Association of Optimal Implementation of Sodium-Glucose Cotransporter 2 Inhibitor Therapy With Outcome for Patients With Heart Failure.

Importance: Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) therapy provided incremental survival benefit to patients with heart failure and reduced ejection fraction (HFrEF) who received guideline-directed medical therapy regardless of type 2 diabetes status in a recent clinical trial. To date, estimation of the potential benefits that could be gained from optimal implementation of SGLT2-i therapy at the population level has not been quantified. Objective: To quantify the projected gains for deaths prevented or postponed with comprehensive implementation of SGLT2-i therapy for patients with HFrEF in the United States. Design, Setting, and Participants: This decision analytical model, performed from September 25 to October 20, 2019, used published sources to estimate the US population of patients with HFrEF eligible for SGLT2-i therapy and the numbers needed to treat to prevent or postpone overt death. Sensitivity analyses were performed to account for the range of potential benefits. Main Outcomes and Measures: All-cause mortality. Results: Of the 3.1 million patients with HFrEF in the United States, 2 132 800 (69%) were projected to be candidates for SGLT2-i therapy. Optimal implementation of SGLT2-i therapy was empirically estimated to prevent up to 34 125 deaths per year (range 21 840-49 140 deaths per year). A secondary analysis excluding patients on the basis of N-terminal-pro brain natriuretic peptide levels and other trial entry criteria would yield a potential benefit of 25 594 deaths per year prevented (range, 16 380-36 855 deaths per year prevented). Conclusions and Relevance: This study suggests that a substantial number of deaths in the United States could be prevented by optimal implementation of SGLT2-i therapy. These data support implementation of the current evidence into practice in a timely manner to achieve important public health benefits and to reduce the mortality burden of HFrEF.

Increasing heart transplant donor pool by liberalization of size matching.

BACKGROUND: The heart transplant (HT) guidelines recommendation to match recipient and donors within 30% of body weight lacks a strong evidence base and is not well established in patients bridged to transplant with left ventricular assist devices (LVAD). In light of the scarcity of donor hearts, we investigated the effect of size mismatch on hemodynamics, one-year survival and length of stay (LOS) following HT. METHODS: Single-center retrospective analysis of consecutive HT patients from April 2007 to September 2017. Recipients were divided into 3 cohorts based on donor-to-recipient weight ratio (DRWR): (1) undersized (<0.7), (2) size-matched, (0.7-1.3); (3) oversized (>1.3). RESULTS: 288 consecutive patients were identified (mean age 53 ± 11 years; 76% male), 46 were undersized (0.61 ± 0.05), 210 size-matched (0.94 ± 0.16), and 32 oversized (1.65 ± 0.38). There was no significant difference in donor left ventricular end diastolic diameter (LVEDD) between the 3 groups (p = 0.11). The donor/recipient (D/R) predicted heart mass (PHM) was lowest in the undersized group (0.92 ± 0.13). There were no significant differences in 1-year survival in the overall and LVAD cohort (p = 0.65 and 0.59, respectively). Neither donor LVEDD nor D/R PHM differed among survivors or non-survivors. LOS was longer in the undersized group than the size-matched cohort (p = 0.004). The undersized group had hearts with the highest filling pressures and lowest cardiac index at 1 week among the remaining groups (p = 0.009, 0.017, and p = 0.05, respectively). There were no clinically significant differences in hemodynamics at 1 or 6 months. CONCLUSIONS: HT undersizing affects hemodynamics early but not later in the course and does not impact 1-year survival. The liberalization of size matching may increase the HT donor pool significantly.

Prevention of Heart Failure in Patients with Diabetes: Role of Diabetes Medications.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). In patients with DM, preventing HF using diabetes medications should be an imperative for primary care physicians and cardiologists alike. RECENT FINDINGS: Prior studies with DPP-IV inhibitors, thiazolidinediones (TZDs), and GLP-1 agonists have demonstrated either a neutral effect on HF or increased HF hospitalizations. Two recent large-scale randomized controlled trials (RCTs), EMPA-REG OUTCOME and CANVAS, compared sodium glucose transporter-2 inhibitor (SGLT-2i) to placebo. Use of SGLT-2i led to a substantial reduction in HF events and hospitalizations in patients with DM, with or without history of HF. Use of SGLT-2i therapy has been shown to reduce HF in patients with DM.

Evolution of Omega-3 Fatty Acid Therapy and Current and Future Role in the Management of Dyslipidemia.

Omega-3 fatty acids have shown modest benefit in certain subgroups at higher cardiovascular risk. Ongoing trials are investigating cardiovascular event rate reduction with newer, more efficacious formulations with a focus on these higher risk patients. This article focuses on the previously demonstrated benefits of omega-3 fatty acid therapies, currently available formulations, and their current and future role in reducing cardiovascular risk.

T-tubule remodeling and increased heterogeneity of calcium release during the progression to heart failure in intact rat ventricle.

A highly organized transverse-tubule (TT) system is essential to normal Ca2+ cycling and cardiac function. We explored the relationship between the progressive disruption of TTs and resulting Ca2+ cycling during the development of heart failure (HF). Confocal imaging was used to measure Ca2+ transients and 2-D z-stack images in left ventricular epicardial myocytes of intact hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats. TT organization was measured as the organizational index (OI) derived from a fast Fourier transform of TT organization. We found little decrease in the synchrony of Ca2+ release with TT loss until TT remodeling was severe, suggesting a TT "reserve" characterized by a wide range of TT remodeling with little effect on synchrony of release but beyond which variability in release shows an accelerating sensitivity to TT loss. To explain this observation, we applied a computational model of spatially distributed Ca2+ signaling units to investigate the relationship between OI and excitation-contraction coupling. Our model showed that release heterogeneity exhibits a nonlinear relationship on both the spatial distribution of release units and the separation between L-type Ca2+ channels and ryanodine receptors. Our results demonstrate a unique relationship between the synchrony of Ca2+ release and TT organization in myocytes of intact rat ventricle that may contribute to both the compensated and decompensated phases of heart failure.

Choosing the right heart: proper donor selection in cardiac transplantation.

PURPOSE OF REVIEW: Orthotopic heart transplantation remains a definitive treatment for advanced heart failure. This review describes, on an individual patient level, how best to select donor hearts. RECENT FINDINGS: In selecting hearts, recipient health factors and comorbidities tend to outweigh most donor factors. Expanded donor criteria will allow for transplanting a larger group of patients. More work remains on developing scoring systems, ex-vivo perfusion of the donor heart, and use of donor biomarkers. SUMMARY: Considering the power of the donor heart allows for optimization of donor-recipient matching.

Omega-3 carboxylic acids monotherapy and combination with statins in the management of dyslipidemia.

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management placed greater emphasis on statin therapy given the well-established benefits in primary and secondary prevention of cardiovascular disease. Residual risk may remain after statin initiation, in part because of triglyceride-rich lipoprotein cholesterol. Several large trials have failed to show benefit with non-statin cholesterol-lowering medications in the reduction of cardiovascular events. Yet, subgroup analyses showed a benefit in those with hypertriglyceridemia and lower high-density lipoprotein cholesterol level, a high-risk pattern of dyslipidemia. This review discusses the benefits of omega-3 carboxylic acids, a recently approved formulation of omega-3 fatty acid with enhanced bioavailability, in the treatment of dyslipidemia both as monotherapy and combination therapy with a statin.

The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter?

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects.

Lifestyle modification for metabolic syndrome: a systematic review.

BACKGROUND: All 5 components of metabolic syndrome have been shown to improve with lifestyle and diet modification. New strategies for achieving adherence to meaningful lifestyle change are needed to optimize atherosclerotic cardiovascular risk reduction. We performed a systematic literature review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework (PRISMA), investigating optimal methods for achieving lifestyle change in metabolic syndrome. METHODS: We submitted standardized search terms to the PubMed Central, CINAHL, Web of Science, and Ovid databases. Within those results, we selected randomized controlled trials (RCTs) presenting unique methods of achieving lifestyle change in patients with one or more components of the metabolic syndrome. Data extraction using the population, intervention, comparator, outcome, and risk of bias framework (PICO) was used to compare the following endpoints: prevalence of metabolic syndrome, prevalence of individual metabolic syndrome components, mean number of metabolic syndrome components, and amount of weight loss achieved. RESULTS: Twenty-eight RCTs (6372 patients) were included. Eight RCTs demonstrated improvement in metabolic syndrome risk factors after 1 year. Team-based, interactive approaches with high-frequency contact with patients who are motivated made the largest and most lasting impact. Technology was found to be a useful tool in achieving lifestyle change, but ineffective when compared with personal contact. CONCLUSION: Patient motivation leading to improved lifestyle adherence is a key factor in achieving reduction in metabolic syndrome components. These elements can be enhanced via frequent encounters with the health care system. Use of technologies such as mobile and Internet-based communication can increase the effectiveness of lifestyle change in metabolic syndrome, but should not replace personal contact as the cornerstone of therapy. Our ability to derive quantitative conclusions is limited by inconsistent outcome measures across studies, low power and homogeneity of individual studies, largely motivated study populations, short follow-up periods, loss to follow-up, and lack of or incomplete blinding.

Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure.

Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.

BACKGROUND: Abnormalities in intracellular calcium (Ca) cycling during Ca overload can cause triggered activity because spontaneous calcium release (SCR) activates sufficient Ca-sensitive inward currents to induce delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue scale. METHODS AND RESULTS: Laser scanning confocal microscopy was used to measure the spatiotemporal properties of SCR within large myocyte populations in intact rat heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. We measured the average and standard deviation of the latency distribution of SCR within a large population of myocytes in intact tissue. We found that as external [Ca] is increased, and with faster pacing rates, the average and SD of the latency distribution decreases substantially. This result demonstrates that the timing of SCR occurs with less variability as the sarcoplasmic reticulum (SR) Ca load is increased, causing more sites to release Ca within each cell. We then applied a mathematical model of subcellular Ca cycling to show that a decrease in SCR variability leads to a higher DAD amplitude and is dictated by the rate of SR Ca refilling following an action potential. CONCLUSIONS: Our results demonstrate that the variability of the timing of SCR in a population of cells in tissue decreases with SR load and is dictated by the time course of the SR Ca content.