Effectiveness of β-Blockers in Heart Failure With Left Ventricular Systolic Dysfunction and Chronic Kidney Disease

BackgroundEstablishing medication effectiveness outside of a randomized trial requires careful study design to mitigate selection bias. Previous observational studies of β-blockers in patients with chronic kidney disease and heart failure have had methodologic limitations that may have introduced bias. We examined whether initiation of β-blocker therapy was associated with better outcomes among patients with chronic kidney disease and newly diagnosed heart failure with left ventricular systolic dysfunction.Methods and ResultsWe identified 668 adults in the Kaiser Permanente Northern California system from 2006 to 2008 with chronic kidney disease, incident heart failure, left ventricular systolic dysfunction, and no previous β-blocker use. We defined chronic kidney disease as estimated glomerular filtration rate <60 mL min^?1 1.73 m^?2 or proteinuria, and we excluded patients receiving dialysis. We used extended Cox regression to assess the association of treatment with death and the combined end point of death or heart failure hospitalization. Initiation of β-blocker therapy was associated with a significantly lower crude risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.35–0.63), but this association was attenuated and no longer significant after multivariable adjustment (HR 0.75, CI 0.51–1.12). β-Blocker therapy was significantly associated with a lower risk of death or heart failure hospitalization even after adjustment for potential confounders (HR 0.67, CI 0.51–0.88).Conclusionsβ-Blocker therapy is associated with lower risk of death or heart failure hospitalization among patients with chronic kidney disease, incident heart failure, and left ventricular systolic dysfunction.     

Left Ventricular Diastolic Dysfunction in β-Thalassemia Major with Heart Failure

We studied the clinical, electrocardiographic, echocardiographic, Doppler and T2* cardiac magnetic resonance (CMR) data of all adult β-thalassemia major (β-TM) patients with heart failure (HF) consecutively observed at our referral center of the Sicilian region between 2008 and 2016. There were 16 patients enrolled in the study. Echocardiographic examination showed that only one patient had HF with systolic dysfunction of the left ventricle (HFrEF), whereas the others had HF with preserved systolic function of the left ventricle (HFpEF). Systolic dysfunction of the right ventricle (RV) was observed in 13 cases. Furthermore, 30.0% of the patients presented T2* CMR values consistent with intermediate risk of systolic dysfunction of the left ventricle (LV) due to iron overload, whereas 70.0% had normal values. Typical electrocardiographic abnormalities (wide T wave inversion and low voltages) were observed in 11 out of 16 patients. In conclusion, in the adult β-TM patients with HF recently observed at our center, the predominant form was that with diastolic dysfunction of the LV, and with systolic dysfunction of the RV. Only 30.0% had low values of T2* CMR. Typical electrocardiographic abnormalities were found in 69.0%.     

Left Ventricular Dysfunction and Exercise Capacity Trajectory: Implications for Subclinical Heart Failure Staging Criteria

ObjectivesThis study aimed to determine the association of stage B heart failure (SBHF) and its constituent left ventricular (LV) abnormalities with trajectory of exercise capacity over time, and assess whether this association is modified by reversion of these LV abnormalities to normal.BackgroundThe LV abnormalities of SBHF may coincide with a reduction in exercise capacity that precedes the overt exercise intolerance of clinical heart failure (HF). Determining the predictive capacity of established and novel SBHF criteria for exercise capacity decline may improve HF risk stratification.MethodsLV structure/function (echocardiography) and exercise capacity (6-min walk distance [6MWD]) were assessed at baseline and 3-year follow-up in 268 patients from the NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) study (all stage A [SAHF] or SBHF). Changes (Δ) in 6MWD were compared between SAHF and SBHF and across each of 4 constituent components of SBHF: LV hypertrophy, regional wall motion abnormality(ies) (RWMA), left ventricular systolic dysfunction (LVSD) (ejection fraction <45%) and elevated early diastolic filling/annular velocity ratio (E/e’ ≥15).ResultsΔ6MWD was similar in those with SAHF (n = 141) and SBHF (n = 127; ?5 m [95% confidence interval (CI): ?21 to +11 m]; covariate-adjusted). However, within the setting of SBHF there was substantive heterogeneity; that is, reductions in 6MWD were observed with persistent elevated E/e’ (?34 m [95% CI: ?62 to ?6 m]) and persistent LVSD (?41 m [95% CI: ?74 to ?8 m]), but not with LV hypertrophy (+17 m [95% CI: ?15 to +49 m) or RWMA (+5 m [?27 to +36 m]), nor in patients whose elevated E/e’ or LVSD reverted to normal by 3 years (p > 0.10).ConclusionsElevated E/e’ is associated with a similar degree of exercise capacity decline to LVSD, supporting that both LV functional criteria be considered in distinguishing SBHF from SAHF. That reversion of either manifestation of LV dysfunction was associated with preserved exercise capacity advocates targeting of these factors by HF preventive interventions.     

Intravenous Infusion of the β3-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs With Systolic Heart Failure

BackgroundUnlike β₁- and β₂-adrenergic receptors (ARs), β₃-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β₃-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous infusions of the β₃-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF).Methods and ResultsThree separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35–15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure.ConclusionsIntravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF.     

Potential Usefulness and Clinical Relevance of Adding Left Atrial Strain to Left Atrial Volume Index in the Detection of Left Ventricular Diastolic Dysfunction

Objectives

The purpose of this study was to analyze the potential usefulness and clinical relevance of adding left atrial (LA) strain to left atrial volume index (LAVI) in the detection of left ventricular diastolic dysfunction (LVDD) in patients with preserved left ventricular ejection fraction (LVEF).

New and Emerging Biomarkers in Left Ventricular Systolic Dysfunction—Insight into Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by deteriorating cardiac performance, impaired contraction and dilation of the left ventricle (or both ventricles). Blood markers—known as “biomarkers”—allow insight into underlying pathophysiologic mechanisms and biologic pathways while predicting outcomes and guiding heart failure management and/or therapies. In this review, we provide an alternative approach to conceptualize heart failure biomarkers: the cardiomyocyte, its surrounding microenvironment, and the macroenvironment, integrating these entities which may impact cellular processes involved in the pathogenesis and/or propagation of DCM. Newer biomarkers of left ventricular systolic dysfunction can be categorized under: (a) myocyte stress and stretch, (b) myocyte apoptosis, (c) cardiac interstitium, (d) inflammation, (e) oxidative stress, (f) cardiac energetics, (g) neurohormones, and (h) renal biomarkers. Biomarkers provide insight into the pathogenesis of DCM while predicting and potentially providing prognostic information in these patients with heart failure.     

Doppler Tissue Imaging Assessment of Left Ventricular Systolic Dyssynchrony in Severe Heart Failure Patients With a Normal QRS Duration

Objectives To assess the prevalence of systolic dyssynchrony of the left ventricular （LV） walls in patients of heart failure（HF） with a normal QRS duration by Doppler tissue imaging （DTI）. Methods 20 patients of HF with a normal QRS duration and 20 healthy individuals were investigated with DTI to quantitatively analyze their pulsed-wave Doppler spectrum of basal and middle segments in six walls of left ventricle. The time between the onset of the QRS complex of the surface ECG and the onset of the systolic wave of pulsed-wave Doppler spectrum was measured （TS）. LV systolic synchronization was assessed by the maximal difference （MD） in time of TS, the standard deviation （SD） and the coefficient of variation （CV） of TS in the all 12 LV segments. Results When a TS-MD of TS〉 53.08 ms, a TS-SD of TS 〉18.08 ms and a TS-CV of TS 〉 0.91 （＋1.65 SD of normal controls） was used to define significant systolic dyssynchrony, the prevalence of systolic dyssynchrony was 55.0 %, 55.0 % and 55.0 %, respectively, in the HF patients group, significantly higher than those in the normal control and the locations of delayed contraction of these patients were different. Conclusions LV systolic dyssynchrony could be commonly demonstrated by DTI in HF patients with a normal QRS duration. This finding will support the view about the possibility that more HF patients could benefit from cardiac resynchronization therapy.     

Proenkephalin,Renal Dysfunction,and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study

Background

Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis.

Left Ventricular Restoration: How Important is the Surgical Treatment of Ischemic Heart Failure Trial?

If the Surgical Treatment of Ischemic Heart Failure (STICH) trial demonstrates that surgical therapy is superior to medical therapy, early aggressive evaluation of coronary artery disease as a potentially correctable cause of new-onset heart failure would be the preferred strategy. This strategy could tremendously change the treatment of ischemic heart disease. Confirming the STICH revascularization hypothesis will dramatically increase the use of coronary artery bypass grafting among the millions of patients now being medically treated without evaluation for an ischemic cause.     

Echocardiographic Evaluation of Right Ventricular Stroke Work Index in Advanced Heart Failure: A New Index?

BackgroundRight ventricular (RV) function plays a pivotal role in advanced heart failure patients, especially for screening those who may benefit from left ventricular assist device (LVAD) implantation. We introduce RV contraction pressure index (RVCPI) as a new echo-Doppler parameter of RV function. The accuracy of RVCPI in detecting RV failure was compared with the criterion standard, the RV stroke work index (RVSWI) obtained through right heart catheterization in advanced heart failure patients referred for heart transplantation or LVAD implantation.Methods and ResultsRight heart catheterization and echo-Doppler were simultaneously performed in 94 consecutive patients referred to our center for advanced heart failure (ejection fraction (EF) 24 ± 8.8%, 40% NYHA functional class IV). RV stroke volume and invasive pulmonary pressures were used to obtain RVSWI. Simplified RVCPI (sRVCPI) was derived as TAPSE × (RV ? right atrial pressure gradient). Close positive correlation between sRVCPI and RVSWI was found (r = 0.68; P < .001). With logistic regression, we found that increased sRVCPI showed an independent reduced risk (odds ratio 0.98, 95% confidence interval [CI] 0.97–0.99; P = .016) for patients to present a depressed RVSWI (<0.25 mm Hg/L·m²). Simplified RVCPI showed high diagnostic accuracy (area under the receiver operating characteristic curve 0.94, 95% CI 0.89–0.99) and good sensitivity and specificity (92% and 85%, respectively) to predict depressed RVSWI with the use of a cutoff value of <400 mm·mm Hg.ConclusionsIn patients with advanced heart failure, the new simple bedside sRVCPI closely correlated with RVSWI, providing an independent, noninvasive, and easy tool for the evaluation of RV function.     

Heart Transplantation and Left Ventricular Assist Device Therapy: Two Comparable Options in End‐Stage Heart Failure?

Heart transplantation is the only curative therapy for chronic heart failure, and it plays an important role in the treatment of chronic heart failure with a survival rate of approximately 50% of all patients after 10 years. This has to be kept in mind when alternative therapies enter into our daily routine in treating this patient population. However, the shortage of appropriate donor organs and the expanding pool of patients waiting for heart transplantation have led to growing interest in alternative strategies, particularly in left ventricular assist device (LVAD) therapy. With growing clinical experience and continued technical advances, continuous‐flow pumps are evolving as a bridge to transplantation or as a destination therapy for advanced heart failure. Nevertheless, the importance of this new indication of chronic cardiac support compared to heart transplantation is still completely open and the object of controversial ongoing discussion. This review (1) describes the clinical use and long‐term outcome of a currently available miniaturized LVAD in the context to the standard of care—heart transplantation, (2) provides an outlook of the ongoing process of further optimization of LVADs, and (3) comments on the challenges with assist devices as alternatives to transplantation with a 5‐year outlook.     

Overexpansion of the SAPIEN 3 Transcatheter Heart Valve: An Ex Vivo Bench Study

Objectives

This study assessed the effect of overexpansion beyond labeled size (diameter) of transcatheter heart valves through an ex vivo bench study.

Coronary Artery Bypass Surgery Improves Outcomes in Patients With Diabetes and Left Ventricular Dysfunction

Background

The role of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with diabetes mellitus (DM) and multivessel coronary artery disease (CAD) has been established by large trials; however, these trials largely excluded patients with left ventricular dysfunction (LVD).

Cost-Effectiveness of Eplerenone in Patients with Left Ventricular Dysfunction after Myocardial Infarction—An Analysis of the EPHESUS Study from a Swiss Perspective

Objective The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting. Materials and methods A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16 months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%. Results The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively. Conclusion Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AMI.     

Assessment of reproducibility – automated and digital caliper ECG measurement in the Framingham Heart Study

Background

Digitized electrocardiography permits the rapid, automated quantification of electrocardiograms (ECGs) for analysis. Community- and population-based studies have increasingly integrated such data. Assessing the reproducibility of automated ECG measures with manual measures is a critical step in preparation for using automated measures for research purposes. We recently established an ECG repository of digitally recorded ECGs for the Framingham Heart Study and we sought to assess the reproducibility of automated and manual measures.

Methods

We selected 185 digitally recorded ECGs from routine visits of Framingham Heart Study participants spanning from 1986 to 2012. We selected the following ECG measures for their relevance to clinical and epidemiologic research: P wave duration, P wave amplitude, and PR interval in lead II; QRS duration and R wave amplitude in lead V6; and QT interval in lead V5. We obtained automated values for each waveform, and used a digital caliper for manual measurements. Digital caliper measurements were repeated in a subset (n = 81) of the samples for intrarater assessment.

Results

We calculated the intraclass correlation coefficient (ICC) values for the interrater and intrarater assessments. P wave duration had the lowest interrater ICC (r = 0.46) and lowest intrarater ICC (r = 0.57). R wave amplitude had the highest interrater and intrarater ICC (r = 0.98) indicating excellent reproducibility. The remaining measures had interrater and intrarater ICCs of r ≥ 0.81.

Conclusions

The interrater reproducibility findings for P wave amplitude, PR interval, QT interval, QRS duration, and R wave amplitude were excellent. In contrast, the reproducibility of P wave duration was more modest. These findings indicate high reproducibility of most automated and manual ECG measurements.