Elisa Merli

Tumor Necrosis Factor-α Receptor 1 Is a Major Predictor of Mortality and New-Onset Heart Failure in Patients With Acute Myocardial Infarction The Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) Study

Background—Tumor necrosis factor alpha-&agr; (TNF-&agr;) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. Methods and Results—We performed a systematic evaluation of TNF-&agr; and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64±12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-&agr; and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65±6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. Conclusions—sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction.

Therapeutic Effects of l-Carnitine and Propionyl-l-carnitine on Cardiovascular Diseases: A Review

Abstract: Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl‐CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high‐energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti‐ischemic properties. In small short‐term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end‐diastolic pressure. These short‐term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long‐chain acyl‐CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative‐induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long‐chain acyl‐CoA; and (4) reducing the ischemia‐induced apoptosis and the consequent remodeling of the left ventricle. Propionyl‐l‐carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl‐l‐carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase‐2 studies in chronic heart failure patients showed that long‐term oral treatment with propionyl‐l‐carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl‐l‐carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl‐l‐carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.

Serum From Patients With Acute Coronary Syndromes Displays a Proapoptotic Effect on Human Endothelial Cells: A Possible Link to Pan-Coronary Syndromes

Background—Endothelial apoptosis of atherosclerotic lesions is a possible determinant for the stable-to-vulnerable plaque transition. Recent data support the notion that plaque activation may be a pan-coronary process, advocating the existence of circulating triggers. Methods and Results—Serum from 40 healthy subjects (group 1) and 73 patients with stable angina (n=32; group 2) or acute coronary syndromes (n=41; group 3) was incubated with human umbilical vein endothelial cells. The percentage of apoptosis by flow cytometry and Fas, Bax, and Bcl-2 protein expression by immunoblotting were evaluated at entry in patients and control subjects and repeated after 12 months in group 3. At baseline, apoptotic nuclei were higher in group 3 (14±6%) than in group 2 (3.3±1.8%) and group 1 (1.35±0.8%) (P <0.001). Fas and Bcl-2 were increased in group 3 with respect to groups 1 and 2 (P <0.01). Coincubation of group 3 serum with anti–tumor necrosis factor-&agr; and anti–interleukin-6 monoclonal antibodies did not affect the human umbilical vein endothelial cell apoptotic process, whereas addition of Trolox decreased apoptosis to <50%. The percentage of apoptosis in group 3 significantly correlated to the numbers of coronary complex lesions at angiography (r =0.58, P <0.0005). In group 3, apoptosis and the Bax/Bcl-2 ratio decreased at 1 year (P <0.0001, P <0.05 respectively). Conclusions—Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells, supporting the theory of the existence of circulating triggers potentially able to activate atherosclerotic lesions.

Abnormalities of Left Ventricular Function in Asymptomatic Patients with Systemic Sclerosis Using Doppler Measures of Myocardial Strain

OBJECTIVE To verify whether myocardial impairment can be detected by tissue Doppler imaging (TDI) in patients with asymptomatic systemic sclerosis (SSc), 35 patients with SSc with normal left ventricular (LV) ejection fraction and 35 control subjects were studied. METHODS Myocardial longitudinal peak systolic velocity, strain, and strain rate (SR) were measured by TDI at a regional level, and for each parameter the average value was calculated using an LV 12-segment model. In addition, the mitral annulus diastolic velocities and the E/Ea ratio were obtained. Myocardial calibrated integrated backscatter (cIB) was used as an index of fibrosis. RESULTS Compared with controls, patients with SSc showed lower peak strain (-19.5% +/- 2.3% vs -26.1% +/- 2.4%, P < .001), peak SR (-1.34 +/- 0.14 s(-1) vs -1.59 +/- 0.14 s(-1), P < .001), septal cIB (-19.5 +/- 3.1 dB vs -23.8 +/- 1.6 dB, P < .001), and posterior wall cIB (-23.4 +/- 2.9 dB vs -28.6 +/- 2.5 dB, P = .001), and higher E/Ea (11.7 +/- 2.5 vs 9.8 +/- 1.1, P < .001), whereas peak systolic velocities did not differ. Strain, SR, and E/Ea correlated better with cIB than systolic velocities. CONCLUSION TDI-derived strain, SR, and E/Ea can detect impairment of LV myocardial function in asymptomatic patients with SSc with normal LV ejection fraction better than TDI systolic velocities.

Metabolic modulation and optimization of energy consumption in heart failure

Chronic heart failure (CHF) is a common and disabling syndrome with a poor prognosis. It is a major and increasing public health problem. Angiotensin-converting enzyme inhibitors, diuretics, and digitalis are the standards treatments for CHF. Other drugs, such as beta-blockers, spironolactone, calcium antagonists, vasodilators, and antiarrhythmic agents are used to counteract the progression of the syndrome or to improve the hemodynamic profile. Despite optimum treatment with neurohumoral antagonists, prognosis of CHF remains poor; the patients complain of persistent reductions in their exercise capacity and quality of life. Fatigue and shortness of breath, two common and disabling symptoms in patient with CHF, are relatively independent from hemodynamic and neuroendocrine changes, although they seem to be related to the impairment of peripheral muscle metabolism and energetic phosphate production. Therefore, CHF is a complex metabolic syndrome in which the metabolism of cardiac and peripheral muscles is impaired and novel therapeutic strategies have been aimed at positive modulation with compounds such as carnitine, trimetazidine, and ranolazine.

Neurohormones, cytokines and programmed cell death in heart failure: A new paradigm for the remodeling heart

Marco Valgimigli1, Salvatore Curello2, Claudio Ceconi2, Laura Agnoletti3, Laura Comini3, Tiziana Bachetti3, Elisa Merli1, and Roberto Ferrari1,3 1Chair of Cardiology, University of Ferrara, Cardiology and Intensive Cardiology Care Unit, S. Anna Hospital, Italy; 2Chair of Cardiology, University of Brescia, Spedali Civili Hospital, Italy; 3Cardiovascular Physiopatholgy Research Center, Salvatori Maugeri Foundation, Gussago (BS), Italy