Post-ischemic Heart Failure Research Articles

A Randomized Clinical Trial of Trimetazidine, a Partial Free Fatty Acid Oxidation Inhibitor, in Patients With Heart Failure

This study sought to assess whether the long-term addition of trimetazidine to conventional treatment could improve functional class, exercise tolerance, and left ventricular function in patients with heart failure (HF). Previous small studies have shown that trimetazidine may be beneficial in terms of left ventricular function preservation and control of symptoms in patients with post-ischemic HF. Fifty-five patients with HF were randomly allocated in an open-label fashion to either conventional therapy plus trimetazidine (20 mg three times daily) (28 patients) or conventional therapy alone (27 patients). Mean follow-up was 13 +/- 3 months. At study entry and at follow-up, all patients underwent exercise testing and two-dimensional echocardiography. Among the others, New York Heart Association (NYHA) functional class and ejection fraction (EF) were evaluated. In the trimetazidine group, NYHA functional class significantly improved compared with the conventional therapy group (p < 0.0001). Treatment with trimetazidine significantly decreased left ventricular end-systolic volume (from 98 +/- 36 ml to 81 +/- 27 ml, p = 0.04) and increased EF from 36 +/- 7% to 43 +/- 10% (p = 0.002). On the contrary, in the conventional therapy group, both left ventricular end-diastolic and -systolic volumes increased from 142 +/- 43 ml to 156 +/- 63 ml, p = 0.2, and from 86 +/- 34 ml to 104 +/- 52 ml, p = 0.1, respectively; accordingly, EF significantly decreased from 38 +/- 7% to 34 +/- 7% (p = 0.02). In conclusion, long-term trimetazidine improves functional class and left ventricular function in patients with HF. This benefit contrasts with the natural history of the disease, as shown by the decrease of EF in patients on standard HF therapy alone.

Regional and Global Protective Effects of Tissue Kallikrein Gene Delivery to the Peri-Infarct Myocardium

The kallikrein-kinin system participates in the maintenance of the cardiovascular phenotype. We previously demonstrated that human tissue kallikrein gene (hTK) transfer promotes the healing of ischemic limbs. The present investigation aimed to test the original hypothesis that hTK delivery to the peri-infarct myocardium would prevent post-ischemic heart failure. Myocardial infarction (MI) was induced in anesthetized mice by permanently occluding the left coronary descendant. hTK was delivered to the peri-infarct myocardium via an adenoviral vector (Ad.hTK). Controls received Ad.Null or saline. Survival rate was similar among groups. Ad.hTK increased the number of circulating endothelial progenitor cells and promoted the growth of capillaries and arterioles in the peri-infarct myocardium. In addition, Ad.hTK increased the abundance of cardiac progenitor cells (CPCs) in the peri-infarct and suppressed the apoptotic death of peri-infarct cardiomyocytes in vivo and ex vivo. As a consequence of these beneficial effects, at 5 weeks from MI, hTK-transduced hearts were protected from post-MI ventricular dilatation and showed better systolic and diastolic functions. Ad.hTK benefits the neovascularization and viability of peri-infarct myocardium and increases CPC abundance, thereby decreasing ventricular dysfunction. Our study significantly adds to the knowledge of the protective effects of TK gene transfer on ischemic diseases and opens new avenues for the treatment of post-MI cardiac failure.

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Spironolactone improves carotid artery fibrosis and distensibility in rat post-ischaemic heart failure

Myocardial infarction causes neurohormonal activation involving aldosterone and angiotensin II (AngII). These hormones may increase arterial stiffness, an independent cardiovascular risk factor contributing to progression of congestive heart failure (CHF). This study aimed to determine the effect of aldosterone and AngII blockade on carotid artery distensibility and collagen density in adult Wistar rats with MI-induced CHF. Five groups were studied: Sham-operated, CHF, CHF + spironolactone, CHF + lisinopril, CHF + Spironolactone + Lisinopril. After echocardiography, in vitro isobaric carotid distensibility (echo-tracking technique) and collagen density were measured, and the incremental elastic modulus (Einc) calculated. In the CHF group, intra-ventricular pressure and cardiac weight were increased; carotid distensibility was reduced (CHF: 0.42 ± 0.30 per mmHg 3 versus sham: 1.75 ± 0.50 per mmHg 3; P < 0.001), and collagen content increased by 87% when compared to sham. All treatments reduced intra-ventricular pressure, carotid distensibility and fibrosis when compared to CHF but did not change cardiac weight. However, carotid distensibility and intra-ventricular pressure were not completely restored towards sham values and were significantly and inversely related. Spironolactone, which did not decrease significantly blood pressure, was the only drug reducing Einc independently of wall stress (WS). Thus, MI-induced CHF was associated with carotid artery remodeling. This vascular change, which may contribute to maintain cardiac hypertrophy and CHF, is largely prevented by AngII and aldosterone blockade. Only spironolactone reduced the stiffness of carotid wall material independently of blood pressure and WS.

Induction of Angiogenesis and Inhibition of Apoptosis by Hepatocyte Growth Factor Effectively Treats Postischemic Heart Failure

Heart failure following myocardial infarction (MI) is a significant cause of morbidity and mortality and remains a difficult therapeutic challenge. Hepatocyte growth factor (HGF) is a potent angiogenic and anti-apoptotic protein whose receptor is upregulated following MI. This study was designed to investigate the ability of HGF to prevent heart failure in a rat model of experimental MI. The rats underwent direct intramyocardial injection with replication-deficient adenovirus encoding HGF (n = 7) or null virus as control (n = 7) 3 weeks following ligation of the left anterior descending coronary artery. Analysis of the following was performed 3 weeks after injection: cardiac function by pressure-volume conductance catheter measurements; LV wall thickness; angiogenesis by Von Willebrand's factor staining; and apoptosis by the TUNEL assay. The expression levels of HGF and the anti-apoptotic factor Bcl-2 were analyzed by Western blot. Adeno-HGF-treated animals had greater preservation of maximum LV pressure (HGF 77 +/- 3 vs. control 64 +/- 5 mmHg, p < 0.05), maximum dP/dt (3024 +/- 266 vs. 1907 +/- 360 mmHg/sec, p < 0.05), maximum dV/dt (133 +/- 20 vs. 84 +/- 6 muL/sec, p < 0.05), and LV border zone wall thickness (1.98 +/- 0.06 vs. 1.53 +/- 0.07 mm, p < 0.005). Angiogenesis was enhanced (151 +/- 10.0 vs. 90 +/- 4.5 endothelial cells/hpf, p < 0.005) and apoptosis was reduced (3.9 +/- 0.3 vs. 8.2 +/- 0.5%, p < 0.005). Increased expression of HGF and Bcl-2 protein was observed in the Adeno-HGF-treated group. Overexpression of HGF 3 weeks post-MI resulted in enhanced angiogenesis, reduced apoptosis, greater preservation of ventricular geometry, and preservation of cardiac contractile function. This technique may be useful to treat or prevent postinfarction heart failure.

YM598, an Orally Active ETA Receptor Antagonist, Ameliorates the Progression of Cardiopulmonary Changes and Both-side Heart Failure in Rats with Cor Pulmonale and Myocardial Infarction

The effects of the novel, selective endothelin-A (ETA) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.1 and 1 mg/kg for 4 weeks), but not bosentan (30 mg/kg), significantly inhibited the progression of pulmonary hypertension and the development of right ventricular hypertrophy. YM598 also improved hypoxemia and morphological pulmonary lesions in these rats. In CHF rats, moreover, long-term oral administration of YM598 (1 mg/kg/day for approximately 30 weeks) significantly ameliorated their poor survival rate (P < 0.05). In the measurement of cardio-hemodynamic parameters, YM598 improved the contractile/diastolic capacity of the left ventricle and the preload in the right ventricle to the levels seen in sham-operated rats. YM598 also markedly inhibited both ventricular hypertrophy and pulmonary congestion, as well as lowering high plasma brain natriuretic peptide levels in CHF rats. These findings suggest that YM598 may have a clinical benefit with regards to ameliorating the cardiopulmonary changes of right-side heart failure, and the cardiac dysfunction and mortality/morbidity of CHF.

Cell transplantation in heart failure management

Heart failure is becoming a major issue for public health in western countries and the effect of currently available therapies is limited. Therefore cell transplantation was developed as an alternative strategy to improve cardiac structure and function. This review describes the multiple cell types and clinical trials considered for use in this indication. Most studies have been developed in models of post-ischemic heart failure. The transplantation of fetal or neonatal cardiomyocytes has proven to be functionally successful, but ethical as well as immunological and technical reasons make their clinical use limited. Recent reports, however, suggested that adult autologous cardiomyocytes could be prepared from stem cells present in various tissues (bone marrow, vessels, adult heart itself, adipose tissue). Alternatively, endothelial progenitors originating from bone marrow or peripheral blood could promote the neoangiogenesis within the scar tissue. Hematopietic stem cells prepared from bone marrow or peripheral blood have been proposed but their differentiation ability seems limited. Finally, the transplantation of skeletal muscle cells (myoblasts) in the infarcted area improved myocardial function, in correlation with the development of skeletal muscle tissue in various animal models. The latter results paved the way for the development of a first phase I clinical trial of myoblast transplantation in patients with severe post-ischemic heart failure. It required the scale-up of human cell production according to good manufacturing procedures, started in june 2000 in Paris and was terminated in november 2001, and was followed by several others. The results were encouraging and prompted the onset of a blinded, multicentric phase II clinical trial for skeletal muscle cells transplantation. Meanwhile, phase I clinical trials also evaluate the safeness and efficacy of various cell types originating from the bone marrow or the peripheral blood. However, potential side effects related to the biological properties of the cells or the delivery procedures are being reported. High quality clinical trials supported by strong pre-clinical data will help to evaluate the role of cell therapy as a potential treatment for heart failure.

Stem cell mobilization and auto-implantation by sen procedure in post-ischemic chronic heart failure. Results of a pilot phase 11 study

Stem cell mobilization and auto-implantation by sen procedure in post-ischemic chronic heart failure. Results of a pilot phase 11 study

Reappraisal of β-blocker therapy in the acute and chronic post–myocardial infarction period

In patients presenting with acute myocardial infarction (MI), the early use of intravenous β-blockade followed by short-term oral administration in the absence of reperfusion therapy has shown a modest reduction in mortality. In contrast, major reductions in mortality and reinfarction have been shown when β-blockers have been used soon after an acute MI and continued long term. These benefits were observed in trials conducted in the 1970s and 1980s, before the widespread use of reperfusion therapies, antiplatelet agents, and angiotensin-converting enzyme inhibitors; those trials excluded patients with postischemic heart failure. Recently, the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial has shown a significant reduction in all-cause mortality and reinfarction in post-MI patients with systolic dysfunction, in response to carvedilol. Despite compelling evidence supporting the use of β-blockers in the post-MI setting, data published by the National Cooperative Cardiovascular Project have shown that <50% of all post-MI patients receive β-blockers as long-term therapy. It appears that post-MI patients with perceived contraindications, such as advanced age, diabetes, heart failure, peripheral vascular disease, and/or chronic pulmonary obstructive disease, may derive a substantial benefit from the use of β-blockers. Given the considerable evidence from randomized clinical trials, the use of β-blockers is recommended in all post-MI patients without a contraindication, particularly in those with left ventricular systolic dysfunction.Am J Cardiol 2004;93(suppl):21B–29B. This article is reprinted with permission from Reviews in Cardiovascular Medicine 2003;4(suppl 3):S13–S24. ©MedReviews, LLC. All rights reserved.

Baseline/post-nitrate Tc-99m tetrofosmin mismatch for the assessment of myocardial viability in patients with severe left ventricular dysfunction: comparison with baseline Tc-99m tetrofosmin scintigraphy/FDG PET imaging

Background Positron emission tomography (PET) flow/metabolic mismatch is considered the nuclear medicine gold standard for the assessment of myocardial viability. The aim of this study was to investigate whether baseline/nitrate technetium 99m tetrofosmin single photon emission computed tomography (SPECT) mismatch may provide equivalent clinical information. Methods and results We studied 23 patients (aged 62 ± 10 years, 19 men) with previous myocardial infarction (16 anterior, 4 inferior, and 3 anterior plus inferior) and postischemic heart failure (gated SPECT [G-SPECT] ejection fraction, 26% ± 8%). All patients underwent Tc-99m tetrofosmin G-SPECT at rest and after nitrates (intravenous isosorbide dinitrate, 0.2 mg/mL, 10 mL/h) as well as a fluorine 18 fluoro-2-deoxy- d-glucose (FDG) PET scan. Regional wall motion analysis was performed with quantitative G-SPECT (QGS). Myocardial dysfunction was defined as a regional QGS score of 2 or greater. Regional perfusion was assessed by quantitative perfusion score (QPS) providing percent Tc-99m tetrofosmin uptake in a 20-segment model. Semiquantitative analysis of FDG uptake was performed by use of polar maps generated by Siemens ECAT HR + software. In areas with a perfusion rate lower than 80%, PET viability was identified by a normalized FDG percent uptake/baseline Tc-99m tetrofosmin percent uptake ratio greater than 1.2. We analyzed 460 segments; 298 (64%) were dysfunctional by QGS analysis. Of these, 170 were viable by PET imaging whereas 128 were nonviable. Regional Tc-99m tetrofosmin uptake was higher in viable than in nonviable segments both at rest (60% ± 24% vs 42% ± 12%, P < .01) and after nitrates (67% ± 20% vs 41% ± 18%, P < .01). According to receiver operating characteristic curve analysis, a cutoff value of 63% for resting as well as post-nitrate G-SPECT provided the highest diagnostic accuracy for the detection of myocardial viability (67% and 72% at rest and after nitrates, respectively). When the same algorithm used for the comparison with PET (normalized nitrate percent uptake/baseline percent uptake) was applied to G-SPECT, we obtained the highest agreement with PET (accuracy, 93%; sensitivity, 95%; specificity, 92%). Conclusions In patients with severe left ventricular dysfunction, perfusion data alone, both at rest and after nitrates, do not allow an accurate estimate of myocardial viability. In dysfunctioning segments, the analysis of rest/post-nitrate Tc-99m tetrofosmin mismatch provides results similar to those obtained by PET flow/metabolic mismatch.

Cardiopulmonary alterations in mRNA expression for interleukin-1beta, the interleukin-6 superfamily and CXC-chemokines during development of postischaemic heart failure in the rat.

Cytokines and chemokines are believed to play a pathogenic role in heart failure (HF). Although some cytokines and chemokines have been examined in HF, information about others is still lacking. We aimed to examine the expression of cytokines belonging to the interleukin (IL)-6 superfamily [IL-6 and ciliary neurotrophic factor (CNTF)], as well as IL-1beta and the CXC-chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8. We examined their expression in the heart, lung and spleen during development of postischaemic HF 1 and 6 weeks following left coronary artery ligation. Rats, which after myocardial infarction had a left ventricular end-diastolic pressure above 15 mmHg, were considered to be in HF. Sham-operated rats served as controls. A substantial upregulation of cardiac IL-1beta was measured in HF at 1 week, whereas a downregulation was measured in the lungs. At 6 weeks no altered regulation was seen. CNTF was only upregulated in the viable left ventricle at 6 weeks and IL-6 was upregulated in the infarcted region at 1 week. Cardiac MCP-1 was upregulated in the viable and the infarcted region of the failing left ventricle at 1 week, with the highest expression in the latter. In the lung, another pattern of regulation was seen with a significant increase in pulmonary MCP-1 at 6 weeks. IL-8 was only detected in the infarcted region at 1 week. In the spleen, no regulation of cytokines was found. In conclusion, we report an organ-specific regulation of cytokines and chemokines in postischaemic HF. Our novel findings of increased cardiac CNTF and cardiopulmonary MCP-1 mRNA indicate a role for these factors in the pathogenesis of HF.

Early and chronic captopril or Losartan therapy reduces infarct size and avoids congestive heart failure after myocardial infarction in rats

Background Angiotensin converting enzyme (ACE) inhibitors and angiotensin II AT 1-receptor antagonists prolong survival in experimental postischemic heart failure (CHF) in rats. The aim of this study was to investigate whether potential beneficial effects of early and long-term therapy with low doses of captopril or losartan occur in hemodynamics and heart morphometry, as well as in infarct size during establishment of CHF after myocardial infarction. Methods Male Wistar rats were subjected to myocardial infarction by left coronary ligation. Subsequently, 24 h after surgery captopril (2.5 mg/kg/day/28 days) or losartan (3 mg/kg/day/28 days) was administered by mini-osmotic pump release. Hemodynamics, infarct size, and heart morphometry were measured in sham, untreated, and treated operated rats. Results Morphometric and hemodynamic parameters were modified after myocardial infarction indicating hypertrophy of the heart and CHF establishment; however, either captopril or losartan partially avoided hypertrophy. Captopril reverted hemodynamics to sham values, while losartan induced further decrease in systolic blood pressure. Both drugs were able to drastically reduce infarct size produced by myocardial infarction. Conclusions Data show that early and chronic therapy with low doses of captopril or losartan prevent CHF establishment, probably by limiting extension of infarcted area after coronary occlusion, and suggest AT 1 receptor pathway involvement in this pathology.

Pathophysiology and diagnosis of hibernating myocardium in patients with post-ischemic heart failure: the contribution of PET.

Identification and treatment of hibernating myocardium (HM) lead to improvement in LV function and prognosis in patients with post-ischemic heart failure. Different techniques are used to diagnose HM: echocardiography, MRI, SPECT and PET and, in patients with moderate LV impairment, their predictive values are similar. There are few data on patients with severe LV dysfunction and heart failure in whom the greatest benefits are apparent after revascularization. Quantification of FDG uptake with PET during hyperinsulinemic euglycemic clamp is accurate in these patients with the greatest mortality risk in whom other techniques may give high false negative rates. The debate on whether resting myocardial blood flow to HM is reduced or not has stimulated new research on heart failure in patients with coronary artery disease. PET with H2(15)O or 13NH3 has been used for the absolute quantification of regional blood flow in human HM. When HM is properly identified, resting blood flow is not different from that in healthy volunteers although a reduction of approximately 20% can be demonstrated in a minority of cases. PET studies have shown that the main feature of HM is a severe impairment of coronary vasodilator reserve that improves after revascularization in parallel with LV function. Thus, the pathophysiology of HM is more complex than initially postulated. The recent evidence that repetitive ischemia in patients can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and HM are two facets of the same coin.

Effects of angiotensin II type 1 receptor blockade in ApoE-deficient mice with post-ischemic heart failure.

We investigated in mice whether atherosclerosis exacerbates the development of post-ischemic heart failure and alters the beneficial effects of long-term angiotensin II type 1 receptor blockade in this model. ApoE-deficient (ApoE(-/-)) and C57BL/6J (C57) mice with myocardial infarction (coronary ligation) received vehicle (C57 and ApoE(-/-)) or irbesartan (Ir, 50mg/kg/d orally, C57-Ir and ApoE(-/-)-Ir). Ten months post myocardial infarction, survival rates were similar in C57 (58%) and ApoE(62%). Atherosclerosis induced no significant alteration in blood pressure, cardiac output (fluospheres), total peripheral resistance, or shortening fraction (echocardiography) but increased renal resistance (+50%, P<0.05). Chronic Ir treatment significantly improved survival to a similar extent in both C57-Ir (85%) and ApoE(-/-)-Ir (86%). It also decreased blood pressure to a similar extent in both strains (-16% and -18%, both P<0.05). In C57-Ir mice, Ir did not modify cardiac output or total peripheral resistance, but it decreased renal resistance (-28%, P<0.001) and left-ventricular weight (-28%, P<0.05). In ApoE(-/-)-Ir mice, Ir limited atherosclerotic lesions (-13%, P<0.05), increased cardiac output (+28%, P<0.05) and shortening fraction (+24%, P<0.05), and decreased total peripheral resistance (-33%, P<0.01), renal resistance (-61%, P<0.001), and left-ventricular weight (-27%, P<0.001). In conclusion, atherosclerosis does not worsen heart failure development in mice and, although the beneficial cardiovascular effects of AT1 receptor blockade are greater in ApoE(-/-) than in C57, reduction in mortality is similar in both strains.

Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction.

Interleukin (IL)-18 has been reported to be an important predictor for mortality in ischemic heart disease. IL-18 has proinflammatory properties, induces cell death and stimulates nitric oxide production. We hypothesized that following myocardial infarction (MI) an increased myocardial IL-18 production occurs, which may be involved in the pathogenesis of post-ischemic heart failure. Seven days after induction of MI in the mouse, myocardial hypertrophy and pulmonary edema were observed. RNase protection assay of tissue from the non-infarcted left ventricular myocardium revealed an increase in IL-18 (2.0-fold; P<0.001) and IL-1 beta (1.6-fold; P<0.001) mRNA after MI. Enhanced abundance of pro-IL-18 (1.4-fold; P<0.05), IL-18 receptor (3.5-fold; P<0.05) and IL-18 binding proteins (1.6-fold; P<0.05) was also demonstrated, whereas cardiac IL-18 protein decreased by 25% (P<0.05) following MI. However, the concentration of circulating IL-18 was significantly elevated (MI; 90.4+/-11.7 pg/ml, sham; 47.2+/-4.2 pg/ml; P<0.001). After MI, enhanced cardiac activity of the pro-IL-18 processing enzyme, caspase-1, was measured. Additionally, a 3.4-fold increase (P<0.001) in the activity of the IL-18 degrading enzyme, caspase-3, was found in cardiac tissue, which may explain the observed reduction of cardiac IL-18 protein abundance. Finally, IL-18 reduced shortening of electrically stimulated adult cardiomyocytes and left ventricular contractility in vivo. After MI in the mouse, increased production of cardiac IL-18 mRNA and pro-IL-18, as well as circulating IL-18 occurs. Since IL-18 also reduced myocardial contractility, we suggest that IL-18 may be involved in the pathogenesis of contractile dysfunction following MI.

P362 Beneficial effect on atrial remodelling of spironolactone in a rat model of post-ischaemic heart failure

P362 Beneficial effect on atrial remodelling of spironolactone in a rat model of post-ischaemic heart failure

Hibernation and congestive heart failure.

The most common cause of heart failure is coronary artery disease, and whilst intensive treatment of acute coronary syndromes and myocardial infarction continue to reduce the mortality associated with these conditions, many survivors develop heart failure. In general, heart failure secondary to ischaemic heart disease results from: (i) irreversible myocyte loss due to infarction with scar formation; (ii) chronic left ventricular dysfunction which may recover after revascularisation (hibernating myocardium); (iii) changes in remote myocardium (adverse remodelling). A number of studies suggest that patients with post-ischaemic heart failure may derive symptomatic and prognostic benefit from coronary revascularisation and most of this benefit is thought to derive from functional improvement of hibernating myocardium. Although the mechanisms of hibernation remain poorly understood, studies with positron emission tomography have shown that blood flow to hibernating myocardium is usually within or only slightly below the normal range whilst the coronary vasodilator reserve is always severely reduced and the concept that stunning and hibernation may be causally related has gained support in recent years. There is increasing consensus amongst clinicians regarding the importance of identifying and treating hibernating myocardium in patients with coronary artery disease and heart failure, and a randomised study comparing optimum medical treatment to optimum medical treatment with complete revascularisation has just commenced in the United Kingdom (HEART-UK) and will provide guidance regarding diagnosis and treatment of these patients.

Viral Gene Transfer of the Antiapoptotic Factor Bcl-2 Protects Against Chronic Postischemic Heart Failure

Apoptosis secondary to acute ischemia and chronic remodeling is implicated as a mediator of heart failure. This study was designed to assess the effect of in vivo viral gene transfer of the anti-apoptotic factor Bcl-2 to block apoptosis and preserve ventricular geometry and function. In a rabbit model of regional ischemia followed by reperfusion, an experimental group treated with adeno-Bcl-2 was compared with a control group receiving empty vector adeno-null. Function was assessed by echocardiography, and sonomicrometry of the border zone was compared with the normal left ventricle (LV). Animals were killed at 6 weeks, and an additional group was killed after 3 days to see whether virus administration conferred an immediate effect. Animals that were administered Bcl-2 maintained higher ejection fractions at 2, 4, and 6 weeks compared with controls. Sonomicrocrystals demonstrated greater protection of border zone fractional shortening at 6 weeks. The Bcl-2 group had superior preservation of LV geometry with less ventricular dilatation and wall thinning. There was also reduced apoptosis compared with the controls. Finally, in the animals killed at 3 days, no functional difference was observed between the Bcl-2 and control groups. Gene transfer of Bcl-2 preserves LV function after ischemia despite the absence of an observed acute protective effect. The benefit at 6 weeks is postulated to result from a Bcl-2-mediated reduction in apoptosis and ventricular remodeling. Adeno-Bcl-2 administration offers a potential strategy to protect the heart from late postischemic heart failure.

Combined angiotensin II AT1-receptor blockade and angiotensin I–converting enzyme inhibition on survival and cardiac remodeling in chronic heart failure in rats

Background: Angiotensin I–converting enzyme inhibition (ACEI) and angiotensin II AT1-receptor blockade are effective at improving survival and limiting cardiac remodeling in the rat model of postischemic heart failure. Whether their combination yields additive/synergistic effects is unknown. Methods and Results: Rats underwent coronary artery ligation and 7 days later were treated orally for 9 months with placebo (controls), 5 mg/kg valsartan, 1 mg/kg enalapril (doses submaximally effective at reducing mortality in the experimental model used), or 5 mg/kg valsartan and 1 mg/kg enalapril combined. Compared with controls, valsartan, enalapril, and their combination decreased mortality by 40% (P =.006), 21% (P =.065), and 33% (P =.032), respectively, but there was no significant difference between the 3 treatments. At the doses used, valsartan, but neither enalapril nor the combination, slightly limited cardiac hypertrophy and fibrosis development and reduced left ventricular end-diastolic pressure as assessed in the surviving animals at 9 months. Conclusions: In experimental chronic heart failure in rats, valsartan reduces mortality similar to other AT1-receptor blockers and a combination of AT1-receptor blockade (valsartan) and ACEI (enalapril) at submaximal doses does not exert additive/synergistic beneficial effects on mortality.

Coronary artery surgery for ischemic heart failure: Risks, benefits, and the importance of assessment of myocardial viability

Heart failure and left ventricular dysfunction are common and are most often caused by myocardial ischemia/infarction secondary to occlusive coronary artery disease. Although recent refinements in medical therapy have resulted in improved survival, morbidity and mortality remain high in patients with advanced heart failure. Heart transplantation remains an option for selected patients, and implantable left ventricular assist devices may soon provide another treatment strategy for such patients. However, patients with established postischemic heart failure, significant myocardial viability, and coronary artery anatomy amenable to surgical revascularization can derive significant functional and survival benefit after coronary artery surgery, albeit with an increased perioperative risk. We discuss the role of coronary artery surgery in ischemic heart failure and review the evidence for such an approach. Copyright © 2001 by W.B. Saunders Company