34 mmol/L]) relative to the lowest quintile were 1.29, 1.73, 2.21, and 3.42. Of all CHD deaths, 46% were estimated to be excess deaths attributable to serum cholesterol levels 180 mg/dL or greater (≥4.65 mmol/L), with almost half the excess deaths in serum cholesterol quintiles 2 through 4. The pattern of a continuous, graded, strong relationship between serum cholesterol and six-year age-adjusted CHD death rate prevailed for nonhypertensive nonsmokers, nonhypertensive smokers, hypertensive nonsmokers, and hypertensive smokers. These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintiles, but rather is a continuously graded one that powerfully affects risk for the great majority of middle-aged American men.(JAMA 1986;256:2823-2828)
We conducted a randomized, controlled trial in 72 patients with heterozygous familial hypercholesterolemia to test whether reducing plasma low-density lipoprotein levels by diet and combined drug regimens can induce regression of coronary lesions. Four hundred fifty-seven lesions were measured before and after a 26-month interval by computer-based quantitative angiography. The primary outcome variable was within-patient mean change in percent area stenosis. Mean low-density lipoprotein cholesterol levels decreased from 7.32 ±1.5 to 4.45 ±1.6 mmol/L. The mean change in percent area stenosis among controls was + 0.80, indicating progression, while the mean change for the treatment group was -1.53, indicating regression (P =.039 by two-tailed t test for the difference between groups). Regression among women, analyzed separately, was also significant. The change in percent area stenosis was correlated with low-density lipoprotein levels on trial. We conclude that reduction of low-density lipoprotein cholesterol levels can induce regression of atherosclerotic lesions of the coronary arteries in patients with familial hypercholesterolemia. The anticipation of benefit from treatment applies to women and men alike.(JAMA. 1990;264:3007-3012)
Objective.
—To examine trends in overweight prevalence and body mass index of the US adult population.Design.
—Nationally representative cross-sectional surveys with an in-person interview and a medical examination, including measurement of height and weight.Setting/Participants.
—Between 6000 and 13000 adults aged 20 through 74 years examined in each of four separate national surveys during 1960 to 1962 (the first National Health Examination Survey [NHES I]), 1971 to 1974 (the first National Health and Nutrition Examination Survey [NHANES I]), 1976 to 1980 (NHANESII), and 1988 to 1991 (NHANES III phase 1).Results.
—In the period 1988 to 1991,33.4% of US adults 20 years of age or older were estimated to be overweight. Comparisons of the 1988 to 1991 overweight prevalence estimates with data from earlier surveys indicate dramatic increases in all race/sex groups. Overweight prevalence increased 8% between the 1976 to 1980 and 1988 to 1991 surveys. During this period, for adult men and women aged 20 through 74 years, mean body mass index increased from 25.3 to 26.3; mean body weight increased 3.6 kg.Conclusions.
—These nationally representative data document a substantial increase in overweight among US adults and support the findings of other investigations that show notable increases in overweight during the past decade. These observations suggest that the Healthy People 2000 objective of reducing the prevalence of overweight US adults to no more than 20% may not be met by the year 2000. Understanding the reasons underlying the increase in the prevalence of overweight in the United States and elucidating the potential consequences in terms of morbidity and mortality present a challenge to our understanding of the etiology, treatment, and prevention of overweight.(JAMA. 1994;272:205-211)
Saturated fatty acids and cholesterol in the diet raise the plasma cholesterol concentration, and a reduction in these constituents is recommended widely. However, there is not general agreement as to which nutrients should replace saturated fatty acids. Several different substitute nutrients are possible. In this study, three cholesterol-lowering diets were compared in nine men living in a domiciliary. On a typical American diet at baseline, cholesterol levels were in the normal range. One replacement diet was high in polyunsaturated fatty acids (High Poly); another had 30% fat and corresponded to the American Heart Association's (AHA) recommended diet for the general public (AHA phase I); the third diet had 20% fat, equivalent to the AHA phase III diet for treatment of hypercholesterolemia. Compared with baseline levels, all diets caused similar reductions in total cholesterol and low-density lipoprotein cholesterol levels, but the High Poly and AHA phase III diets lowered the high-density lipoprotein cholesterol level more than the AHA phase I diet. Thus, for the limited number of patients in this study, the diet recommended for the general public appeared as effective for lowering of cholesterol levels as diets containing more polyunsaturates or more carbohydrates.(JAMA 1986;256:2351-2355)
The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol hydrochloride and niacin therapy in 162 nonsmoking men aged 40 to 59 years with previous coronary bypass surgery. During two years of treatment there was a 26% reduction in total plasma cholesterol, a 43% reduction in low-density lipoprotein cholesterol, plus a simultaneous 37% elevation of high-density lipoprotein cholesterol. This resulted in a significant reduction in the average number of lesions per subject that progressed (P<.03) and the percentage of subjects with new atheroma formation (P<.03) in native coronary arteries. Also, the percentage of subjects with new lesions (P<.04) or any adverse change in bypass grafts (P<.03) was significantly reduced. Deterioration in overall coronary status was significantly less in drug-treated subjects than placebo-treated subjects (P<.001). Atherosclerosis regression, as indicated by perceptible improvement in overall coronary status, occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated (P =.002).
(JAMA 1987;257:3233-3240)
It has yet to be established whether substantial reduction of plasma lipids will lead to retardation, and to what extent and how quickly, of diffuse and focal coronary atheroma. The Multicentre Anti-Atheroma Study (MAAS) is a randomised double-blind clinical trial of 381 patients with coronary heart disease assigned to treatment with diet and either simvastatin 20 mg daily or placebo for 4 years. Patients on simvastatin had a 23% reduction in serum cholesterol, a 31% reduction in low-density lipoprotein cholesterol, and a 9% increase in high-density lipoprotein cholesterol compared with placebo over 4 years. Quantitative coronary angiography was done at baseline, and after 2 and 4 years. 167 patients (89%) on placebo and 178 (92%) on simvastatin had baseline and follow-up angiograms. In the placebo group there were reductions in mean lumen diameter (-0·08 mm) and in minimum lumen diameter (-0·13 mm). Treatment effects were +0·06 (95% Cl 0·02 to 0·10) and +0·08 mm (0·03 to 0·14) for mean and minimum lumen diameter, respectively (combined p=0·006). Patients on placebo had an increase in mean diameter stenosis of 3·6% and the treatment effect of simvastatin was - 2·6% (-4·4 to -0·8). Treatment effects were observed regardless of diameter stenosis at baseline. On a per-patient basis, angiographic progression occurred less often in the simvastatin group, 41 versus 54 patients; and regression was more frequent, 33 versus 20 patients (combined p = 0·02). Significantly more new lesions and new total occlusions developed in the placebo group, 48 versus 28, and 18 versus 8, respectively. There was no difference in clinical outcome. The numbers of patients who died or had a myocardial infarction were 16 and 14 in the placebo and simvastatin groups, respectively. In the placebo group more patients underwent coronary angioplasty or re-vascularisation, 34 versus 23 on simvastatin.The trial showed that 20 mg simvastatin daily over 4 years reduces hyperlipidaemia and slows progression of diffuse and focal coronary atherosclerosis.
We assessed the relation of risk factors for cardiovascular disease to early atherosclerotic lesions in the aorta and coronary arteries in 35 persons (mean age at death, 18 years). Aortic involvement with fatty streaks was greater in blacks than in whites (37 vs. 17 percent, P less than 0.01). However, aortic fatty streaks were strongly related to antemortem levels of both total and low-density lipoprotein cholesterol (r = 0.67, P less than 0.0001 for each association), independently of race, sex, and age, and were inversely correlated with the ratio of high-density lipoprotein cholesterol to low-density plus very-low-density lipoprotein cholesterol (r = -0.35, P = 0.06). Coronary-artery fatty streaks were correlated with very-low-density lipoprotein cholesterol (r = 0.41, P = 0.04). Mean systolic blood-pressure levels also tended to be higher in the four subjects with coronary-artery fibrous plaques than in those without them: 112 mm Hg as compared with 104 (P = 0.09). These results document the importance of risk-factor levels to early anatomical changes in the aorta and coronary arteries. The progression of fatty streaks to fibrous plaques is uncertain, but these data suggest that a rational approach to the prevention of cardiovascular disease should begin early in life.
Conflicting results have been reported concerning the association between body weight and longevity. The shape of the curve relating weight to all-cause mortality has been variously described as linear, J-shaped, and even U-shaped. To assess the validity of the evidence for optimal weight recommendations, we examined the 25 major prospective studies on the subject. Each study had at least one of three major biases: (1) failure to control for cigarette smoking, (2) inappropriate control of biologic effects of obesity, such as hypertension and hyperglycemia, and (3) failure to control for weight loss due to subclinical disease. The presence of these biases leads to a systematic underestimate of the impact of obesity on premature mortality. Although these biases preclude a valid assessment of optimal weight from existing data, available evidence suggests that minimum mortality occurs at relative weights at least 10% below the US average.
(JAMA 1987;257:353-358)
Lipid and lipoprotein values, including fasting triglycerides and high density lipoproteins (HDL), low density lipoproteins (LDL) and total cholesterol levels, were obtained on 2,815 men and women aged 49 to 82 years chiefly between 1969 and 1971 at Framingham. In the approximately four years following the characterization of lipids, coronary heart disease developed in 79 of the 1,025 men and 63 of the 1,445 women free of coronary heart diseases. At these older ages the major potent lipid risk factor was HDL cholesterol, which had an inverse association with the incidence of coronary heart disease (p less than 0.001) in either men or women. This lipid was associated with each major manifestation of coronary heart disease. These associations were equally significant even when other lipids and other standard risk factors for coronary heart disease were taken into consideration. A weaker association with the incidence of coronary heart disease (p less than 0.05) was observed for LDL cholesterol. Triglycerides were associated with the incidence of coronary heart disease only in women and then only when the level of other lipids was not taken into account. At these ages total cholesterol was not associated with the risk of coronary heart disease.
This report describes the status of the coronary arteries in nine patients (average age, 29 years) with juvenile onset diabetes mellitus (average age at onset, nine years), and compares the clinical and morphologic observations in them to those in nine control subjects (average age, 29 years). The nine patients with juvenile diabetes had significantly more extramural coronary luminal narrowing by atherosclerotic plaques than did the control subjects. The lumens of one or more of the four major epicardial coronary arteries were narrowed more than 75 per cent in cross-sectioned area in six of the diabetic patients and in none of the control subjects. This difference in degree of narrowing of the epicardial coronary arteries was even more striking when the per cent of narrowing of the entire lengths of the four major coronary arteries was examined: of the 191 cm of major coronary artery examined in the nine diabetic patients, the lumen in 90.5 cm (47 per cent) was narrowed more than 50 per cent in cross-sectioned area, whereas of 155 cm of coronary artery examined in the nine control subjects, the lumen of only 2 cm (1 per cent) was narrowed to this degree.Minor degrees of intimal fibrous proliferation, considered of no functional consequence, were observed in the intramural coronary arteries in the ventricles (excluding papillary muscle) in six of the nine diabetic patients but in none of the nine control subjects. Periodic acid-Schiff-positive material was more frequent and of greater intensity in the diabetic patients (all nine) than in the control subjects (four of nine).
To assess the effect of dietary reduction of plasma cholesterol concentrations on coronary atherosclerosis, we set up a randomised, controlled, end-point-blinded trial based on quantitative image analysis of coronary angiograms in patients with angina or past myocardial infarction. Another intervention group received diet and cholestyramine, to determine the effect of a greater reduction in circulating cholesterol concentrations. 90 men with coronary heart disease (CHD), who had a mean (SD) plasma cholesterol of 7.23 (0.77) mmol/l were randomised to receive usual care (U, controls), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 (SD 3.5) months. Mean plasma cholesterol during the trial period was 6.93 (U), 6.17 (D), and 5.56 (DC) mmol/l. The proportion of patients who showed overall progression of coronary narrowing was significantly reduced by both interventions (U 46%, D 15%, DC 12%), whereas the proportion who showed an increase in luminal diameter rose significantly (U 4%, D 38%, DC 33%). The mean absolute width of the coronary segments (MAWS) studied decreased by 0.201 mm in controls, increased by 0.003 mm in group D, and increased by 0.103 mm in group DC (p less than 0.05), with improvement also seen in the minimum width of segments, percentage diameter stenosis, and edge-irregularity index in intervention groups. The change in MAWS was independently and significantly correlated with LDL cholesterol concentration and LDL/HDL cholesterol ratio during the trial period. Both interventions significantly reduced the frequency of total cardiovascular events. Dietary change alone retarded overall progression and increased overall regression of coronary artery disease, and diet plus cholestyramine was additionally associated with a net increase in coronary lumen diameter. These findings support the use of a lipid-lowering diet, and if necessary of appropriate drug treatment, in men with CHD who have even mildly raised serum cholesterol concentrations.
Cardiac necropsy findings are described in a 72-year-old man with Tangier disease whose plasma total cholesterol levels averaged 70 mg/dL, low-density lipoprotein cholesterol level was 45 mg/dL, and high-density lipoprotein cholesterol level was 1.4 mg/dL, and who had coronary artery bypass grafting for severe atherosclerotic coronary artery disease. At necropsy, 24 of the 72 (33%) 5-mm segments of the 4 major (right, left main, left anterior descending, and left circumflex) native coronary arteries and 4 of the 27 (15%) 5-mm segments of the saphenous vein aortocoronary bypass conduits were narrowed by more than 75% in cross-sectional area by atherosclerotic plaques. The plaques were composed primarily (91% to 97%) of fibrous tissue. Oil red O staining, polarized light microscopy, and electron microscopy revealed cholesterol deposits in the plaques and in the walls of coronary arteries, saphenous vein grafts, and aorta. Such deposits also were found in foam cells of histiocytic origin, fibroblasts in all four cardiac valves, and in Schwann cells of cardiac nerves.
This study describes quantitatively the components of atherosclerotic plaques in saphenous vein grafts used for aortocoronary bypass and compares the findings with the plaques in the native coronary arteries in the same men. A total of 607 five-mm segments of saphenous veins and 797 five-mm segments of native coronary arteries were examined by computerized planimetric technique in 19 men, aged 39 to 82 years (mean 61), who had survived bypass operation for > 1 year. Comparison of the mean percentages of the plaque components in saphenous vein grafts in place for 14 to 26 months with those of the native coronary arteries revealed significant differences: cellular fibrous tissue, 86 vs 7%; dense fibrous tissue, 13 vs 82%; p < 0.05. As survival time after the bypass operation increased, composition of the plaques in the saphenous veins changed so that by approximately 80 months the amounts of cellular and dense fibrous tissue in both saphenous vein grafts and native coronary arteries were similar: 10 vs 16%, and 75 vs 71%; p = not significant. Thus, by about 7 years after a coronary bypass operation the composition of plaques in saphenous vein grafts is similar to that in the native coronary arteries of the same patients.
The composition of atherosclerotic plaques in 331 five-mm segments of the 4 major (left main, left anterior descending, left circumflex, and right) epicardial coronary arteries of 8 patients with juvenile (mean age at onset, 9 years; mean age at death, 29 years) diabetes mellitus was determined by computerized planimetric analysis. Analysis of all coronary segments disclosed that the plaques consisted primarily of dense (53%) and cellular (38%) fibrous tissue. Pultaceous debris (7%), foam cells (1.2%) and calcific deposits (0.7%) occupied a small percentage of the plaques. Thus, 91% of the coronary plaques in these young diabetic patients consisted of fibrous tissue and nearly all of the remaining 9% consisted of lipid deposits. Analysis of composition according to degrees of cross-sectional luminal narrowing revealed marked increases in dense fibrous tissue (from 31 to 74%), pultaceous debris (from 3 to 12%), and calcific deposits (from 0% to 3%) as the cross-sectional area narrowing increased from < or = 25% to > 75%. Compared with older patients with fatal coronary artery disease, the patients with juvenile diabetes had more dense fibrous tissue and pultaceous debris and less calcific deposits.
Significant regression of coronary and femoral atherosclerotic lesions has been documented by angiographic studies using aggressive lipid-lowering treatment. This study tested the applicability and effects of intensive physical exercise and low-fat diet on coronary morphology and myocardial perfusion in nonselected patients with stable angina pectoris.
Patients were recruited after routine coronary angiography for stable angina pectoris; they were randomized to an intervention group (n = 56) and a control group on "usual care" (n = 57). Treatment comprised intensive physical exercise in group training sessions (minimum, 2 hr/wk), daily home exercise periods (20 min/d), and low-fat, low-cholesterol diet (American Heart Association recommendation, phase 3). No lipid-lowering agents were prescribed. After 12 months of participation, repeat coronary angiography was performed; relative and minimal diameter reductions of coronary lesions were measured by digital image processing. Change in myocardial perfusion was assessed by 201Tl scintigraphy. In patients participating in the intervention group, body weight decreased by 5% (p less than 0.001), total cholesterol by 10% (p less than 0.001), and triglycerides by 24% (p less than 0.001); high density lipoproteins increased by 3% (p = NS). Physical work capacity improved by 23% (p less than 0.0001), and myocardial oxygen consumption, as estimated from maximal rate-pressure product, by 10% (p less than 0.05). Stress-induced myocardial ischemia decreased concurrently, indicating improvement of myocardial perfusion. Based on minimal lesion diameter, progression of coronary lesions was noted in nine patients (23%), no change in 18 patients (45%), and regression in 13 patients (32%). In the control group, metabolic and hemodynamic variables remained essentially unchanged, whereas progression of coronary lesions was noted in 25 patients (48%), no change in 18 patients (35%), and regression in nine patients (17%). These changes were significantly different from the intervention group (p less than 0.05).
In patients participating in regular physical exercise and low-fat diet, coronary artery disease progresses at a slower pace compared with a control group on usual care.
The frequency and type of acute lesions in the four major (right, left main, left anterior descending, left circumflex) epicardial coronary arteries were examined at necropsy in 14 patients with unstable angina pectoris, 21 patients with sudden coronary death and 32 patients with a fatal first acute myocardial infarction. None of the 67 patients had a grossly visible left ventricular scar (healed myocardial infarct) and only the group with acute myocardial infarction had left ventricular myocardial necrosis. Although the frequency of intraluminal thrombus was similar in patients with unstable angina (29%) and sudden death (29%) and significantly lower than in those with acute infarction (69%) (p = 0.02), the thrombus in the patients with unstable angina and sudden death consisted almost entirely of platelets and was nonocclusive, whereas the thrombus in the group with acute infarction consisted almost entirely of fibrin and was occlusive. The frequency of plaque rupture was insignificantly different in the groups with unstable angina (36%) and sudden death (19%), and was significantly lower than in the group with acute infarction (75%) (p = 0.02). The frequency of plaque hemorrhage was insignificantly different in the groups with unstable angina (64%) and sudden death (38%) and was significantly lower than in the group with acute infarction (90%) (p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)
In a prospective, randomised, controlled trial to determine whether comprehensive lifestyle changes affect coronary atherosclerosis after 1 year, 28 patients were assigned to an experimental group (low-fat vegetarian diet, stopping smoking, stress management training, and moderate exercise) and 20 to a usual-care control group. 195 coronary artery lesions were analysed by quantitative coronary angiography. The average percentage diameter stenosis regressed from 40.0 (SD 16.9)% to 37.8 (16.5)% in the experimental group yet progressed from 42.7 (15.5)% to 46.1 (18.5)% in the control group. When only lesions greater than 50% stenosed were analysed, the average percentage diameter stenosis regressed from 61.1 (8.8)% to 55.8 (11.0)% in the experimental group and progressed from 61.7 (9.5)% to 64.4 (16.3)% in the control group. Overall, 82% of experimental-group patients had an average change towards regression. Comprehensive lifestyle changes may be able to bring about regression of even severe coronary atherosclerosis after only 1 year, without use of lipid-lowering drugs.
In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P<.001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein—cholesterol level (24% to 40%), increased high-density lipoprotein—cholesterol level (6.6% to 9.5 %), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein—cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P<.001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia.
(Arch Intern Med. 1991;151:43-49)
Mode of death, frequency of a healed or an acute myocardial infarct, or both, number of major epicardial coronary arteries severely narrowed by atherosclerotic plaque, and heart weight were studied at necropsy in 889 patients 30 years of age or older with fatal atherosclerotic coronary artery disease. No patient had had a coronary bypass operation or coronary angioplasty. The 889 patients were classified into four major groups and each major group was classified into two subgroups: 1) acute myocardial infarct without (306 patients) or with (119 patients) a healed myocardial infarct; 2) sudden out of hospital death without (121 patients) or with (118 patients) a healed myocardial infarct; 3) chronic congestive heart failure with a healed myocardial infarct without (137 patients) or with (33 patients) a left ventricular aneurysm; and 4) sudden in-hospital death without (20 patients) or with (35 patients) unstable angina pectoris. The mean age of the 687 men (77%) was 60 +/- 11 years, and of the 202 women (23%), 68 +/- 13 years (p = 0.0001). Although men included 77% of all patients, they made up approximately 90% of the out of hospital (nonangina) sudden death group. The frequency of systemic hypertension and angina pectoris was similar in each of the four major groups. The frequency of diabetes mellitus was least in the sudden out of hospital death group and similar in the other three major groups. The mean heart weight and the percent of patients with a heart of increased weight were highest in the chronic congestive heart failure group; values were lower and similar in the other three major groups.(ABSTRACT TRUNCATED AT 250 WORDS)
The randomized, double-blind, placebo-controlled trial described in this report was undertaken to clarify the dose-response relation of lovastatin therapy to lipid-modifying efficacy (lipid/lipoprotein modification) and drug-related adverse events in a population with moderately elevated fasting plasma total cholesterol (240 to 300 mg/dl) and low-density lipoprotein cholesterol (greater than or equal to 160 mg/dl). Men or women (postmenopausal or surgically sterile), aged 18 to 70 years, were entered into the trial with minimal exclusion criteria. After 4 to 6 weeks of an American Heart Association phase I diet or a more stringent diet, 8,245 patients from 362 sites were randomized to 1 of 5 parallel diet and drug treatment groups: placebo (n = 1,663) or lovastatin, 20 mg (n = 1,642) and 40 mg (n = 1,645) with the evening meal, and 20 mg (n = 1,646) or 40 mg twice daily (n = 1,649). The regimen of diet and lovastatin (or placebo) was followed for 48 weeks. The 5 treatment groups were similar at baseline. The total cohort had the following characteristics: 59% were men (mean age 56 years); 92% were white; 59% had completed at least 1 year of education beyond high school; 57% had a history of cardiovascular and associated disease; 40% had a history of hypertension; and 29% had coronary artery disease. Health habits were similar among groups, with 18% of patients reporting cigarette smoking, 14% reporting that they consume greater than 1 alcoholic beverage daily and 67% reporting no strenous exercise. Mean lipid/lipoprotein levels were also similar among groups, with the following average levels: total cholesterol (258 mg/dl), low-density lipoprotein cholesterol (180 mg/dl), high-density lipoprotein cholesterol (45 mg/dl) and triglycerides (median = 155 mg/dl). The large size of this trial, its placebo-controlled, double-blind design and the similarity of treatment groups at baseline should allow clear documentation of the long-term effects of lovastatin treatment and generalization of the results to a substantial portion of patients who may be candidates for lipid-modifying therapy.
The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years.
When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71 +/- 0.91 vs. 6.14 +/- 0.89 mmol per liter [mean +/- SD]; P less than 0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68 +/- 0.78 vs. 4.30 +/- 0.89 mmol per liter; P less than 0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08 +/- 0.26 vs. 1.04 +/- 0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction greater than or equal to 50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined--death due to coronary heart disease and confirmed nonfatal myocardial infarction--was 35 percent lower in the surgery group (125 vs. 82 events; P less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P less than 0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction.
Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2 1/2-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated).
The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7 and +5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-32 and +43 percent). In the conventional-therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; P less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77).
In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.
The Cholesterol Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol-niacin therapy in 162 subjects. Two-year results (CLAS-I) showed decreased atherosclerosis progression and increased regression. We now describe a subgroup of 103 subjects treated for 4 years (CLAS-II). Changes in blood lipid, lipoprotein-cholesterol, and apolipoprotein levels were maintained, and at 4 years significantly more drug-treated subjects demonstrated nonprogression (52% drug- vs 15% placebo-treated) and regression (18% drug- vs 6% placebo-treated) in native coronary artery lesions. Significantly fewer drug-treated subjects developed new lesions in native coronary arteries (14% drug- vs 40% placebo-treated) and bypass grafts (16% drug- vs 38% placebo-treated). These results confirm CLAS-I findings and indicate that regression can continue for 4 years. They reaffirm the need for early initiation of vigorous long-term lipid lowering therapy in coronary bypass subjects.
A prominent article in the lay press in 1989 stressed that coronary artery disease was an “old person's disease.”1 Apparently many physicians also consider coronary artery disease to be an “old person's disease.” Recently, Roberts et al2 reported a large series of necropsy patients with fatal coronary artery disease. Using data from the earlier study, these investigators examined the age of death in men and in women with fatal coronary artery disease, the ages at death in the various types of fatal coronary events, and the ages at death in 3 different decades.
Coronary artery plaque morphology was studied in 354 five-mm segments of the 4 major (left main, left anterior descending, left circumflex and right) epicardial coronary arteries in 10 patients with isolated unstable angina pectoris with pain at rest. The 4 major coronary arteries were sectioned at 5-mm intervals and a drawing of each of the resulting 354 Movat-stained histologic sections was analyzed using a computerized morphometry system. The major component of plaque was a combination of dense acellular and cellular fibrous tissue with much smaller portions of plaque being composed of pultaceous debris, calcium, foam cells with and without inflammatory infiltrates and inflammatory infiltrates without foam cells. There were no differences in plaque composition among any of the 4 major epicardial coronary arteries. Plaque composition varied as a function of the degree of luminal narrowing. Linear increases were observed in the mean percent of dense fibrous tissue (from 5 to 50%), calcific deposits (from 1 to 10%), pultaceous debris (from 0 to 10%) and inflammatory infiltrates without significant numbers of foam cells (from 0 to 5%), and a linear decrease was observed in the mean percent of cellular fibrous tissue (from 94 to 22%) in sections narrowed up to 25% to more than 95% in cross-sectional area. Multiluminal channels were seen in all 10 patients (28 [19%] of the 146 sections narrowed greater than 75% in cross-sectional area and in 36 [10%] of all 354 segments); occlusive thrombi in no patient; nonocclusive thrombi in 2 patients (1 section each of 2 arteries); plaque rupture in 2 patients (4 segments from 2 arteries); and plaque hemorrhages in 6 patients (11 sections from 10 arteries).
We studied at necropsy atherosclerotic plaque composition in the four major (right, left main, left anterior descending, and left circumflex) epicardial coronary arteries in 15 patients who died of consequences of an acute myocardial infarction (AMI) and in 12 patients with sudden coronary death (SCD) without AMI. The coronary epicardial arteries were sectioned at 5-mm intervals, and a Movat-stained section of each segment of artery was prepared and analyzed using a computerized morphometry system. Within the AMI group and within the SCD group, there were no differences in plaque composition among any of the four major epicardial coronary arteries. Within both groups, plaque morphology varied as a function of cross-sectional-area narrowing of the segments. In both groups, the amount of dense relatively acellular fibrous tissue, calcified tissue, and pultaceous debris (amorphous debris containing cholesterol clefts, presumably rich in extracellular lipid) increased in a linear fashion with increasing degrees of cross-sectional-area narrowing of the segments, and the amount of cellular fibrous tissue decreased linearly. In the AMI group, the percentage of plaque consisting of pultaceous debris and of cellular fibrous tissue separated significantly narrowed (greater than 75% cross-sectional area) segments from less narrowed (less than 75%) segments. A comparison of the AMI group to the SCD group showed significant differences. The percentage of plaque consisting of pultaceous debris (16% in the AMI group and 7% in the SCD group), of cellular fibrous tissue (11% vs. 18%), and of heavily calcified tissue (8% vs. 16%) were significantly different in the severely narrowed segments in the AMI and SCD groups. When all arteries containing thrombi were deleted from the analysis, there were no significant changes in the results. Occlusive coronary thrombi were present in 13 of the 15 AMI patients and in one of the 12 SCD patients. Thus, the frequency of coronary thrombi and plaque composition differ in patients with AMI and in those with SCD without AMI.
The amounts of narrowing of the 4 major (left main, left anterior descending, left circumflex and right) epicardial coronary arteries by atherosclerotic plaques were compared in 4 subsets of coronary patients. Of the 129 patients studied at necropsy, an average of 2.7 of the 4 arteries was narrowed greater than 75% in cross-sectional area at some point (0.7/4 in controls), and the group with unstable angina pectoris (3.2/4) had more narrowing than did the groups with sudden coronary death (2.8/4), acute myocardial infarction (2.7/4) and healed myocardial infarction (2.3/4). Each of the 4 major epicardial coronary arteries was divided into 5-mm long segments and a histologic section was prepared and stained by the Movat method of each of the 6,461 segments in the 129 patients and in the 1,849 segments in the 40 control subjects. In the 129 patients, 35% of the 5-mm segments were narrowed 75 to 100% in cross-sectional area (3% in controls) and the group with unstable angina had the highest percent (48%) of segments severely narrowed compared to the groups with sudden coronary death (36%), acute myocardial infarction (34%) and healed myocardial infarction (31%). Thus, of the 4 subsets of patients with fatal coronary artery disease studied at necropsy, those with unstable angina pectoris had the most severe and extensive coronary atherosclerosis.
The Expert Panel of the National Cholesterol Education Program has identified 10 risk factors for the occurrence of an atherosclerotic event. Each of these factors does not represent an independent risk. Male sex, family history of premature coronary events, cigarette smoking (> 10/day), systemic hypertension, diabetes mellitus and severe obesity (>30% overweight) should be viewed as cholesterol-dependent atherosclerotic risk factors and not in themselves as atherogenic. There is no doubt that atherosclerotic events are more common in people with these risk factors, but only in those populations with an average serum total cholesterol level above 3.9 mmol/l. Those most prone to having an atherosclerotic event are those who have already had such an event or who have pre-existing coronary heart disease. However, by including these as risk factors, no distinction is made between primary and secondary prevention. Atherosclerotic events of any kind, though predictive of future events are not, by definition, true risk factors and should not be viewed as such. The only absolute, unequivocal, independent atherosclerotic risk factor is an elevated serum total or, more specifically, low density lipoprotein (LDL)-cholesterol level. Whether a low level of high density lipoprotein cholesterol is an independent risk factor is not clear, but it should probably be regarded as an additive risk when the serum LDL-cholesterol is elevated.
The clinical frequencies of systemic hypertension and necropsy evidence of cardiomegaly in various cardiovascular conditions are summarized. Systemic hypertension is present in greater than 50% of patients with various coronary events, in greater than 75% of patients with various cerebrovascular events and in greater than 90% of patients with aortic dissection. Hypertension is the sole underlying factor in most patients with nontraumatic cerebral arterial or aortic (dissection = partial rupture) rupture. In association with hypercholesterolemia (serum total cholesterol levels greater than 150 mg/dl), hypertension clearly accelerates atherosclerosis and its devastating consequences.