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Background Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction. Methods and Results In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg −1 ·h −1 ) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (−18 mL; P =0.009) and end-systolic volume (−14 mL; P =0.005) occurred at end infusion in the highest dose cohort. Conclusions This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose–effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02388464.

Cardiovascular clinical trials are increasingly conducted globally as a means to reduce costs, expedite timelines, provide broad applicability, and satisfy regulatory authorities. Potential problems with trial globalization include regional differences in patient characteristics, medical practice patterns, and health policies which may influence outcomes and limit generalizability. Moreover, concerns have been raised about ethical misconduct and unsatisfactory quality oversight in regions with less trial experience and infrastructure. This article reviews geographical differences in cardiovascular trials in heart failure, acute coronary syndromes, hypertension and atrial fibrillation. It also explores potential explanations for these differences and methods to standardize the presentation of trial results. This review is based on discussions between basic scientists and clinical trialists at the 8th Global Cardio Vascular Clinical Trialists Forum 2011 in Paris, France, from December 2 to 3.

Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF #35% and narrow QRSrandomizedtooptimalmedicaltreatment(OMT)plusCCM(n5215)versusOMTalone(n5213)and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. Methods and Results: The protocol specified that multiregression analysis would be used to determine if baselineEF,NYHAfunctional class,pVO2,oretiologyofheartfailure influencedtheimpactofCCM onAT. Etiology and baseline pVO2 did not affect efficacy. However, baseline NYHA functional class III and EF $25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMTand 109 CCM patients, w48% of the entire population) VAT increased by 0.10 6 2.36 in CCM versus � 0.54 6 1.83 mL kg � 1 min � 1 in OMT (P 5 .03) and pVO2 increased by 0.34 6 3.11 in CCM versus � 0.97 6 2.31 (P 5 .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of $1 class in NYHA functional class (P 5 .002), and 59% of CCM versus 42% of OMT subjects showed a $10-point reduction in Minnesota Living with Heart Failure Questionnaire (P 5 .01). All of these findings were similar to those seen at 50 weeks. Conclusions: The results of this retrospective hypothesis-generating analysis indicate that CCM significantlyimprovesobjectiveparametersofexercisetoleranceinasubgroupofpatientscharacterizedbynormal QRS duration, NYHA functional class III symptoms, and EF O25%. (J Cardiac Fail 2011;17:710e717)

Background: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF).Methods and Results: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR 60; corresponding data for the combined end point was HR. 0.44 (95% CI, 0.31 to 0.63; P Conclusions: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR 60. (J Cardiac Fail 2009;15:310-318)

Objectives: β-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different β1-selective adrenoceptor blockers, namely atenolol and metoprolol succinate, on left ventricular (LV) function and remodeling in dogs with coronary microembolization-induced HF [LV ejection fraction (EF) 30–40%]. Methods: Twenty HF dogs were randomized to 3 months of therapy with atenolol (50 mg once daily, n = 6), metoprolol succinate (100 mg, once daily, n = 7) or to no therapy (control, n = 7). LV EF and volumes were measured before initiating therapy and after 3 months of therapy. The change (Δ) in EF and volumes between measurements before and after therapy was calculated and compared among study groups. Results: In controls, EF decreased and end-systolic volume increased. Atenolol prevented the decrease in EF and the increase in ESV. In contrast, metoprolol succinate significantly increased EF and decreased end-systolic volume. ΔEF was significantly higher and Δend-systolic volume significantly lower in metoprolol succinate-treated dogs compared to atenolol-treated dogs (EF: 6.0 ± 0.86% vs. 0.8 ± 0.85%, p < 0.05; end-systolic volume: –4.3 ± 0.81 ml vs. –1 ± 0.52 ml, p Conclusions: In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.

Long-term monotherapy with the aldosterone receptor blocker eplerenone in dogs with HF was previously shown to improve LV systolic and diastolic function. This study examined the effects of long-term monotherapy with the aldosterone receptor blocker eplerenone on mRNA and protein expression of the cytoskeletal proteins titin, tubulin, fibronectin and vimentin, the matrix metalloproteinases (MMPs)-1, -2 and -9, and the tissue inhibitors of MMPs (TIMPs)-1 and -2 in left ventricular (LV) myocardium of dogs with heart failure (HF). HF was produced in 12 dogs by intracoronary microembolizations. Dogs were randomized to 3 months oral therapy with eplerenone (10 mg/kg twice daily, n = 6) or to no therapy at all (HF-control, n = 6). LV tissue from six normal dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction (RT-PCR) and protein expression using Western blots. Compared to NL dogs, control dogs showed upregulation of mRNA and protein expression for tubulin, fibronectin, MMP-1, -2 and -9, and down-regulation of mRNA and protein expression for total titin. Normalization of mRNA and protein expression for all these genes was seen after treatment with eplerenone. N2BA/N2B-titin mRNA expression ratio increased significantly in dogs with HF treated with eplerenone. No differences in expression for vimentin, TIMP-1 and -2 were observed among groups. In dogs with HF, long-term eplerenone therapy normalizes mRNA and protein expression of key cytoskeletal proteins and MMPs. Reversal of these molecular maladaptations may partly explain the improvement in LV diastolic function seen after long-term therapy with eplerenone.

Objectives This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF). Background 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or “statins” possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs). Methods Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change (Δ) from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)-α in LV tissue and the number of circulating Sca-1–positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison. Results There were no differences in ΔEDV, ΔESV, and ΔEF between control group and LD RSV. In contrast, ΔEDV and ΔESV were significantly lower, and ΔEF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF-α and was associated with a significant increase in the number of circulating BMSCs. Conclusions In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF-α expression and partly from increased mobilization of BMSCs.

Background Assessment of global left ventricular (LV) remodeling is important in evaluating the efficacy of pharmacologic and device therapies for the treatment of chronic heart failure (HF). The effects of pharmacologic or device therapies on global left atrial (LA) remodeling in HF, although also important, are not often examined. We showed that long-term therapy with the Acorn Cardiac Support Device (CSD), a passive mechanical ventricular containment device, prevents or reverses LV remodeling in dogs with HF. This study examined the effects of the CSD on global LA remodeling in dogs with moderate and advanced HF. Methods and Results Studies were performed in 24 dogs with coronary microembolization-induced HF. Of these, 12 had moderate HF (ejection fraction, EF 30% to 40%) and 12 advanced HF (EF ≤25%). In each group, the CSD was implanted in 6 dogs and the other 6 served as controls. Dogs were followed for 3 months in the moderate group and 6 months in the advanced HF group. LA maximal volume (LAVmax), LA volume at the onset of the p-wave (LAVp), LA minimal volume (LAVmin), LA active emptying volume (LAAEV), and LA active emptying fraction (LAAEF) were measured from 2-dimensional echocardiograms obtained before CSD implantation and at the end of the treatment period. Treatment effect (Δ) comparisons between CSD-treated dogs and controls showed that CSD therapy significantly decreased LA volumes (ΔLAVmax: 3.33 ± 0.70 vs. –2.87 ± 1.31 mL, P = .002; 7.77 ± 1.76 versus –0.37 ± 0.87 mL, P = .002) and improved LA function (ΔLAAEF: –6.00 ± 1.53 versus 1.85 ± 1.32%, P = .003; –2.39 ± 1.10 versus 3.13 ± 1.66%, P = .02) in the moderate HF and advanced HF groups, respectively. Conclusions Progressive LA enlargement and LA functional deterioration occurs in untreated dogs with HF. Monotherapy with the CSD prevents LA enlargement and improves LA mechanical function in dogs with moderate and advanced HF indicating prevention or reversal of adverse LA remodeling.

Objectives This study sought to explore the gender-related differences in etiology and outcomes in chronic heart failure (HF) patients from 5 randomized trials. Background Each year, 550,000 new cases of HF are identified; however, there remain limited data on gender-related differences in etiology and outcomes among patients with HF with systolic dysfunction. Methods We analyzed data from 8,791 men and 2,851 women randomized in 5 clinical trials (PRAISE [Prospective Randomized Amlodipine Survival Evaluation], PRAISE-2, MERIT-HF [Metoprolol Extended Release Randomized Intervention Trial in Heart Failure], VEST [Vesnarinone Trial], and PROMISE [Prospective Randomized Milrinone Survival Evaluation]) to explore gender-related differences in etiology (ischemic vs. nonischemic) and outcomes (all-cause mortality and death or all-cause hospitalization). Hazard ratios (HR), 95% confidence intervals (CIs), and Kaplan-Meier survival curves were generated by gender and etiology. Results A total of 18% of ischemic and 31% of nonischemic patients were women. Irrespective of etiology, women were older, more ethnically diverse, and had higher systolic blood pressures, more diabetes, and severe HF symptoms, but less often smoked or had prior myocardial infarctions than men. Mean ejection fractions were similar between women (23.6%) and men (23.2%). The 1-year Kaplan-Meier survival estimates varied by gender and etiology (female nonischemics, HR 0.88 [95% CI 0.85 to 0.89]; female ischemics, HR 0.83 [95% CI 0.81 to 0.85]; male nonischemics, HR 0.84 [95% CI 0.83 to 0.85]; male ischemics, HR 0.79 [95% CI 0.78 to 0.81]). After adjustment, female gender (HR 0.77 [95% CI 0.69 to 0.85]) and nonischemic etiology (HR 0.80 [95% CI 0.72 to 0.89]) were associated with longer survival time. Time to death or hospitalization was longer among nonischemics (HR 0.83 [95% CI 0.78 to 0.89], p Conclusions Our data clarify that outcomes differ by both gender and etiology among patients with HF with systolic dysfunction. Understanding these differences may lead to better management of HF patients and improved overall prognosis.

Data from a number of clinical trials of beta blocker therapy in heart failure, although limited in the size of African American patients included, suggest that they achieve a similar benefit as Caucasians. African Americans were usually at higher risk when enrolled in all of these studies with a higher incidence of hypertension and diabetes mellitus. The only exception is the Beta Blocker Evaluation of Survival Trial (BEST) that studied the efficacy of Bucindolol in heart failure. In that study there appeared to be a unique differential effect in African Americans compared to Caucasians which may have been in part related to the severity of the disease.

The recently reported COMET trial found that the β1/β2/α1 receptor blocking agent carvedilol given in a relatively high β1-receptor blocking dose regimen was superior in mortality reduction to immediate release metoprolol given in a relatively low β1-receptor blocking dose schedule. We analyze the problems with the trial design of COMET from the standpoint of comparing 2 therapeutic agents at different positions on a common dose-response curve, and discuss the theoretical reasons why postjunctional adrenergic receptor blockade that is in addition to β1-receptor antagonism will likely produce only minimal or no incremental benefit in chronic heart failure.

Context: The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups. Objective: To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women). Setting: MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction ≤0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose. Main outcome measures: Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis. Results: Overall, MERIT-HF demonstrated a 34% reduction in total mortality (p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization (p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% (p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily. Conclusion: Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.

1. We examined the effects of eprosartan, an AT(1) receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). 2. Dogs were randomized to 3 months of oral therapy with low-dose eprosartan (600 mg once daily, n=8), high-dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). 3. In the placebo group, LV end-diastolic (EDV) and end-systolic (ESV) volumes increased after 3 months (68+/-7 vs 82+/-9 ml, P

While beta-adrenergic blockers have been used for decades in a variety of cardiovascular illnesses, they have traditionally been avoided in chronic heart failure. In spite of significant advances in management, mortality in patients suffering from heart failure remains unacceptably high and new therapies are urgently needed. Recently, several large clinical trials have shown a significant reduction in both morbidity and mortality in heart failure patients when beta-blockers are added to standard therapy. While further investigation is warranted in certain subgroups, the use of beta-adrenergic blockers in New York Heart Association (NYHA) class II to IV heart failure should now be considered routine. The purpose of this article is to outline and review the five major clinical trials of beta-blocker therapy in chronic heart failure; the US Carvedilol heart failure Program (USCP), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF), the Beta-blocker Evaluation of Survival Trial (BEST) and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS), and to aid the reader in the selection of appropriate candidates for beta-blocker therapy.

Background— In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF. Methods and Results— HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62±4 versus 68±4 mL, P P P Conclusions— Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Objectives We performed a post-hoc subgroup analysis in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) with the aim of reporting on the heart rate (HR) response during the titration phase and clinical outcomes from the three-month follow-up visit to end of study in two dosage subgroups: one that had reached more than 100 mg of metoprolol CR/XL once daily (high-dose group; n = 1,202; mean 192 mg) and one that had reached 100 mg or less (low-dose group; n = 412; mean 76 mg). Background Clinicians have questioned whether patients need to reach the target beta-blocker dose to receive benefit. Methods Outcome (Cox-adjusted) was compared with all placebo patients with dose available at the three-month visit (n = 1,845). Results Data indicated somewhat higher risk in the low-dose group compared with the high-dose group. Heart rate was reduced to a similar degree in the two dose groups, indicating higher sensitivity for beta-blockade in the low-dose group. The reduction in total mortality with metoprolol CR/XL compared with placebo was similar: 38% (95% confidence interval [CI], 16 to 55) in high-dose group (p = 0.0022) and also 38% (95% CI, 11 to 57) in the low-dose group (p = 0.010). Conclusions Risk reduction was similar in the high- and low-dose subgroups, which, at least partly, may be the result of similar beta-blockade as judged from the HR response. The results support the idea of an individualized dose-titration regimen, which is guided by patient tolerability and the HR response. Further research is needed to shed light on why some patients respond with a marked HR reduction and reduced mortality risk on a relatively small dose of a beta-blocker.

We examined the effects of long-term monotherapy with the beta-blocker, metoprolol controlled release/extended release (CR/XL), on the progression of LV dysfunction as well as on global and cellular remodeling in dogs with heart failure (HF). Chronic HF was produced by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to 3 months oral monotherapy with metoprolol CR/XL (100 mg once daily, n = 7) or no therapy at all (control, n = 7). In control dogs, EF decreased from 38 ± 1% to 31 ± 2% (p = 0.002), and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased (37 ± 2 vs 45 ± 2 ml, p = 0.001; 59 ± 3 vs 65 ± 3 ml, p = 0.001; respectively) during the 3 month follow-up period. In dogs treated with metoprolol CR/XL, EF increased after 3 months from 36 ± 1% to 43 ± 1% (p = 0.001), and ESV decreased (42 ± 2 vs 38 ± 2 ml, p = 0.003), whereas EDV remained unchanged. Compared to controls, treatment with metoprolol CR/XL showed 46% reduction in replacement fibrosis, 54% reduction in interstitial fibrosis and 20% reduction in myocyte cross-sectional area, a measure of myocyte hypertrophy. These findings indicate that metoprolol CR/XL improves LV function and attenuates progressive global and cellular LV remodeling in dogs with HF. The benefits are fully attributable to β-blockade alone as no other adjunctive therapy was used.

Background. The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure. Methods. LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30–40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6). Results. During the 3 months of follow-up, LV EF in control dogs decreased from 37 ± 1% to 28 ± 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 ± 3 vs. 84 ± 5 ml, P < 0.01); ESV: 45 ± 1 vs. 60 ± 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 ± 1% vs. 37 ± 2%), EDV (79± 5 vs. 78± 6 ml) and ESV (52 ± 3 vs. 49 ± 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control. Conclusion. Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.

Congestive heart failure continues to be a very significant problem in cardiovascular medicine. Up to 8–10 million people in the western world are affected by clinical or subclinical forms of heart failure. Ischemic heart disease and consequent systolic dysfunction is the major cause of heart failure. However, in up to 40% of patients, the cause is not well understood [1]. Whether the original cause is a viral infection, prior myocardial infarctions, or hypertensive heart disease, the end result or phenotype is similar. The annual mortality, even with current therapy, remains between 5 to 20% depending upon the severity of the clinical state. Approximately 50% of deaths are sudden [2], presumed to be due to ventricular arrhythmias or asystole. The importance of sudden death as the mode of death in heart failure has been reemphasized in the last decade. This is the result of information collected from clinical trials, which have provided further insight into the natural history of the disease. The mode of death in heart failure is related in part to the severity of the disease. In patients with mild to moderate heart failure (NYHA class II and III) sudden death represents the major mode of death, accounting for approximately two thirds of the mortality. In more severe heart failure, progressive heart failure is the most frequent mode of death although sudden death still accounts for about a third of the deaths. The arrhythmia associated with sudden death is usually ventricular tachycardia or fibrillation although bradycardia or asystole is also seen in advanced heart failure [3,4]. Despite investigations, the underlying mechanisms responsible for sudden death in these patients remain poorly understood [4]. Heart failure is a heterogeneous problem where multiple mechanisms may contribute to the development of arrhythmias. These include fibrosis, conduction system disease, electrolyte abnormalities such as hypokalemia and hypomagnesemia, increased stretch of the heart chamber, hypertrophy and increased muscle mass, abnormal neurohormonal activation as well as the addition of antiarrhythmic drugs with potentially proarrhythmic effects. In addition to these, it is being increasingly recognized that these hearts may also have abnormalities in ion channels/currents as well as ion transport mechanisms which can lead to electrical dysfunction in both systole and diastole. In this article we will review the electrophysiological mechanisms that are thought to underlie the risk of sudden death in this condition, especially the available evidence on abnormalities of ion currents in patients with heart failure and their potential relevance to arrhythmogenesis.

Heart failure (HF) is a major public health problem in the United States. Nearly 5 million patients in this country have HF, and nearly 500,000 patients are diagnosed with HF for the first time each year. The disorder is the underlying reason for 12 to 15 million office visits and 6.5 million hospital days each year (1). During the last 10 years, the annual number of hospitalizations has increased from approximately 550,000 to nearly 900,000 for HF as a primary diagnosis and from 1.7 to 2.6 million for HF as a primary or secondary diagnosis (2). Nearly 300,000 patients die of HF as a primary or contributory cause each year, and the number of deaths has increased steadily despite advances in treatment. HFs primarily a disease of the elderly (3). Approximately 6% to 10% of people older than 65 years have HF (4), and approximately 80% of patients hospitalized with HF are more than 65 years old (2). HF is the most common Medicare diagnosis-related group, and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis (5). The total inpatient and outpatient costs for HF in 1991 were approximately $38.1 billion, which was approximately 5.4% of the healthcare budget that year (1). In the United States, approximately $500 million annually is spent on drugs for the treatment of HF. The American College of Cardiology (ACC) and the American Heart Association (AHA) first published guidelines for the evaluation and management of HF in 1995 (6). Since that time, a great deal of progress has been made in the development of both pharmacological and nonpharmacological approaches to treatment for this common, costly, disabling, and generally fatal disorder. For this reason, the 2 organizations believed that the time was right to reassess and update these …

OBJECTIVES This study analyzed the effect of the beta1-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure. BACKGROUND There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure. METHODS A subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction

Background International placebo-controlled survival trials (Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effects of β-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Program indicated an effect on these end points. Although none of these trials are large enough to provide definitive results in any particular subgroup, it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefined and post hoc subgroups in the MERIT-HF trial to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. Methods The study was conducted at 313 clinical sites in 16 randomization regions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalization (second primary end point) were analyzed on a time to first event. The first secondary end point was total mortality plus hospitalization for heart failure. Results Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mortality and 0.81 for mortality plus all-cause hospitalization. The hazard ratio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as for nearly all post hoc subgroups. The results of the post hoc US subgroup showed a mortality hazard ratio of 1.05. However, the US results regarding both the second primary combined outcome of total mortality plus all-cause hospitalization and of the first secondary combined outcome of total mortality plus heart failure hospitalization were in concordance with the overall results of MERIT-HF. Tests of country by treatment interaction (14 countries) revealed a nonsignificant P value of .22 for total mortality. The mortality hazard ratio for US patients in New York Heart Association (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have not been able to identify any confounding factor in baseline characteristics, baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mortality hazard ratio to be due to chance. Conclusions Just as we must be extremely cautious in overinterpreting positive effects in subgroups, even those that are predefined, we must also be cautious in focusing on subgroups with an apparent neutral or negative trend. We should examine subgroups to obtain a general sense of consistency, which is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup is the estimate of the hazard ratio for the overall trial. (Am Heart J 2001;142:502-11.)

Major changes in the treatment of heart failure have occurred in the last fifty years that have had a dramatic effect on its morbidity and mortality. Over two hundred years have passed since the demonstration of the benefit of digitalis in heart failure to the development of potent loop diuretics. The observation that vasodilators could improve both cardiac function and mortality led to the investigation of the Angiotensin Converting Enzyme Inhibitors (ACEI). Although these agents had significant vasodilator properties, their major benefit appears to be related to their ability to effect remodeling of the failing left ventricle. The most recent randomized clinical trials demonstrate that Beta Adrenergic Blocking agents can provide an incremental effect on both mortality and morbidity when added to therapy with ACEI. Although these agents have improved the outlook for the heart failure patient, they have had very little effect on the improvement of left ventricular function. Future research must be directed at methods to deal with this issue by either changing the contractile properties of the cardiomyocyte by pharmacologic or electrical therapy or by transplanting functional cells that can increase the number of functioning contractile units.

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered ‘on demand’ and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic™ signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca2+ transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

Objective To analyze the effect of delay times on racial differences in thrombolysis for acute myocardial infarction. Background Lower rates of thrombolytic therapy in blacks with acute myocardial infarction have recently been reported, but the reasons for this disparity are unknown. We hypothesized that lower rates of thrombolysis are caused by delay in presentation after symptom onset. Methods From November 1992 through November 1996, consecutive patients with a first acute myocardial infarction presenting to a large, urban teaching hospital were prospectively enrolled. Delay times were determined retrospectively from review of medical records. Patients were prospectively followed up for in-hospital cardiac events and death. A multivariable regression model was built to relate presentation times and other variables to thrombolysis administration. Results A total of 395 patients were included in the study, of which 33% were black. Symptom onset to emergency department presentation and door-to-needle times were significantly longer in blacks. Thrombolysis was administered significantly less often in blacks compared with whites (47% vs 68%, P = .001). Black race and age above 60 years were independently associated with delayed presentation and prolonged door-to-needle times. Black race, time to presentation, and non-Q-wave myocardial infarction were independently associated with not receiving thrombolysis. In-hospital mortality rates were similar in both groups. Conclusions Blacks presented later than whites for first acute myocardial infarction. Late arrival strongly influenced the rate of thrombolysis administration. Lower rates of thrombolysis and prolonged door-to-needle times were apparent in blacks after adjustment for delay times and other clinical factors, a finding that merits further investigation. (Am Heart J 2000;140:643-50.)

The use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure (HF) is limited by proarrhythmic and positive chronotropic effects. In the present study, we compared the hemodynamic effects of intravenous LY366634 (LY), a Na+ channel enhancer, with dobutamine (DOB), in eight dogs with HF produced by intracoronary microembolizations. We also determined whether intravenous LY has synergistic effects when combined with digoxin. After baseline measurements, infusion of DOB was initiated at a dose of 2 µg/kg/min and increased until an increase of heart rate (HR) >30% of baseline or ventricular arrhythmias developed. Once hemodynamics returned to baseline, LY was infused at a dose of 2 µg/kg/min and increased until the LV fractional area of shortening (FAS), determined echocardiographically, reached a similar level as with DOB. Both drugs increased FAS equivalently compared to baseline (DOB, 24 ± 3 to 47 ± 2; LY, 27 ± 2 to 46 ± 2%). DOB increased HR from 78 ± 4 min-1 at baseline to 107 ± 7 min-1 at maximal dose (p < 0.05) and provoked serious arrhythmias in one dog. In contrast, LY infusion did not increase HR (82 ± 7 vs. 80 ± 8 min-1) or elicit arrhythmias. After 1 week of oral digoxin, dogs were infused again with LY. A lower dose of LY was needed to achieve the same increase in FAS compared to LY alone, but this was not statistically significant. The combination of LY with digoxin did not increase HR or evoke arrhythmias. We conclude that in dogs with HF, intravenous LY improves LV function to the same extent as DOB without increasing HR or evoking ventricular arrhythmias. The combination of LY with digoxin elicits a safe positive inotropic response.

An important feature of heart failure is the progressive deterioration of left ventricular function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known. We and others have advanced the hypothesis that this hemodynamic deterioration results from progressive intrinsic contractile dysfunction of viable cardiomyocytes and/or from ongoing loss of cardiomyocytes. This review will focus on the concept of ongoing cardiac myocyte loss as a contributing factor to the progression of left ventricular dysfunction that characterizes the heart failure state. Specifically, the discussion will center on apoptosis or "programmed cell death" as a potential mediator of cardiomyocyte loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Studies have also shown that cardiomyocyte apoptosis occurs following acute myocardial infarction, in the hypertrophied heart as well as in the aging heart; conditions frequently associated with the development of failure. While available data support the existence of myocyte apoptosis in the failing heart, lacking are studies which address the importance of myocyte apoptosis in the progression of LV dysfunction. As part of this discussion, we will address this issue and construct a case in support of a concept that the failing myocardium is subject to regional hypoxia, an abnormality that can potentially trigger cardiomyocyte apoptosis. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if exact physiologic and molecular factors that trigger apoptosis in the heart can be identified, the stage will be set for the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.

Objective To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. Methods Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction ≤35%, taking stable doses of angiotensin-converting enzyme inhibitor, diuretics, and optionally digoxin were enrolled in a randomized, double-blind, placebo-controlled dose-escalation study of ecadotril 50 to 400 mg twice daily versus conventional therapy alone. Results: No increases in deaths, serious adverse events, or dropouts from adverse events were observed for the ecadotril group compared with placebo. The serum measures of neurohormonal activation were highly variable. Changes in signs and symptoms of heart failure, New York Heart Association class, and patient self-assessment of symptoms were not observed with ecadotril therapy; however, the study was not designed to detect differences in these parameters. Conclusion In this small pilot study, ecadotril in doses of 50 to 400 mg twice daily was generally well-tolerated and without severe short-term adverse effects in patients with mild to moderate heart failure. Evaluation of the clinical efficacy and long-term safety of ecadotril and other neutral endopeptidase inhibitors in patients with heart failure requires further study. (Am Heart J 1999;138:1140-8.)

This study analyzed differentials between permanent and temporary migrants and compared them to non-migrants in Vietnam. It is based on a survey undertaken in 1997 in four urban and two rural locations in different regions of the country. The design of the survey was to explore the migration situation about 10 years after economic reforms were introduced with particular attention to differentials among the various migrant segments of the population their adjustment and their impact on places of origin and destination. These data reveal patterns very similar to those found in a survey undertaken in Hubei Province China in 1988. Both sets of data indicate the importance of taking government policy into consideration when analyzing migration patterns. In addition it is emphasized that permanent migration and temporary migration in the years after economic reform have served to complement each other and in combination have come to resemble more closely migration patterns in developing countries where such movement is unrestricted by government policy. Gender differentials are also clear. Finally the analysis makes clear that full understanding of the redistribution process and its role in development requires the attention be paid to both permanent and temporary migration.

BACKGROUND: Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure. METHODS: We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. FINDINGS: The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% CI 0.53-0.81]; p=0.00009 or adjusted for interim analyses p=0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p=0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p=0.0023). INTERPRETATION: Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated.

The remodeling of the left ventricle occurs as a response to a number of pathophysiologic events. It commonly occurs after a myocardial infarction as a response to loss of muscle mass, in the setting of myocarditis or idiopathic cardiomyopathy as a response to an intrinsic contractile dysfunction of cardiomyocytes or to acute loss of myocytes, or as a result of hypertension in a response to chronic pressure overload. All of these adverse events lead to a change in the size and shape of the left ventricle, and each alters the myocellular milieu and can provoke an adaptive response among constituent elements of the left ventricular wall. Remodeling can also be expressed as a compensatory process, as a result of hypertrophy and dilation of nonischemic tissue after myocardial infarction or as a maladaptive response of hypertrophy secondary to long-standing systemic hypertension. The remodeling process itself can become autoinductive, leading to further progression of ventricular dysfunction 54 and the induction of apoptosis. 58 At the same time, the inciting stimulus, such as ischemia or myocarditis, may continue to be active and lead to further tissue loss and progressive remodeling. The change in shape and size of the left ventricle develops in response to focal loss of functional cardiac units, as in infarction, or in response to homogeneous degeneration of cardiomyocytes, as seen in various cardiomyopathies or in myocarditis. In the case of infarction, the unaffected myocardium hypertrophies, as evidenced by increases in both length and width of residual viable cardiocytes. Because myocytes lack the ability to replicate, global distortion ensues. Progressive ventricular remodeling therefore occurs either as a result of a continuing pathologic process or as a result of compensatory mechanisms that occur in response to the initial insult. This progression can lead to a series of adverse neurohormonal and hemodynamic consequences manifested by ventricular enlargement, hypertrophy, and dilation. These features of ventricular remodeling ultimately result in the expression of clinical heart failure. In contrast, studies indicate that the modification of remodeling can limit the occurrence of heart failure in a number of disease states. The treatment of hypertension 32 and the prevention of the activation of the renin angiotensin system (RAS) after acute myocardial infarction 47 can limit the stimulus to ventricular remodeling and prevent the occurrence of heart failure. Infarct size is a major determinant of the remodeling process, just as continued arterial hypertension represents a continued stimulus to hypertrophic remodeling. The early administration of thrombolytic and β-adrenergic blocking agents has the potential to achieve limitation of ischemia and ischemic myocyte loss.

It has been shown that patients with an acute myocardial infarction and persistent electrocardiographic ST-segment depression are at high risk for subsequent cardiac events. The purpose of this retrospective analysis was to examine the long-term effects of propranolol therapy in patients with their first acute myocardial infarction and persistent electrocardiographic ST-segment depression.The outcomes of 2877 patients enrolled in the Beta-Blocker Heart Attack Trial (BHAT) with their first myocardial infarction (75% of patients in BHAT) were reviewed. Patients were divided into three groups on the basis of presence or absence ofor =1 mm ST-segment depression in two contiguous leads of the 12-lead electrocardiogram obtained soon after admission or at the time of randomization, which occurred 10.1+/-3.5 days after the index myocardial infarction. Group 1 included 774 patients (392 randomly assigned to placebo and 382 to propranolol) with no ST-segment depression; group 2 included 1447 patients (713 placebo, 734 propranolol) with ST-segment depression at admission or at the time of randomization (labeled as transient); and group 3 included 656 patients (339 placebo and 317 propranolol) who had electrocardiographic ST-segment depression from the time of admission to the time of randomization (labeled as persistent).In group 3, patients with persistent electrocardiographic ST depression, the mortality rate in patients randomly assigned to placebo was 13.6% compared with 7.6% in patients with propranolol (p = 0.012; log rank test). Sudden death in the placebo arm was 9.7% compared with 4.7% in the propranolol group (p = 0.012, log rank test). The results of the Cox regression analysis, adjusting for all baseline variables with p values0.25, showed the relative risk of overall mortality rate and the relative risk of sudden death were 2.13 ( 1.22, 3.70) and 2.56 (1.27, 5.26), respectively, for the placebo group compared with the propranolol group. Patients with persistent ST-segment depression had the greatest benefit from propranolol (47.2 fewer events [deaths/reinfarctions] per 1000 person-years compared with 78 and 2.1 fewer events in patients with transient and no ST-segment depression, respectively).It appears that the greatest benefit for beta-blocker therapy in patients after myocardial infarction is observed in patients with persistent ST-segment depression who are at greatest risk for death and reinfarction. Definitive conclusions regarding therapy with beta-adrenergic blocking agents in patients with persistent ST-segment depression cannot be made because our analysis, given its retrospective nature, is only hypothesis generating.

Heart failure is characterized by progressive worsening of left ventricular (LV) function over time. The mechanism(s) responsible for this hemodynamic deterioration are not known. It is often assumed, but by no means established, that progressive LV dysfunction results largely from ongoing loss of functional cardiac units. If ongoing myocyte loss occurs during the course of evolving heart failure and can indeed account for the progressive deterioration of LV dysfunction, then the identification of factors responsible for this loss of muscle mass can potentially lead to novel therapeutic modalities aimed at preventing the transition toward intractable heart failure. Recent studies in experimental animals have shown that cardiac myocyte loss through apoptosis, or programmed cell death, occurs 1) following myocardial infarction, 2) in the presence of cardiac hypertrophy, 3) in the aging heart, and 4) in the setting of chronic heart failure. The observation of myocyte apoptosis in experimental animal models of heart failure has since been confirmed in the failed human heart. Considerable work has also been accomplished, and credible concepts advanced, in an attempt to uncover the physiological and molecular triggers of myocyte apoptosis in heart failure. While, at present, one can comfortably accept the existence of the phenomenon of myocyte apoptosis in the failing heart, two integral questions remain essentially unanswered. First, what pathophysiological factors(s), inherent to heart failure, trigger myocyte apoptosis? Second, how important is myocyte apoptosis in the progression of LV dysfunction and the transition to overt failure? The present article will summarize our current knowledge of myocyte apoptosis based largely on data available from animal models of myocardial infarction, hypertrophy, and failure.

With greater understanding of the impact of neuroendocrine stimulation on the adverse outcomes of heart failure, especially lethal arrhythmias and sudden cardiac death, focus has returned to the potential benefits of β-adrenergic blockade. In patients with myocardial infarction and left ventricular (LV) dysfunction, particularly those prone to life-threatening arrhythmias, β-blocker therapy has been associated with a lower incidence of arrhythmias and improved survival. Even in the absence of angiotensin-converting enzyme (ACE) inhibition, β blockade has improved cardiac function and LV contractility in nonischemic heart failure, leading to a decrease in LV end-diastolic pressure and improved clinical status. Both the Metoprolol in Dilated Cardiomyopathy (MDC) trial and the Cardiac Insufficiency Bisoprolol Study (CIBIS) found β blockade to be associated with decreased mortality rates in patients with nonischemic heart failure. Of the 3 large randomized mortality trials now under way, the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) is specifically designed to investigate the effects of β blockade on total mortality when used as an adjunct to ACE inhibition in patients with ischemic or nonischemic heart failure. Unresolved issues to be addressed include whether: (1) β-blocker therapy in heart failure can improve survival and/or reduce the incidence of sudden cardiac death; (2) β blockade is equally effective in ischemic and nonischemic heart failure; (3) any specific β blocker may be better tolerated initially and cause fewer adverse effects; and (4) all β blockers result in improved exercise tolerance and quality of life.

Progressive deterioration of left ventricular function is a characteristic feature of the heart failure state and is often speculated to result from ongoing loss of viable myocytes. We previously showed that in dogs with chronic heart failure, cardiocyte death through apoptosis occurs in the border region of fibrous scars (old infarcts). In the present study we examined the structural integrity of cardiocytes in regions bordering fibrous scars using transmission electron microscopy. Morphometric studies were performed using left ventricular tissue obtained from ten dogs with chronic heart failure produced by intracoronary microembolizations. Mitochondrial number increased significantly with proximity to the scar, while mitochondrial size decreased leading to a gradual decrease in mitochondrial volume fraction. Severe injury to mitochondria was present in only 5% of organelles in myocytes far from the scar but increased markedly to 28-41% in myocytes adjacent to or incorporated within the scar. Similarly, severe myofibrillar abnormalities were present in only 3% of myocytes that were far from the scar but increased significantly to 12-73% in myocytes adjacent to or incorporated within the scar. These results indicate that in dogs with chronic heart failure, constituent myocytes of left ventricular regions bordering fibrous scars manifest heterogeneity in the extent of degeneration. The extent of degeneration is greatest in myocytes closest to the scar and least in myocytes far from the scar. We postulate that this wavefront of myocyte degeneration is a dynamic process that may lead to progressive expansion of the scar through loss of viable myocytes and ultimately may contribute, in part, to the progressive left ventricular dysfunction that characterizes the heart failure state.

Heart failure is associated with a hypercoagulable state. A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that warfarin will modify a hypercoagulable state in heart failure. This study included 76 patients with heart failure. At baseline, patients had evidence for a hypercoagulable state with elevated plasma levels of thrombin/antithrombin III (TAT) complexes (3.4 +/- 2.0 ng/ml), prothrombin fragment F1 + 2 (1.5 +/- 0.9 nmol/L), and D-dimers (630 +/- 401 ng/ml). Warfarin therapy (international normalized ratio [INR] 2.7 +/- 1.3) significantly decreased plasma levels of TAT complexes (p < 0.002), F1 + 2 (p < 0.001), and D-dimers (p < 0.001) when compared with baseline values at 1, 2, and 3 months of therapy. In contrast, patients receiving placebo had persistent elevation of TAT complexes (p = not significant [NS]), F1 + 2 (p = NS), and D-dimers (p = NS) during follow-up at 1, 2, and 3 months. The two treatment groups followed different trends over time for all three markers (p < 0.001). The effect of low-intensity warfarin (INR 1.3 +/- 0.08) versus moderate-intensity warfarin (INR 2.3 +/- 1.1 ) on markers of hypercoagulability was evaluated in 14 patients. When compared with baseline, low-intensity warfarin administration decreased plasma levels of TAT complexes (p = NS), F1 + 2 (p = 0.05), and D-dimers (p = 0.04). In these patients F1 + 2 was further reduced with moderate-intensity warfarin (p < 0.001). Our findings suggest that a hypercoagulable state in heart failure can be modified by warfarin therapy.

Since the development of beta-adrenergic blocking agents over 30 years ago, they have been established as an important therapeutic modality in the treatment of coronary heart disease. This article reviews the role of beta-blockers in the treatment of hypertension, angina, acute myocardial infarction, and heart failure. A number of multicenter studies indicate that beta-blockers have an important effect in decreasing morbidity and mortality in patients with hypertension and appear to have a relatively increased importance in elderly patients with hypertension. Although their long-term effects on the mortality of angina pectoris have not been fully investigated, investigations indicate that, compared with other drugs, beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris. The largest use of these drugs has been examined in the treatment of acute myocardial infarction. Two major trials, the Norwegian Timolol Trial and the Beta Blocker Heart Attack Trial, confirm the long-term benefit in patients following acute myocardial infarction. Their use in heart failure is under close investigation following a series of preliminary studies suggesting they may decrease mortality risk. Although the tolerability of these drugs has been questioned, careful examination of clinical trials indicate that they are relatively well tolerated. These observations emphasize the importance of beta-adrenergic blocking agents in hypertension, angina, and acute myocardial infarction and speak to a wider clinical use of these drugs.

The relation between the circadian occurrence of ventricular premature depolarizations (VPD) and sudden arrhythmic death was examined in a subset of patients entered into the Cardiac Arrhythmia Suppression Trial (CAST). Ambulatory electrocardiographic recordings with hourly measurement of VPD frequency were available in 357 patients. Forty percent of the patients (142 of 357) demonstrated circadian variation in VPD frequency between 6:00 a.m. and 9:59 a.m. that was significantly higher (p (Am J Cardiol 1996;78:881–885)

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate70 beats/min (p0.001).

Abnormal left ventricular (LV) filling has been observed in patients with heart failure. One feature of this abnormality is a reduction in the left atrial (LA) contribution to filling, a feature that can adversely affect overall LV stroke output. In this study we examined the effects of early, long-term monotherapy with the beta-blocker, metoprolol, on LA contribution to ventricular filling in dogs with moderate heart failure. LV dysfunction (ejection fraction 30 percent to 40 percent) was produced in 14 dogs by multiple, sequential intracoronary microembolizations. Dogs were randomized to 3 months' therapy with metoprolol (25 mg twice daily; n = 7) or to no therapy at all (control; n = 7). Mitral inflow velocity was measured before randomization and after completion of therapy by using pulsed Doppler echocardiography. The percentage of LA contribution to LV filling was calculated as the ratio of the time-velocity integral of the LA component of mitral inflow velocity (Ai) to the time-velocity integral of total diastolic inflow velocity (Ti) times 100. In control dogs, the percentage of LA contribution to filling decreased after 3 months of follow-up compared with that before randomization (14 percent +/- 3 percent vs 23 percent +/- 5 percent; p = 0.02). In contrast, in dogs treated with metoprolol, the percentage of LA contribution to filling increased after 3 months of therapy compared with that before randomization (26 percent +/- 3 percent vs 21 percent +/- 2 percent; p = 0.001). Therapy with metoprolol produced a decrease in LV end-diastolic pressure, end-diastolic wall stress and stiffness, and an increase in LA fractional shortening compared with no therapy at all. We conclude that early, long-term therapy with metoprolol improves LA contribution to LV filling. This beneficial effect is likely caused by the ability of beta-blockers to reduce LA workload and consequently improve LA performance.

From information on mortality of Jews obtained from individual death certificates and population data from surveys of the Jewish population undertaken in 1963 and 1987, age specific death rates and life expectancy of the Jewish population of Rhode Island are compared with those of the total white population for 1963 and 1987 to assess changing differentials. The Jewish mortality experience continues to differ from that of the larger population even while both groups have experienced noticeable improvements. For males, the age standardized rates have widened in favor of Jews as have the life expectancies at birth and the percentage surviving to old age. By contrast, for females, the standardized death rate has widened considerably in favor of whites, while life expectancy has improved almost identically for both groups and therefore remained about equal, as it was in 1963. Reasons for these patterns are explored through attention to differences between Jews and the general white population in death rates at particular stages of the life cycle. Jews tend to be more advantaged at all but the most advanced ages, age groups in which proportionally more of the Jewish population and Jewish deaths are concentrated.

Contains fulltext : 119127.pdf (Publisher’s version ) (Closed access) Thrombotic events (coronary thrombosis, venous thromboembolism, intraventricular thrombosis, intracranial and systemic thromboembolism) occur frequently in patients with heart failure. These events may be precipitated by several mechanisms including hypercoagulability through enhancement of procoagulant reactions, impairment of the protein C pathway, protease activated receptor (PAR) activation, adenosine-mediated thrombosis, or neurohormonal activation; stasis secondary to low cardiac output; and endothelial dysfunction from neurohormonal activation or systemic inflammation. Pathophysiologic evidence and analyses of retrospective data support the hypothesis that antithrombotic agents may improve outcomes in patients with heart failure. Warfarin has not been shown to reduce clinical events in patients with heart failure, although several of the completed randomized trials were underpowered, and the most recent was not placebo-controlled. Many unanswered questions remain that justify continued research in this area. This paper examines the conceptual framework, opportunities, and challenges of clinical investigative approaches with the newer anti-thrombotic agents in patients with heart failure. Critical questions are raised with regard to clinical trial designs that warrant consideration as the field progresses.

Objectives.This study examined the effects of early long-term monotherapy with enalapril on the severity of functional mitral regurgitation in dogs with moderate heart failure.Background.Functional mitral regurgitation often develops in patients with heart failure and, depending on its severity, can have a marked adverse impact on the stroke output of the failing left ventricle and contribute to progressive deterioration of the heart failure state.Methods.Left ventricular dysfunction (ejection fraction 30% to 40%) was produced in 14 dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 months of therapy with enalapril (10 mg twice daily, n = 7) or no therapy at all (control, n = 7). The severity of functional mitral regurgitation was quantified by Doppler color flow mapping in seven control and six enalapril-treated dogs. Mitral annular diameter was assessed by echocardiography and left ventricular volumes and shape by ventriculography. Measurements were made before initiation and after completion of therapy.Results.In control dogs, the severity of mitral regurgitation increased during the follow-up period ([mean ± SEM] 14 ± 4 vs. 23 ± 4%, p < 0.001) and was associated with increased left ventricular end-systolic and end-diastolic volumes. In contrast, the severity of regurgitation was not significantly changed in dogs treated with enalapril (18 ± 3 vs. 16 ± 6%, p < 0.59) and was associated with preservation of left ventricular volumes.Conclusions.In dogs with moderate heart failure, early long term therapy with enalapril prevents progressive worsening of functional mitral regurgitation. This beneficial effect is most likely achieved by prevention of progressive left ventricular dilation.

Elamipretide is a novel tetrapeptide that targets mitochondrial dysfunction and has the potential to augment cardiac function in HFrEF. To assess the safety of elamipretide, 36 subjects with EF ≤ 35% and stable NYHA Class II-III were randomized (2:1) to a 4-hr IV infusion of elamipretide in 3

A subgroup analysis was performed in black patients who participated in the Metoprolol CR/XL Randomized Intervention trial in Congestive Heart Failure trial. Results suggest a beneficial effect of beta blockade and support the use of beta blockers in black patients with clinically stable heart failure and left ventricular dysfunction.

The Cardiac Arrhythmia Suppression Trial (CAST) showed antiarrhythmic drug suppression of asymptomatic or mildly symptomatic ventricular arrhythmias in survivors of myocardial infarction to be harmful. This study retrospectively searched the CAST results for evidence of mortality and morbidity reduction in patients receiving optional β-blocker therapy. All enrolled (n = 2,611) and suppressed main study (n = 1,735) CAST patients with an ejection fraction of ≤40% were examined using univariate analysis, Kaplan-Meier curves, and a Cox proportional-hazards multivariate analysis with respect to optional β-blocker therapy prescribed at baseline. CAST patients receiving β-blocker therapy had significantly enhanced survival at 30 days, and at 1 and 2 years of follow-up against all-cause and arrhythmic death or nonfatal cardiac arrest. Multivariate analysis showed β-blocker therapy to be independently associated with a one-third reduction in arrhythmic death or cardiac arrest (p = 0.036). In CAST patients with a history of congestive heart failure, β-blocker therapy was independently associated with longer time to occurrence of new or worsened congestive heart failure (p = 0.015). This study supports the secondary preventive benefit of β-blocker therapy in high-risk post-myocardial infarction patients, and calls attention to the possible preventive benefit of β-blocker therapy against proarrhythmic events experienced in the CAST.

Digitalis preparations have been used therapeutically for thousands of years. 1 The first detailed description of digitalis was made by Withering in 1785, who noted that the drug had "a power over the motion of the heart to a degree yet unobserved in any other medicine. ''2 For the next 130 years, the concept was held that digitalis was to be used in the treatment of edema, particularly in the presence of atrial fibrillation. In the 1920s, based on the work of Christian, 3 Luten, 4 and Marvin, 5 this view was opposed, and evidence was presented that the drug was equally as effective in heart failure and sinus rhythm as in atrial fibrillation. The belief that digitalis was an effective drug in the treatment of heart failure and sinus rhythm was reinforced by the emergence of hemodynamic studies in the 1940s. 6,7 Starr and Luchi 8 withdrew digitoxin from elderly women who were in sinus rhythm. Neither patients nor investigators could distinguish difference in symptoms between digitoxin treatment and control periods after 1 month of therapy. Johnston and McDevitt 9 showed that digoxin can be discontinued in many patients with a history of heart failure who were in sinus rhythm without adverse effects. In their study, no objective hemodynamic or exercise parameters were evaluated, and indications for the initial digitalization in the patient cohort were not described. Dall, 1~ Krakauer and Petersen H showed that digoxin therapy could safely be discontinued in three-fourths of geriatric outpatients receiving the drug. Hull and Mackintosh 12 also reported that withdrawal of digoxin in patients with sinus rhythm did not produce any alterations in cardiovascular signs or symptoms. Gheorghiade and Beller 13 showed that cessation of oral maintenance digoxin therapy in patients in sinus rhythm with documented ischemic heart disease and compensated heart failure had few adverse effects. 13 Based on these reports, many questioned the use of digitalis in chronic heart failure, particularly in patients with normal sinus rhythm. 14 In addition, unrecognized drug interactions and problems with the bioavailability of earlier digitalis preparations led to frequent toxicity and reports of increased mortality with digitalis therapy. 15 Whereas the initial report by Starr and Luchi in 1969 was a placebocontrolled, double-blinded study, many of the subsequent studies were either small or had serious methodological flaws. In these latter studies, there was also incomplete characterization of patients and lack of documentation of heart failure. No serial hemodynamic or exercise data were presented. However, these reports renewed interest in the controversy and led to the development of several randomized trials assessing the efficacy of digoxin in patients with chronic heart failure and normal sinus rhythm. Although many of these studies have been performed well, the wide variance in study design and small sample size in many have failed to completely resolve the issue. However, the recent publication of two large, well-designed trials, the Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), has provided additional evidence for the efficacy of digoxin in patients with chronic heart failure because of systolic dysfunction. The purpose of this report is to review the randomized, double-blind, placebocontrolled trials of digoxin in patients with chronic heart failure and normal sinus rhythm, with special attention to the PROVED and RADIANCE trials.

The left atrial (LA) contribution to left ventricular (LV) filling is often attenuated in patients with heart failure. It remains uncertain, however, whether therapy with positive inotropic agents or vasodilators improves or further impairs this maladaptation. In the present study, the effects of intravenous dobutamine and nitroprusside on the LA contribution to LV filling was examined in seven dogs with chronic heart failure produced by multiple sequential intracoronary microembolizations. Pulsed Doppler echocardiography was used to measure mitral inflow velocity before and after an intravenous infusion of dobutamine (4 micrograms/kg/min) and an intravenous infusion of nitroprusside (3 micrograms/kg/min). The percent LA contribution to LV filling was calculated as the ratio of the time-velocity integral of the LA component of mitral inflow velocity (Ai) to the time-velocity integral of total diastolic inflow velocity (Ti) times 100. Dobutamine increased LV filling pressure, LV end-diastolic wall stress, LV end-diastolic stiffness, and Ei, but had no effect on Ai or the percent LA contribution to filling (14% +/- 3% vs 12% +/- 2%) (p0.34). In contrast, nitroprusside decreased LV filling pressure, LV end-diastolic wall stress, and end-diastolic stiffness, and increased Ei, Ai, and the percent LA contribution to LV filling (12% +/- 2% vs 17% +/- 2%) (p0.01). The results indicate that dobutamine and nitroprusside have divergent effects on the LA contribution to LV filling. In dogs with chronic heart failure, dobutamine appears to impair LA contribution to the LV filling by augmenting LA workload, whereas nitroprusside appears to elicit greater LA contribution to LV filling by reducing the LA workload.