BackgroundIn a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. MethodsWe randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. ResultsAt 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, −14.1 ml per square meter and −14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-...

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Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation

Background Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited. Methods We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank. Results At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement g...

/pdf/mitral-valve-repair-versus-replacement-for-severe-ischemic-3lhmn3v6eu.pdf

Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation

Ventricular remodeling, first described in animal models of left ventricular (LV) stress and injury, occurs progressively in untreated patients after large myocardial infarction and in those with dilated forms of cardiomyopathy. The gross pathologic changes of increased LV volume and perturbation in the normal elliptical LV chamber configuration is driven, on a histologic level, by myocyte hypertrophy and apoptosis and by increased interstitial collagen. Each of the techniques used for tracking this process—echocardiography, radionuclide ventriculography, and cardiac magnetic resonance—carries advantages and disadvantages. Numerous investigations have demonstrated the value of LV volume measurement at a single time-point and over time in predicting clinical outcomes in patients with heart failure and in those after myocardial infarction. The structural pattern of LV remodeling and evidence of scarring on cardiac magnetic resonance have additional prognostic value. Beyond the impact of abnormal cardiac structure on cardiovascular events, the relationship between LV remodeling and clinical outcomes is likely linked through common local and systemic factors driving vascular as well as myocardial pathology. As demonstrated by a recent meta-analysis of heart failure trials, LV volume stands out among surrogate markers as strongly correlating with the impact of a particular drug or device therapy on patient survival. These findings substantiate the importance of ventricular remodeling as central in the pathophysiology of advancing heart failure and support the role of measures of LV remodeling in the clinical investigation of novel heart failure treatments.

Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment.

Background—The purpose of this study was to determine the effects of systemic exercise training on endothelium-mediated arteriolar vasodilation of the lower limb and its relation to exercise capacity in chronic heart failure (CHF). Endothelial dysfunction is a key feature of CHF, contributing to increased peripheral vasoconstriction and impaired exercise capacity. Local handgrip exercise has previously been shown to enhance endothelium-dependent vasodilation in conduit and resistance vessels in CHF. Methods and Results—Twenty patients were prospectively randomized to a training group (n=10, left ventricular ejection fraction [LVEF] 24±4%) or a control group (n=10, LVEF 23±3%). At baseline and after 6 months, peak flow velocity was measured in the left femoral artery using a Doppler wire; vessel diameter was determined by quantitative angiography. Peripheral blood flow was calculated from average peak velocity (APV) and arterial cross-sectional area. After exercise training, nitroglycerin-induced endotheli...

Regular Physical Exercise Corrects Endothelial Dysfunction and Improves Exercise Capacity in Patients With Chronic Heart Failure.

Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome—apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.

https://www.pnas.org/content/pnas/108/49/19725.full.pdf

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse

Quantitative Evaluation of Drug or Device Effects on Ventricular Remodeling as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction: A Meta-Analytic Approach

Background While peak oxygen consumption (peak VO2), 6 minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction (LVD). Methods and Results We identified drug or device therapies for which there exists at least one randomized controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies we identified RCTs assessing the short term changes in VO2, 6MW, BNP and NT-proBNP (few of the mortality RCTs assessed the short term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n = 73,267 patients) with a median follow-up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak VO2 trials (n = 4,646 patients), 34 6MW trials (n= 6,995 patients), 15 BNP trials (n = 7,233) and 6 NT-proBNP trials (n=1,946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak VO2 and the odds ratio for mortality (r = 0.158, p = 0.26). Increased drug or device induced average change in 6MW was correlated with increased odds ratio for mortality (r = 0.373, p = 0.036). There was no significant correlation between the average therapy-induced placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP: r = -0.065, p = 0.82, NTproBNP: r = -0.667, p = 0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality. Conclusions This analysis, limited to trial level data from different therapeutic eras, suggests that drugor device-induced effects on peak VO2, 6MW, and natriuretic peptides found in short term trials do not predict the corresponding average long term therapeutic effects on mortality for patients with HF and LVD.

Drug and Device Effects on Peak Oxygen Consumption, 6 Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients with Heart Failure and Reduced Ejection Fraction Wessler et al: Surrogate Markers in Heart Failure

Background— Although peak oxygen consumption (peak Vo2), 6-minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short-term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction.

Methods and Results— We identified drug or device therapies for which there exists at least 1 randomized, controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies, we identified RCTs assessing the short-term changes in Vo2, 6MW, BNP, and NT-proBNP (few of the mortality RCTs assessed the short-term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug- or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n=73 267 patients) with a median follow-up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak Vo2 trials (n=4646 patients), 34 6MW trials (n=6995 patients), 15 BNP trials (n=7233), and 6 NT-proBNP trials (n=1946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak Vo2 and the odds ratio for mortality ( r =0.158, P =0.26). Increased drug or device-induced average change in 6MW was correlated with increased odds ratio for mortality ( r =0.373, P =0.036). There was no significant correlation between the average therapy-induced, placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP: r =−0.065, P =0.82, NT-proBNP: r =−0.667, P =0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality.

Conclusions— This analysis, limited to trial level data from different therapeutic eras, suggests that drug- or device-induced effects on peak Vo2, 6MW, and natriuretic peptides found in short-term trials do not predict the corresponding average long-term therapeutic effects on mortality for patients with HF and left ventricular dysfunction.

Drug and Device Effects on Peak Oxygen Consumption, 6-Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction

Daniel G. Kramer

Papers

Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment.

Quantitative Evaluation of Drug or Device Effects on Ventricular Remodeling as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction: A Meta-Analytic Approach

Drug and Device Effects on Peak Oxygen Consumption, 6 Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients with Heart Failure and Reduced Ejection Fraction Wessler et al: Surrogate Markers in Heart Failure

Drug and Device Effects on Peak Oxygen Consumption, 6-Minute Walk Distance, and Natriuretic Peptides as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction