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Acute myocarditis is an acute inflammatory syndrome characterized by acute myocardial damage and dysfunction followed by a variable recovery over time with some patients progressing toward severe dilated cardiomyopathy. Cardiomyocyte apoptosis, a key pathologic feature of heart failure, may play a critical role in functional recovery in patients with acute myocarditis. The aim of the study was to investigate whether apoptosis predicts functional recovery in patients with acute myocarditis. Sixteen patients with biopsy-documented acute myocarditis were followed for 1 year with serial transthoracic echocardiography. Functional recovery was defined as 12-month left ventricular ejection fraction >40%. Cardiomyocyte apoptosis, leukocyte infiltration, and cell proliferation was assessed in all samples. A group of cases in which the diagnosis of acute myocarditis was made after death was also selected for comparison, and morphologically normal hearts from patients who died from a noncardiac cause were selected as controls. Six patients (38%) had functional recovery at 12 months, whereas 10 (62%) did not. The 2 groups had similar characteristics except for lower baseline left ventricular ejection fraction in the group with functional recovery. Apoptotic rate was found to be significantly higher in patients with acute myocarditis than in control hearts, and, unexpectedly, patients with functional recovery had significantly higher apoptotic rates than patients without recovery (3.2% vs 0.5%, p = 0.001). None of the patients with apoptotic rates below the median had functional recovery versus 86% of patients with apoptotic rates above the median (p <0.001). In conclusion, higher rates of cardiomyocyte apoptosis in patients with acute myocarditis are associated with functional recovery at 1 year.

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = -0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent.

Background: Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction., Methods and Results: Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1+/-0.2% versus 0.5+/-0.3% [P<0.001] and 4.2+/-0.4% versus 1.1+/-0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities., Conclusions: Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

In the natural history of pressure overload, the hypertrophy response of the left ventricle initially normalizes wall stress and allows preservation of a normal ejection fraction. Nevertheless, patients progress gradually or suddenly from compensated hypertrophy to ventricular dilation with heart failure. Long-standing hypertrophy entails a maladaptive response, which is due to derangements inherent in the myocardium rather than to a progressive increase in the cause of pressure overload. Despite this condition being linked to major clinical consequences and an unfavourable prognosis, the cellular and molecular mechanisms in pressure-overload cardiomyopathy have not yet been established. This review discusses the available experimental and clinical evidence with respect to the role played by myocardial apoptosis in pressure-overload cardiomyopathy.

Heart failure is a complex syndrome characterized by impaired emptying and/or impaired filling of the heart chambers. The use of parameters of diastolic function has provided novel tools for risk stratification and management of patients with heart failure. This study evaluated the potential correlation between apoptosis at time of death and left ventricular (LV) diastolic function after acute myocardial infarction. We selected, at routine postmortem examination, 14 subjects who died 10 to 62 days after an acute myocardial infarction and had an available echocardiographic report from the most recent hospital admission. The apoptotic rate was calculated at the region bordering the infarct, using co-localization of in situ end-labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3. Transthoracic echocardiographic studies were retrospectively reevaluated and pulse-wave Doppler spectra of mitral inflow were analyzed. LV diastolic function was assessed by measuring the ratio of E peak velocity to A peak velocity and E-wave deceleration time; a ratio of E peak velocity to A peak velocity >or=2 and deceleration time <115 ms were considered a restrictive filling pattern. A restrictive pattern was found in 4 cases (29%). All subjects with a restrictive pattern were symptomatic for New York Heart Association class IV heart failure (100% vs 20%, p = 0.015) and had larger transverse heart diameters at pathology (p = 0.014). The apoptotic rate in the peri-infarct region was significantly higher in patients with a restrictive versus nonrestrictive diastolic pattern (13%, 10 to 14, vs 3%, 1 to 6, p = 0.014). At multivariable analysis that included the restrictive pattern, class IV heart failure, and cardiac diameters, the restrictive pattern remained an independent predictor of increased apoptosis (p = 0.030). In conclusion, patients with severe postinfarction LV diastolic dysfunction had significantly higher rates of cardiomyocyte loss by apoptosis, which may partly explain their unfavorable outcome.

Background: Apoptosis plays a major role in the transition to heart failure (HF) in systemic hypertension although the underlying mechanisms are still unclear. The aim of this study was to determine the relationship between apoptosis, left ventricular remodeling, heart failure and the myocyte expression of survivin, an inhibitor of apoptosis., Methods: Spontaneously hypertensive rats (SHR) were used as a model of hypertensive cardiopathy, and Wistar Kyoto Stars rats (WKY) were used as controls. Animals were allowed to survive up to 18 months of age. The animals underwent echocardiography (EDD, ESD and FS were measured). The median section of the heart was processed for in situ end-labeling of DNA fragmentation (TUNEL) and for survivin expression by immunohistochemistry., Results: All SHR presented features of adverse cardiac remodeling. Apoptotic cells were increased in SHR compared with WKY, measured as apoptotic cells per high power field (1.08+/-0.43 vs. 0.27+/-0.15, P<0.001), and as apoptotic rate (0.16+/-0.06% vs. 0.04+/-0.02%, P<0.001). The incidence of apoptosis showed a positive correlation with unfavorable ventricular remodeling, assessed by echocardiogram. Survivin expression was found in all cases, but the survivin expression index was significantly lower in SHR vs. WKY (43+/-40% vs. 86+/-18%, respectively, P=0.014). Moreover the survivin expression index was inversely correlated with features of adverse remodeling (i.e., Heart Weight, R=-0.79, P<0.001) and with apoptosis (i.e., apoptotic rate, R=-0.52, P=0.050)., Conclusion: Survivin myocardial expression in aging SHR is associated with reduced apoptosis and more favorable cardiac remodeling. Modulation of this pathway may prove beneficial in preventing pressure overload cardiac remodeling and heart failure.

Apoptosis is a key pathologic feature in acute myocardial infarction and heart failure. Experimental animal studies have shown beneficial effects of inhibiting apoptosis. Understanding the mechanisms involved in the apoptotic cascade may be useful in better understanding of heart failure and its management. Not only in vivo detection of apoptosis may prove clinically useful in the diagnosis and risk stratification of patients with ischemic heart disease, but anti-apoptotic treatments (specific and non-specific) may be effective in the prevention and treatment of post-infarction remodelling and heart failure.

Aims: Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium., Methods and Results: In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P=0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P<0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P=0.42], Conclusion: Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences.

The open-artery hypothesis states that myocardial reperfusion, even if late for myocardial salvage, provides benefits and prevents adverse cardiac remodeling. While observational data in humans regarding the deleterious impact of a permanent infarct-related artery occlusion and the benefits of spontaneous reperfusion are quite consistent, the reports regarding late revascularization are inconclusive in order to prove such a hypothesis. The observational studies tend to have selection biases, while randomized trials to date are too small to be conclusive. Moreover, the pathophysiological mechanisms underlying presumed benefits of reperfusion are still unclear. However, although the open-artery hypothesis remains unproven, the current evidence suggesting benefits calls for additional studies. Limitations of ischemic left ventricular dilatation and myopathy could markedly reduce cardiovascular morbidity and mortality after acute myocardial infarction. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian target of rapamycin (mTOR) signaling and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Recently, the antigrowth properties of rapamycin have been utilized for cardiovascular benefit as stents impregnated with rapamycin effectively reduce coronary restenosis. We report here a novel role of this drug in protection against ischemia/reperfusion (I/R) injury. Adult male ICR mice were treated with rapamycin (0.25 mg/kg, IP) or volume-matched DMSO (solvent for rapamycin). The hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. The blocker of mitochondrial KATP channel, 5-hydroxydecanoate (5-HD, 100 μM) was given 10 min before ischemia. Infarct size in the DMSO treated group was 28.2 ± 1.3% and was reduced to 10.1 ± 2.8% in the rapamycin-treated mice (64% decrease, P <0.001). 5-HD blocked the protective effect (infarct area 32.2 ± 1.8%, P <0.001 vs. rapamycin). The infarct limiting effect of rapamycin was not associated with improved recovery of ventricular function. We further examined the effect of rapamycin in protection against necrosis and apoptosis in adult cardiomyocytes subjected to simulated ischemia and reoxygenation. Myocytes treated with rapamycin in doses from 25–100 nM demonstrated significantly lower trypan blue-positive necrotic cells and TUNEL-positive apoptotic nuclei, supporting the protective role of drug in the intact heart. These data suggest that rapamycin induces potent preconditioning-like effect against myocardial infarction through opening of mitochondrial KATP channels. We propose that rapamycin may be a novel therapeutic strategy to limit infarction, apoptosis, and remodeling following I/R injury in the heart. [Copyright &y& Elsevier]