Constantine E Kosmas

Vanderbilt University, Nashville, Michigan, United States

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Publications (10)5.07 Total impact

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    ABSTRACT: : The role of high-density lipoprotein (HDL) in cardiovascular atheroprotection is well established. Epidemiological data have clearly demonstrated an inverse relationship between HDL levels and the risk for coronary artery disease, which is independent of the low-density lipoprotein levels. However, more recent data provide evidence that high HDL levels are not always protective and that under certain conditions may even confer an increased risk. Thus, a new concept has arisen, which stresses the importance of HDL functionality, rather than HDL concentration per se, in the assessment of cardiovascular risk. HDL functionality is genetically defined but can also be modified by several environmental and lifestyle factors, such as diet, smoking or certain pharmacologic interventions. Furthermore, HDL is consisted of a heterogeneous group of particles with major differences in their structural, biological and functional properties. Recently, the cholesterol efflux capacity from macrophages was proven to be an excellent metric of HDL functionality, because it was shown to have a strong inverse relationship with the risk of angiographically documented coronary artery disease, independent of the HDL and apolipoprotein A-1 levels, although it may not actually predict the prospective risk for cardiovascular events. Thus, improving the quality of HDL may represent a better therapeutic target than simply raising the HDL level, and assessment of HDL function may prove informative in refining our understanding of HDL-mediated atheroprotection.
    The American Journal of the Medical Sciences 03/2014; · 1.33 Impact Factor
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    ABSTRACT: Coronary artery disease (CAD) is the leading cause of death in the United States. Although CAD was formerly considered a lipid accumulation-mediated disease, it has now been clearly shown to involve an ongoing inflammatory response. Advances in basic science research have established the crucial role of inflammation in mediating all stages of CAD. Today, there is convincing evidence that multiple inter-related immune mechanisms interact with metabolic risk factors to initiate, promote and ultimately activate lesions in the coronary arteries. This review aims to provide current evidence pertaining to the role of inflammation in the pathogenesis of CAD and discusses the impact of inflammatory markers and their modification on clinical outcomes.
    Cardiology in review 01/2014;
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    ABSTRACT: The two most relevant clinical trials investigating the efficacy of multiple neurohormonal drug combinations in the treatment of chronic congestive heart failure (CHF) are the Valsartan Heart Failure Trial (Val-HeFT) and the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-added) studies. The Val-HeFT study randomized patients with CHF to the angiotensin-receptor blocker (ARB) valsartan versus placebo, in addition to baseline angiotensin-converting-enzyme inhibitor (ACE-I) therapy. Overall, valsartan was found to significantly reduce the combined morbidity and mortality end point compared to placebo, mainly due to a reduction in heart failure admissions. However, a subgroup analysis showed that patients receiving triple therapy with valsartan, an ACE-I and a β-adrenoceptor blocker appeared to do worse. These findings led to speculation that "triple therapy" with ARB, ACE-I and nonselective β-blocker might be harmful, possibly due to excessive neurohormonal inhibition. In contrast, in the CHARM-added study, the "triple therapy" combination of ARB, ACE-I and β-adrenoceptor blocker was proven safe and beneficial. We propose that the discrepancy in outcomes observed in these two trials is related to the interaction between the α1-adrenoceptor (α1R) and the angiotensin II type-1 receptor (AT1R) and it is not just an inherent adverse event related to "triple therapy".
    Cardiology in review 05/2013;
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    ABSTRACT: : Coronary heart disease (CHD) is one of the leading causes of death in the United States. Traditional risk factors such as family history, hypertension, hypercholesterolemia, diabetes mellitus and smoking cannot account for the entire risk for incident coronary events. Several other potential risk factors have been identified in an effort to improve risk assessment for CHD. This article reviews the current evidence on new and emerging risk factors for CHD and their current utility in screening, specifically focusing on coronary artery calcium score, C-reactive protein, lipoprotein (a), carotid intima-media thickness, homocysteine, lipoprotein-associated phospholipase A2, as well as high-density lipoprotein functionality.
    The American Journal of the Medical Sciences 05/2013; · 1.33 Impact Factor
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    ABSTRACT: Many theories and clinical trials have attempted to address the effect of low-density lipoprotein (LDL) lowering in chronic congestive heart failure (CHF). The current evidence suggests that there is no convincing reason for administering statins to patients with nonischemic heart failure. Although they do not reduce the mortality rate, statins reduce LDL cholesterol and may provide some benefit to patients with ischemic heart failure. In contrast, some authors believe that statin therapy may actually worsen outcomes in patients with CHF, especially if there is excessive reduction in LDL cholesterol. This review discusses the theories attempting to link the adverse effects of statin-mediated LDL lowering in CHF to increased levels of endotoxin or reduced levels of coenzyme Q10. In addition, the 2 largest randomized, double-blind, placebo-controlled clinical trials (CORONA and GISSI-HF) were discussed. It is clear that more trials are needed to definitely ascertain the effect of statins on CHF.
    The American Journal of the Medical Sciences 11/2012; · 1.33 Impact Factor
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    ABSTRACT: Statins do not appear to have a significant benefit in heart failure (HF) as they do in coronary artery disease (CAD). Significant evidence exists that low serum cholesterol levels may be harmful in HF. This study sought to determine the optimal low-density lipoprotein (LDL) level in patients hospitalized with acute HF. Patients were included if they presented to the hospital with acute HF and had a lipid panel drawn during admission. The primary outcome was all-cause mortality, and secondary outcomes were rates of major cardiovascular (CV) events, left ventricular assist device (LVAD) implantation, and orthotopic heart transplantation (OHT). A total of 2428 patients were followed for a mean of 2.9±2.2 years. For the entire cohort, when compared with those with LDL levels >130 mg/dL, all-cause mortality was higher in those with LDL levels <71 mg/dL (hazard ratio, 1.68; 95% confidence interval, 1.31-2.167; P<.01). Results were similar when analyzing patients with LVEF ≤40%, HF of ischemic etiology only, and in statin users. The rates of CV events, LVAD implantation, or OHT in any comparison did not differ. Low LDL levels (<71 mg/dL), similar to low total cholesterol levels, were associated with a poorer prognosis and higher overall mortality in patients with HF, regardless of etiology and systolic function.
    Congestive Heart Failure 10/2012;
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    ABSTRACT: Paradigms are a part of our human nature. In the world of medicine and science, they allow investigators to work within a particular, previously accepted framework that provides certain constraints. This is the crux of Newton's quote, "If I've seen so far it's because I stood upon the shoulders of giants." However, in the same way that it allows us to build, it can constrain our thought processes if we fail to accept new data that are ill suited to an accepted paradigm. The physiological mechanisms to explain the phenomenon of chronic congestive heart failure (CHF) are similar to other paradigms of science, in that they have undergone several shifts throughout their history, and continue to change with new evidence. Here, we seek to explore how our understanding of CHF has changed.
    Cardiology in review 10/2012;
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    ABSTRACT: This study sought to evaluate the short-, intermediate-, and longer-term outcomes after endovascular versus open repair of abdominal aortic aneurysms (AAA), including both AAA-related and all-cause mortality. Endovascular stent graft placement for AAA has gained broad acceptance as an alternative to open surgical repair due to a lower perioperative morbidity and mortality. The intermediate- and long-term all-cause and aneurysm-related mortality vary among studies. Thus, we sought to perform a meta-analysis of open versus endovascular repair for treating AAA. Electronic databases were queried for identification of prospective, randomized trials of open surgery versus endovascular stent graft repair of AAA. A total of 10 published papers reporting on 6 studies at different follow-up intervals were identified; they involved 2,899 patients with AAA repair procedures, of whom, 1,470 underwent endovascular stent graft AAA exclusion and 1,429 were treated by open AAA repair. At 30 days, the pooled relative risk of all-cause mortality was lower in the endovascular group (relative risk [RR]: 0.35, 95% confidence interval [CI]: 0.19 to 0.64) than in the open surgery group. At intermediate follow-up, the all-cause mortality had a nonsignificant difference (RR: 0.78, 95% CI: 0.57 to 1.08), the AAA-related mortality was significantly lower (RR: 0.46, 95% CI: 0.28 to 0.74) and reintervention rates were higher (RR: 1.48, 95% CI: 1.06 to 2.08) in the endovascular group than in the open surgery group. At long-term follow-up, there was no significant difference in all-cause mortality (RR: 0.99, 95% CI: 0.85 to 1.15) or AAA-related mortality (RR: 1.58, 95% CI: 0.20 to 12.74), whereas the significant difference in the rate of reinterventions persisted (RR: 2.54, 95% CI: 1.58 to 4.08). In patients randomized to open or endovascular AAA repair, all-cause perioperative mortality, as well as AAA-related mortality at short- and intermediate-term follow-up are lower in patients undergoing endovascular stent graft placement. This was associated with greater reintervention in the endovascular group noted at intermediate follow-up. Long-term survival appears to converge between the 2 groups.
    JACC. Cardiovascular Interventions 10/2012; 5(10):1071-80. · 1.07 Impact Factor
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    ABSTRACT: The renin-angiotensin-aldosterone system (RAAS) has evolved in humans as one of the main physiological networks by which blood pressure and blood flow to vital organs is maintained. The RAAS has evolved to circumvent life-threatening events such as hemorrhage and starvation. Although short-term activation of this system had been well suited to counteract such catastrophes of early man, excessive chronic activation of the RAAS plays a fundamental role in the development and progression of cardiovascular disease in modern man. The RAAS is an intricate network comprising a number of major organ systems (heart, kidney, and vasculature) and signaling pathways. The main protagonists are renin, angiotensinogen (Ang), angiotensin I (Ang I), angiotensin II (Ang II), and aldosterone (Aldo). The study and delineation of each of these substances has allowed modern medicine to create targets by which cardiovascular disease can be treated. The main modulators that have been synthesized in this respect are angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor blockers (MRBs), and direct renin inhibitors (DRIs). Over the past few decades, each of these substances has proven efficacious to varying degrees amongst a number of clinical settings. Additionally, there exists data for and against the use of these agents in combination. The use of these agents in combination poses a larger question conceptually: can excessive pharmacological inhibition of the RAAS lead to patient harm? This perspective will examine the concept of a neurohormonal inhibition ceiling in pertinent experimental and clinical trials.
    Current Heart Failure Reports 04/2012; 9(2):81-91.
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    ABSTRACT: Diastolic dysfunction refers to abnormal diastolic filling properties of the left ventricle regardless of whether systolic function is normal or the patient has symptoms. Diastolic heart failure (HF), or more accurately, HF with preserved systolic function, is a distinct clinical entity characterized by the presence of the triad of impaired diastolic function, normal systolic function (left ventricular ejection fraction > 50%), and symptoms of HF. Patients with HF with preserved systolic function are frequently symptomatic from both acute and chronic elevations in left ventricular end-diastolic pressure and/or left atrial pressure.
    Cardiology in review 03/2012; 20(5):230-6.