Background
Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established ...HF with reduced ejection fraction (HFrEF) is unknown.
Methods
We conducted a double‐blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) slope (co‐primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2, ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire MLHFQ), at baseline and 12‐week follow‐up.
Results
The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM−1 min−1, P = .036), VAT (+1.5 mL kg−1 min−1, P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg−1 min−1, P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (−12.1, P = .018).
Conclusions
In this small and short‐term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2, VAT and quality of life.
Despite significant efforts to predict and prevent right heart failure, it remains a leading cause of morbidity and mortality after implantation of left ventricular assist systems (LVAS). In this ...Perspective, we review the underappreciated anatomic and physiologic principles that govern the relationship between left and right heart function and contribute to this phenomenon. This includes the importance of considering the right ventricle (RV) and pulmonary arterial circuit as a coupled system; the contribution of the left ventricle (LV) to RV contractile function and the potential negative impact of acutely unloading the LV; the influence of the pericardium and ventricular twist on septal function; the role of RV deformation in reduced mechanical efficiency after device placement; and the potential of ongoing stressors of an elevated right-sided preload. We believe an appreciation of these complex issues is required to fully understand the expression of the unique phenotypes of right heart failure after LVAS implantation and for developing better prognostic and therapeutic strategies.
After heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has ...limitations. This is a validation study to assess the performance of a sensitive blood biomarker-percent donor-derived cell-free DNA (%ddcfDNA)-for detection of AR in cardiac transplant recipients.
This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection ACR and antibody-mediated rejection AMR), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range IQR) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.
The study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1-23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%-0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% IQR, 0.31-0.83%, versus 0.03% IQR, 0.01-0.14%;
<0.001). The rise was detected 0.5 and 3.2 months before histopathologic diagnosis of ACR and AMR. The area under the receiver operator characteristic curve for AR was 0.92. A 0.25%ddcfDNA threshold had a negative predictive value for AR of 99% and would have safely eliminated 81% of EMBx. In addition, %ddcfDNA showed distinctive characteristics comparing AMR with ACR, including 5-fold higher levels (AMR ≥2, 1.68% IQR, 0.49-2.79% versus ACR grade ≥2R, 0.34% IQR, 0.28-0.72%), higher area under the receiver operator characteristic curve (0.95 versus 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.
We found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
Data for left ventricular assist devices (LVADs) in patients with noninotrope-dependent heart failure (HF) are limited.
The goal of this study was to evaluate HeartMate II (HMII) LVAD support versus ...optimal medical management (OMM) in ambulatory New York Heart Association functional class IIIB/IV patients meeting indications for LVAD destination therapy but not dependent on intravenous inotropic support.
This was a prospective, multicenter (N = 41), observational study of 200 patients (97 LVAD, 103 OMM). Entry criteria included ≥1 hospitalization for HF in the last 12 months and 6-min walk distance (6MWD) <300 m. The primary composite endpoint was survival on original therapy with improvement in 6MWD ≥75 m at 12 months.
LVAD patients were more severely ill, with more patients classified as Interagency Registry for Mechanically Assisted Circulatory Support profile 4 (65% LVAD vs. 34% OMM; p < 0.001) than 5 to 7. More LVAD patients met the primary endpoint (39% LVAD vs. 21% OMM; odds ratio: 2.4 95% confidence interval: 1.2 to 4.8; p = 0.012). On the basis of as-treated analysis, 12-month survival was greater for LVAD versus OMM (80 ± 4% vs. 63 ± 5%; p = 0.022) patients. Adverse events were higher in LVAD patients, at 1.89 events/patient-year (EPPY), primarily driven by bleeding (1.22 EPPY), than with OMM, at 0.83 EPPY, primarily driven by worsening HF (0.68 EPPY). Most patients (80% LVAD vs. 62% OMM; p < 0.001) required hospitalizations. Health-related quality of life (HRQol) and depression improved from baseline more significantly with LVADs than with OMM (Δ visual analog scale: 29 ± 25 vs. 10 ± 22 p < 0.001; Δ Patient Health Questionnaire-9: -5 ± 7 vs. -1 ± 5 p < 0.001).
Survival with improved functional status was better with HMII LVAD compared with OMM. Despite experiencing more frequent adverse events, LVAD patients improved more in HRQol and depression. The results support HMII use in functionally limited, noninotrope-dependent HF patients with poor HRQoL. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device LVAD and Medical Management ROADMAP; NCT01452802).
Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context ...of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection.
The left ventricular assist device (LVAD) is an accepted treatment alternative for the management of end-stage heart failure. As we move toward implantation of LVADs in less severe cases of HF, ...scrutiny of functional capacity and quality of life becomes more important. Patients demonstrate improvements in exercise capacity after LVAD implantation, but the effect is less than predicted. Exercise training produces multiple beneficial effects in heart failure patients, which would be expected to improve quality of life. In this review, we describe factors that are thought to participate in the persistent exercise impairment in LVAD-supported patients, summarize current knowledge about the effect of exercise training in LVAD-supported patients, and suggest areas for future research.
This study aims to describe the outcomes after heart transplantation using a bridge-to-bridge strategy with a sequence of extracorporeal membrane oxygenation (ECMO) support followed by temporary ...total artificial heart implantation (TAH-t).
A retrospective, multicenter analysis of 54 patients who underwent TAH-t implantation following an ECMO for cardiogenic shock was performed (ECMO-TAH-t group). A control group of 163 patients who underwent TAH-t implantation as a direct bridge to transplantation (TAH-t group) was used to assess this strategy's impact on outcomes.
Fifty-four patients, averaging 47 ± 13 year old, underwent implantation of a TAH-t after 5.3 ± 3.4 days of ECMO perfusion for cardiogenic shock. In the ECMO-TAH-t group, 20 patients (20/54%; 37%) died after TAH-t implantation and 57 patients (57/163%; 35%) died in the TAH-t group (Gray test; P = .49). The top 3 causes of death of patients on TAH-t support were multisystem organ failure (40%), sepsis (20%), and neurologic events (20%). Overall, 32 patients (32/54%; 59%) underwent heart transplantation in the ECMO-TAH-t group compared with 106 patients (106/163%, 65%) in the TAH-t group (P = .44). No significant difference in survival was observed at 6 months, 1 year, and 3 years after heart transplant (ECMO-TAH-t group: 94%, 87%, and 80% vs 87%, 83%, and 76% in the TAH-t group, respectively). Deterioration of liver function (bilirubin, aspartate transaminase, and alanine aminotransferase levels on TAH-t) was associated with increased mortality before heart transplant in both groups.
Sequential bridging from ECMO to TAH-t followed by heart transplantation is a viable option for a group of highly selected patients.
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Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance due to impaired myocardial relaxation and/or increased stiffness. Patients with HFpEF often show ...signs of chronic systemic inflammation, and experimental studies have shown that interleukin-1 (IL-1), a key proinflammatory cytokine, impairs myocardial relaxation. The aim of the present study was to determine the effects of IL-1 blockade with anakinra on aerobic exercise capacity in patients with HFpEF and plasma C-reactive protein (CRP) >2 mg/L (reflecting increased IL-1 activity). A total of 12 patients were enrolled in a double-blind, randomized, placebo-controlled, crossover trial and assigned 1:1 to receive 1 of the 2 treatments (anakinra 100 mg or placebo) for 14 days and an additional 14 days of the alternate treatment (placebo or anakinra). The cardiopulmonary exercise test was performed at baseline, after the first 14 days, and after the second 14 days of treatment. The placebo-corrected interval change in peak oxygen consumption was chosen as the primary end point. All 12 patients enrolled in the present study and receiving treatment completed both phases and experienced no major adverse events. Anakinra led to a statistically significant improvement in peak oxygen consumption (+1.2 ml/kg/min, p = 0.009) and a significant reduction in plasma CRP levels (−74%, p = 0.006). The reduction in CRP levels correlated with the improvement in peak oxygen consumption (R = −0.60, p = 0.002). Three patients (25%) had mild and self-limiting injection site reactions. In conclusion, IL-1 blockade with anakinra for 14 days significantly reduced the systemic inflammatory response and improved the aerobic exercise capacity of patients with HFpEF and elevated plasma CRP levels.
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