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• Whether dapagliflozin is beneficial in patients with sleep apnea and heart failure, across the range of ejection fractions, is unknown. • In a pooled individual-level meta-analysis of DAPA-HF and DELIVER, investigator-reported sleep apnea was associated with a greater risk of worsening heart failure events. • Dapagliflozin, compared with placebo, reduced the risk of clinical outcomes and improved health-related quality of life in patients with and without sleep apnea. Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10–1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59–1.03]) and without sleep apnea (HR 0.79 [0.72–0.87]) [P interaction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. Unique identifiers: NCT01920711 In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions. [ABSTRACT FROM AUTHOR]

• Longer duration of chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≥ 45% was associated with a higher comorbidity burden, lower baseline health status and adverse clinical outcomes in the PARAGON-HF trial. • Sacubitril/valsartan was well tolerated across the spectrum of HF duration, with consistent relative and higher absolute treatment effects in participants with the longest baseline HF durations. • Sustained focus on optimization of medical therapy at all stages of the HF disease course, in all clinical settings and across the HF spectrum, is needed to abrogate downstream disease progression. In this post hoc analysis of the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, we evaluated clinical outcomes and responses to sacubitril/valsartan by duration of heart failure (HF) with left ventricular ejection fraction ≥ 45% at initial diagnosis. The primary outcome was a composite of total hospitalizations due to HF and cardiovascular deaths, analyzed by using a semiparametric proportional rates method, stratified by geographic region. Among 4784 (99.7%) randomized participants in the PARAGON-HF trial for whom baseline HF duration was captured, 1359 (28%) had durations of HF of < 6 months, 1295 (27%) of 6 months–2 years, and 2130 (45%) of > 2 years. Longer HF duration was associated with higher comorbidity burdens, worse health status and lower rates of prior hospitalization due to HF. Over a median follow-up of 35 months, longer HF duration was associated with a higher risk of first and recurrent primary events (per 100 patient-years): < 6 months, 12.0 (95% CI, 10.4–14.0); 6 months–2 years, 12.2 (10.6–14.2); > 2 years, 15.8 (14.2–17.5). Relative treatment effects of sacubitril/valsartan vs valsartan were consistent, irrespective of baseline HF duration on the primary endpoint (P interaction = 0.112). Clinically meaningful (≥ 5 point) improvements in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores were also similarly observed, irrespective of HF duration; (P interaction = 0.112). Adverse events were similar between treatment arms across HF duration categories. In PARAGON-HF, longer HF duration was independently predictive of adverse HF outcomes. Treatment effects of sacubitril/valsartan were consistent, irrespective of baseline HF duration, suggesting that even ambulatory patients with longstanding HFpEF and predominantly mild symptoms stand to benefit from treatment optimization. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Therapy guided by pulmonary artery (PA) pressure monitoring reduces PA pressures and heart failure hospitalizations (HFH) during the first year, but durability of efficacy and safety out to two years is not known.Methods and Results: The CardioMEMS Post-Approval Study investigated whether benefit and safety were generalized and sustained. Enrollment at 104 US centers included 1200 patients with NYHA Class III symptoms on recommended HF therapies with prior HFH. Therapy was adjusted toward PA diastolic pressure 8-20 mmHg. Intervention frequency and PA pressure reduction were most intense during first 90 days, with sustained reduction of PA diastolic pressure from baseline 24.7 mmHg to 21.0 at 1 year and 20.8 at 2 years, all patients. Patients surviving to 2 years (n=710) showed similar 2-year reduction (23.9 to 20.8 mmHg), with reduction in PA mean pressure (33.7 to 29.4 mmHg) in patients with reduced LVEF. The HFH rate was 1.25 events/patient/year prior to sensor implant, 0.54 at 1 year, and 0.37 at 2 years, with 59% of surviving patients free of HFH.Conclusions: Reduction in PA pressures and hospitalizations were early and sustained during 2 years of PA pressure guided management, with no signal of safety concern regarding the implanted sensor. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) with preserved ejection fraction are commonly admitted to the hospital for both cardiovascular (CV) and noncardiovascular (non-CV) reasons. The prognostic implications of non-CV hospitalizations in this population are not well understood. In this study, we aimed to examine the prognostic implications of hospitalizations owing to CV and non-CV reasons in a HF with preserved ejection fraction population.Methods and Results: The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) randomized 3445 stable outpatients with chronic HF with a left ventricular ejection fraction of 45% or greater and either prior hospitalization for HF or elevated natriuretic peptides to treatment with spironolactone or placebo. Hospitalizations for any cause were reported by investigators during study follow-up and characterized according to prespecified category causes. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n = 1767), in which 2973 hospitalizations were observed in 1062 subjects (60%) over a mean follow-up of 3.3 years of study follow-up, of which 1474 (49%) were ascribed to CV causes. Among 1056 first hospitalizations, 478 (45%) were for CV reasons and 578 (55%) for non-CV reasons. Mortality rates were lowest for participants not hospitalized during the trial (3.2 per 100 patient-years [PY]), but similarly elevated after first hospitalization for CV and non-CV reasons (11.0 per 100 PY vs 12.6 per 100 PY, respectively; P = .24). Among those hospitalized for CV reasons, mortality rates were similar after hospitalization for HF and non-CV related reasons (15.2 per 100 PY vs 12.6 per 100 PY; P = .23). Recurrent hospitalization, whether owing to CV or non-CV causes, was associated with a heightened risk for subsequent mortality, with similar death rates after hospitalization twice for CV reasons (18.5 per 100 PY), twice for non-CV reasons (21.6 per 100 PY), or once each for CV and non-CV reasons (18.4 per 100 PY).Conclusions: Among patients with HF with preserved ejection fraction, hospitalization for any cause is associated with a heightened risk for postdischarge mortality, with an even higher risk associated with recurrent hospitalization. Given the high burden of non-CV hospitalizations in this population, the targeted management of comorbid medical illness may be critical to decreasing morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Implementation of guideline-directed cholesterol management remains low despite definitive evidence establishing such measures reduce cardiovascular (CV) events, especially in high atherosclerotic CV disease (ASCVD) risk patients. Modern electronic resources now exist that may help improve health care delivery. While electronic medical records (EMR) allow for population health screening, the potential for coupling EMR screening to remotely delivered algorithmic population-based management has been less studied as a way of overcoming barriers to optimal cholesterol management.Methods: In an academically affiliated healthcare system, using EMR screening, we sought to identify 1,000 high ASCVD risk patients not meeting guideline-directed low-density lipoprotein-cholesterol (LDL-C) goals within specific system-affiliated primary care practices. Contacted patients received cholesterol education and were offered a remote, guideline-directed, algorithmic cholesterol management program executed by trained but non-licensed "navigators" under professional supervision. Navigators used telephone, proprietary software and internet resources to facilitate algorithm-driven, guideline-based medication initiation/titration, and laboratory testing until patients achieved LDL-C goals or exited the program. As a clinical effectiveness program for cholesterol guideline implementation, comparison was made to those contacted patients who declined program-based medication management, and received education only, along with their usual care.Results: 1021 patients falling into guideline-defined high ASCVD risk groups warranting statin therapy (ASCVD, type 2 diabetes, LDL ≥ 190 mg/dL, calculated 10-year ASCVD risk ≥7.5%) and not achieving guideline-defined target LDL-C levels and/or therapy were identified and contacted. Among the 698 such patients who opted for program medication management, significant LDL-C reductions occurred in the total cohort (mean -65.4 mg/dL, 45% decrease), and each high ASCVD risk subgroup: ASCVD (-57.2 mg/dL, -48.0%); diabetes mellitus (-53.1 mg/dL, -40.0%); severe hypercholesterolemia (-76.3 mg/dL, -45.7%); elevated ASCVD 10-year risk (-62.8 mg/dL, -41.1%) (P<0.001 for all), without any significant complications. Among 20% of participants with reported statin intolerance, average LDL-C decreased from baseline 143 mg/dL to 85 mg/dL using mainly statins and ezetimibe, with limited PCSK9 inhibitor use. In comparison, eligible high ASCVD risk patients who were contacted but opted for education only, a 17% LDL-C decrease occurred over a similar timeframe, with 80% remaining with an LDL-C over 100 mg/dL.Conclusions: A remote, algorithm-driven, navigator-executed cholesterol management program successfully identified high ASCVD risk undertreated patients using EMR screening and was associated with significantly improved guideline-directed LDL-C control, supporting this approach as a novel strategy for improving health care access and delivery. [ABSTRACT FROM AUTHOR]

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known.Objective: To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations.Methods: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors.Results: A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months.Conclusions: The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials. [ABSTRACT FROM AUTHOR]

Our analysis from a national registry shows that compared to cancer, cardiovascular disease patients referred to palliative care are a decade older, have worse functional status and clinician-estimated prognosis. Both groups have very high symptom burden, with cardiovascular disease patients experiencing more dyspnea while pain, nausea, and fatigue are more common in cancer. [ABSTRACT FROM AUTHOR]

Intravenous (IV) iron repletion in HF with reduced ejection fraction (HFrEF) improves HF symptoms and reduces total HF hospitalizations. IV iron repletion requires specialized infusion and resuscitation equipment and trained personnel for administration and monitoring. This study sought to describe our center's approach for outpatient administration and monitoring of IV iron to patients with HF. This retrospective cohort study included all patients with HF, regardless of ejection fraction, who received at least one outpatient administration of an IV iron product for clinically indicated treatment of iron deficiency at our center's outpatient HF clinic from June 2015 to December 2021. We assessed changes in ferritin and transferrin saturation, infusion reactions, all-cause hospitalizations and deaths. A severe infusion reaction was defined as any reaction that was life-threatening, lead to emergency department visit, hospitalization or death or resulted in persistent or significant disability. Non-severe infusion reactions included pain or burning at the infusion site, dizziness, headache, nausea or itching that began after IV iron administration. A HF nurse documented any abnormal signs or symptoms that occurred during or up to 30 minutes after the iron infusion. Hospitalizations and deaths were abstracted from the medical record. A total of 480 IV iron infusions (ferumoxytol n=368, iron sucrose n=110 and low-molecular weight iron dextran n=2) were administered to 204 patients with HF, including patients that initially started IV iron replacement during hospitalization (n=24) (mean age 66 years, 50% women, 53% HFpEF). The median change from baseline in serum ferritin was 139 ng/dL [n=126; 25th, 75th percentiles: 26, 304] and the median change in transferrin saturation was 11% [n=126;25th, 75th percentiles: 4, 19]. Infusion-related reactions occurred in 15 (7%) patients, including 3 severe reactions requiring glucocorticoid or antihistamine administration and further management or observation in the emergency department. None of these severe reactions required hospitalization. All-cause hospitalization occurred in 103 (51%) patients and 10 (5%) patients died within 6 months of IV iron treatment. An outpatient HF clinic can be adapted to efficiently administer IV iron infusions. Adverse events were rare and could be managed with bedside interventions. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research. [ABSTRACT FROM AUTHOR]

Background: Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual health care expenditure. With the aging of the United States population and increasing evidence of shared risk factors, there is a need to understand the conditions' shared contributions to nationwide mortality. The objectives of this study were to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals.Methods and Results: This retrospective study used National Vital Statistics Data from 1999 to 2016 provided by the Centers for Disease Control and International Classification of Diseases (10th edition) codes for heart failure and dementia as defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed to by both heart failure and dementia totaled 214,706 and constituted 4.00% of all heart failure deaths and 9.04% of all dementia deaths. Women were more affected than men, with higher age-adjusted mortality rates (per 1,000,000 person-years): 38.67 (95% confidence interval [CI] 38.47-38.87) versus 32.90 (95% CI 32.65-33.15; P < .001). Whites were affected more than blacks, with age-adjusted mortality rates (per 1,000,000 person-years) of 38.00 (95% CI 37.83-38.16) versus 31.06 (95% CI 30.54-31.59; P < .001). However, under the age of 65 years, higher crude mortality rates (per 1,000,000 person-years) were reported in men (0.20, 95% CI 0.18-0.22) compared with women (0.15, 95% CI 0.13-0.16; P < .001).Conclusions: This study provides insight into temporal trends and nationwide mortality rates reported for heart failure and dementia. Our results suggest a disproportionate burden on populations over 85 years of age, whites, and women. [ABSTRACT FROM AUTHOR]

We investigate the behavior of a thin fluid with disrupted time-reversal symmetry on a uniformly heated inclined surface under external shear stress using modified Navier–Stokes equations, an energy conservation equation, and incorporating a Navier slip condition. Critical conditions for instability onset are determined by a linear stability analysis within the Orr–Sommerfeld framework. We derive a first-order Benney-type evolution equation to study long-wave instabilities. We find slippery substrate, imposed shear stress along the flow direction, and Marangoni number consistently destabilize the flow, while odd viscosity and imposed counter-flow shear stabilize it. A weakly nonlinear analysis using multiple scales reveal distinct zones of instability. Marangoni number, slip length, odd viscosity, and imposed shear direction significantly impact stability and instability regions. Numerical simulations of the free surface evolution equation of a flow system under consideration provide clear evidence of the contributions of thermocapillary, slip length, odd viscosity, and imposed shear direction. Furthermore, our analysis of linear and weakly nonlinear stability, as well as our numerical simulations, exhibit remarkable consistency. • Analyzed stability of thin film flow along a heated slippery inclined plane. • Broken time-reversal symmetry leads to odd viscosity inclusion. • Downhill shear and increased slip length intensify surface wave instability. • Surface wave instability is heightened by increased wall heating. • Odd viscosity reduces instability, and uphill shear enhances mitigation. [ABSTRACT FROM AUTHOR]

The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890 ; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Relief of congestion is the primary goal of initial therapy for acute decompensated heart failure (ADHF). Early measurement of urine sodium concentration (UNa) may be useful to identify patients with diminished response to diuretics. The aim of this study was to determine if the first spot UNa after diuretic initiation could select patients likely to require more intensive therapy during hospitalization.Methods: At the time of admission, 103 patients with ADHF were identified prospectively, and UNa was measured after the first dose of intravenous diuretic. Clinical outcomes were compared for patients with UNa >60 mmol/L and UNa of ≤60 mmol/L, with the primary outcome of a composite of death at 90 days, mechanical circulatory support during admission, and requirement of inotropic support at discharge.Results: Patients with UNa ≤60 had lower admission blood pressure, had less chronic neurohormonal antagonist prior to admission, and were more than twice as likely to experience the primary end point (hazard ratio 2.40, 95% CI 1.02-5.66, P = .045), which was marginally significant after adjusting for renal function and baseline home loop diuretic. Worsening renal function was significantly more common in patients with UNa <60 (23.6% vs 6.5%, P = .05). Although the initial assessment of congestion was similar at admission, patients with low early UNa had a longer length of stay (11 vs 6 days, P < .006) than patients with UNa >60.Conclusions: Assessment of spot UNa after initial intravenous loop diuretic administration may facilitate identification and triage of a population of HF patients at increased risk for adverse events and prolonged hospitalization. [ABSTRACT FROM AUTHOR]

Background Concerns remain about the burden of nursing care required to implement pulmonary artery pressure monitoring of heart failure patients. Methods We conducted a retrospective analysis of patients (N = 15) with a PAP sensor at our center. We defined three categories of PAP activity and estimated the nursing time spent on PAP monitoring. Results During the 6 months after implantation, the median patient contact time was 67 (55–75) minutes/patient/month and the median frequency of patient contact was 5.8 (4.6–6.4) contacts/patient/month. The intensity of nurse-patient contact decreased after the first 3 months (81 [52–102] minutes/patient/month vs. 45 [29–61] minutes/patient/month; P = 0.005). Conclusions The intensity of nurse-patient contact increased significantly after PAP sensor implantation but declined after the first 3 months with medical stabilization. These data from our center may serve as a benchmark to project the nursing time required to support PAP monitoring in practice. [ABSTRACT FROM AUTHOR]

Background: Admission for diuresis remains a common and costly event in patients with advanced heart failure (HF). We tested whether spot urine sodium could identify patients likely to respond to ambulatory diuretic infusion without hospitalization.Methods and Results: We prospectively followed 176 consecutive patients with advanced heart failure receiving intravenous furosemide for congestion in an ambulatory clinic. Spot urine sodium was measured in 1st voided urine after diuretic infusion and compared with 3-hour urine output and subsequent risk of 30-day hospitalization or emergency department (ED) visit. Spot urine sodium was significantly associated with urine output in a model adjusted for age, renal function, and blood urea nitrogen (P = .02). Higher urine sodium was associated with lower risk of hospitalization or ED visit within 30 days (odds ratio [OR] 0.82 [95% confidence interval 0.72-0.94] per 10 mmol/L increase; P < .001), in a model adjusted for hemoglobin (OR 0.80 [0.66-0.97]; P = .02) and systolic blood pressure (OR 0.82 [0.67-1.0]; P = .05). Spot urine sodium ≥65 mmol/L and urine output ≥1200 mL identified a lower-risk group for outpatient management.Conclusion: High spot urine sodium after diuretic administration identifies HF patients likely to respond to an ambulatory diuretic infusion with lower rates of hospitalization or ED visits at 30 days. [ABSTRACT FROM AUTHOR]

Background: In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up.Methods: We defined the region-specific incidence of hypokalemia (potassium [K+] <3.5 mmol/l) and hyperkalemia (K+ ≥5.5 mmol/l) among both placebo- and spironolactone-assigned patients in TOPCAT. Factors associated with incident hypokalemia and hyperkalemia and the relationship between incident K+ abnormalities and the risk of subsequent mortality were analyzed in multivariable regression models restricted to the Americas.Results: In the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P < .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P < .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline K+, diabetes, and lower hemoglobin were associated with incident hyperkalemia, whereas assignment to placebo, lower K+, younger age, lower estimated glomerular filtration rate, and use of diuretics at baseline were associated with hypokalemia. The combination of spironolactone and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was associated with incremental risk for hyperkalemia and protection from hypokalemia. Independent of region, both hypokalemia and hyperkalemia, were associated with higher risk for cardiovascular and all-cause mortality in multivariable-adjusted Cox regression models.Conclusions: Both hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K+ and creatinine, particularly in high-risk groups. [ABSTRACT FROM AUTHOR]

This study examines the behavior of a thin liquid film flowing on an inclined plane subject to imposed shear stress. The liquid's time-reversal symmetry is broken, and we consider the odd part of the viscosity to describe the Navier–Stokes equation. To investigate the interplay between the imposed shear and odd viscosity on the flow dynamics, we develop a weighted residual model (WRM). We determine the model's critical Reynolds number (R e c ) through linear stability analysis. Our findings indicate that uphill shear tends to stabilize the flow, while downhill shear enhances the instability, albeit reduced by the presence of odd viscosity. We also construct an Orr–Sommerfeld (OS) type eigenvalue problem for normal mode analysis and derive R e c . We discover that in the longwave regime, R e c WRM = R e c OS . Finally, our numerical simulations of the model align well with our linear stability analysis. • Studied stability of time-reversal broken film flow with imposed shear stress. • Broken time-reversal symmetry of the fluid leads to the presence of odd viscosity. • Developed weighted residual model for presenting flow dynamics. • Increasing external shear in the streamwise direction amplifies the instability. • Odd viscosity and reverse flow external shear dampen instability. [ABSTRACT FROM AUTHOR]

Background: In the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association [NYHA] Functional Class III Heart Failure Patients) trial, heart failure hospitalization (HFH) rates were lower in patients managed with guidance from an implantable pulmonary artery pressure sensor compared with usual care.Objectives: This study examined the effectiveness of ambulatory hemodynamic monitoring in reducing HFH outside of the clinical trial setting.Methods: We conducted a retrospective cohort study using U.S. Medicare claims data from patients undergoing pulmonary artery pressure sensor implantation between June 1, 2014, and December 31, 2015. Rates of HFH during pre-defined periods before and after implantation were compared using the Andersen-Gill extension to the Cox proportional hazards model while accounting for the competing risk of death, ventricular assist device implantation, or cardiac transplantation. Comprehensive heart failure (HF)-related costs were compared over the same periods.Results: Among 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.49 to 0.61; p < 0.001). This lower rate of HFH was associated with a 6-month comprehensive HF cost reduction of $7,433 per patient (IQR: $7,000 to $7,884), and was robust in analyses restricted to 6-month survivors. Similar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implantation (HR: 0.66; 95% CI: 0.57 to 0.76; p < 0.001).Conclusions: As in clinical trials, use of ambulatory hemodynamic monitoring in clinical practice is associated with lower HFH and comprehensive HF costs. These benefits are sustained to 1 year and support the "real-world" effectiveness of this approach to HF management. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease.Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype.Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained. [ABSTRACT FROM AUTHOR]

In patients with previous heart failure hospitalization (HFH), ambulatory hemodynamic monitoring reduced HFH by 57% in the CardioMEMS Post-Approval Study (PAS), which translated into a 27% reduction in all-cause hospitalization but no change in other causes of hospitalization. We compared the trajectories of pulmonary artery pressures (PAP) before and after breakthrough HFH and the non-HF hospitalizations (non-HFH) that occurred during chronic PAP monitoring. The PAS was a single arm study of 1200 patients with NYHA 3 HF (all EF) and prior HFH within 12 months who underwent implantation of a CardioMEMS PA sensor. An independent clinical events committee adjudicated all hospitalizations with primary cause HF and non-HF. We analyzed PAP changes during the 6 weeks prior and 1 week following hospitalization for all pts with PAP data through the 7 weeks, excluding overlapping analysis periods. Analysis was available for 751 hospitalizations, only 199 (26.5%) were HFH and 552 were (73.5%) were non-HFH. The rising trajectory of PAP changes in advance of HFH was distinct from non-HFH with an increase in pressure from baseline beginning approximately 4 weeks prior to HFH and a decrease in pressure observed immediately after HFH but no change observed before or after non-HFH. Among patients with chronic HF across a range of EF, PAP rise approximately 4 weeks in advance of HFH and fall by 7 days after, but do not change around non-HFH. These data demonstrate the consistent physiology of rising PAP for breakthrough HFH that occur despite hemodynamic monitoring and the stability of PAP without elevation around the more common hospitalizations for other causes. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) are at high risk for hospital readmission in the first 30 days following HF hospitalization.Objectives: This study sought to determine if treatment with sacubitril/valsartan (LCZ696) reduces rates of hospital readmission at 30-days following HF hospitalization compared with enalapril.Methods: We assessed the risk of 30-day readmission for any cause following investigator-reported hospitalizations for HF in the PARADIGM-HF trial, which randomized 8,399 participants with HF and reduced ejection fraction to treatment with LCZ696 or enalapril.Results: Accounting for multiple hospitalizations per patient, there were 2,383 investigator-reported HF hospitalizations, of which 1,076 (45.2%) occurred in subjects assigned to LCZ696 and 1,307 (54.8%) occurred in subjects assigned to enalapril. Rates of readmission for any cause at 30 days were 17.8% in LCZ696-assigned subjects and 21.0% in enalapril-assigned subjects (odds ratio: 0.74; 95% confidence interval: 0.56 to 0.97; p = 0.031). Rates of readmission for HF at 30-days were also lower in subjects assigned to LCZ696 (9.7% vs. 13.4%; odds ratio: 0.62; 95% confidence interval: 0.45 to 0.87; p = 0.006). The reduction in both all-cause and HF readmissions with LCZ696 was maintained when the time window from discharge was extended to 60 days and in sensitivity analyses restricted to adjudicated HF hospitalizations.Conclusions: Compared with enalapril, treatment with LCZ696 reduces 30-day readmissions for any cause following discharge from HF hospitalization. [ABSTRACT FROM AUTHOR]

Abstract: Background: A subset of patients with heart failure (HF) and preserved left ventricular ejection fraction (EF) previously had EF <40%. We postulated that such “recovered” EF patients would be prevalent in a referral HF population and clinically distinct from those with persistently preserved or reduced EF. Methods and Results: We identified all subjects with a clinical diagnosis of HF seen in the advanced heart disease practice at our center from March to October 2008. Patients were classified into 1 of 3 groups based on retrospective review of the medical record: EF persistently ≥40% (HF-PEF), EF recovered to ≥40% (HF-REF) and low EF, <40% (HF-LEF). Clinical and echocardiographic characteristics were compared across groups using standard chi-square and analysis of variance tests. A total of 358 heart failure patients were identified, including 56 with HF-PEF, 121 with HF-REF, and 181 with HF-LEF. Compared with HF-PEF, HF-REF patients were younger with less atrial fibrillation, hypertension, and diabetes. Also, they tended to have lower systolic blood pressure, better renal function, and larger left ventricular diameter at end diastole. HF-REF patients were more similar to HF-LEF, but were younger and had lower rates of coronary artery disease. Of the 3 groups, HF-REF patients had the mildest reported HF symptoms and fewest previous HF hospitalizations. Conclusions: Patients with HF-REF comprise a substantial proportion of those with HF and EF ≥40% followed in an ambulatory referral practice. These patients appear to be clinically distinct from the residual HF population and should be specifically targeted for further research. [Copyright &y& Elsevier]

Abstract: Background: Although renin-angiotensin system (RAS) inhibitors have little demonstrable effect on mortality in patients with heart failure and preserved ejection fraction (HF-PEF), some trials have suggested a benefit with regard to reduction in HF hospitalization. Methods and Results: Here, we systematically review and evaluate prospective clinical studies of RAS inhibitors enrolling patients with HF-PEF, including the 3 major trials of RAS inhibition (Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction [CHARM-Preserved], Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction [I-PRESERVE], and Perindopril in Elderly People with Chronic Heart Failure [PEP-CHF]). We also conducted a pooled analysis of 8021 patients in the 3 major randomized trials of RAS inhibition in HF-PEF (CHARM-Preserved, I-PRESERVE, and PEP-CHF) in fixed-effect models, finding no clear benefit with regard to all-cause mortality (odds ratio [OR] 1.03, 95% confidence interval [CI], 0.92-1.15; P =.62), or HF hospitalization (OR 0.90, 95% CI 0.80-1.02; P =.09). Conclusions: Although RAS inhibition may be valuable in the management of comorbidities related to HF-PEF, RAS inhibition in HF-PEF is not associated with consistent reduction in HF hospitalization or mortality in this emerging cohort. [Copyright &y& Elsevier]

Abstract: Background: Indications for implantable cardioverter-defibrillators (ICDs) in heart failure (HF) are expanding and may include more than 1 million patients. This study examined patient expectations from ICDs for primary prevention of sudden death in HF. Methods and Results: Study participants (n = 105) had an EF <35% and symptomatic HF, without history of ventricular tachycardia/fibrillation or syncope. Subjects completed a written survey about perceived ICD benefits, survival expectations, and circumstances under which they might deactivate defibrillation. Mean age was 58, LVEF 21%, 40% were New York Heart Association Class III-IV, and 65% already had a primary prevention ICD. Most patients anticipated more than10 years survival despite symptomatic HF. Nearly 54% expected an ICD to save ≥50 lives per 100 during 5 years. ICD recipients expressed more confidence that the device would save their own lives compared with those without an ICD (P < .001). Despite understanding the ease of deactivation, 70% of ICD recipients indicated they would keep the ICD on even if dying of cancer, 55% even if having daily shocks, and none would inactivate defibrillation even if suffering constant dyspnea at rest. Conclusions: HF patients anticipate long survival, overestimate survival benefits conferred by ICDs, and express reluctance to deactivate their devices even for end-stage disease. [Copyright &y& Elsevier]

Abstract: Background: Hypertension is an important risk factor for the development of heart failure with preserved ejection fraction. Although heart failure in hypertensive patients is usually ascribed to intrinsic myocardial abnormalities, noncardiac factors may contribute. Methods and Results: Using arterial tonometry and Doppler echocardiography, we assessed arterial stiffness and cardiac diastolic function in 53 individuals with ejection fraction >=0.50, including 23 with hypertension but no heart failure, 16 with hypertension and heart failure, and 14 healthy, normotensive controls. Relative to healthy controls and hypertensives, subjects with heart failure had higher systolic blood pressure, body mass index, creatinine, and left ventricular mass. Diastolic function, as estimated by myocardial relaxation velocity, was not different among the 3 groups. Peripheral arterial stiffness was similar across all groups, but key measures of central aortic stiffness (carotid-femoral pulse wave velocity, characteristic impedance, forward wave amplitude) steadily increased with progression from healthy to hypertensive to heart failure despite adjustment for body mass index, systolic blood pressure, and renal function and were positively correlated with both left ventricular mass and filling pressure. Conclusions: We conclude that patients with heart failure and preserved ejection fraction have increased central aortic stiffness relative to age-matched healthy and hypertensive subjects without heart failure. These changes exceed differences in diastolic function and suggest that abnormal ventricular-vascular coupling may contribute to the pathophysiology of heart failure with preserved ejection fraction. [Copyright &y& Elsevier]

Abstract: Objective: In chronic heart failure (HF), diuretic doses increase as the disease progresses, often after hospitalization for instability, and have been associated with worsening renal function and increased mortality. Methods and Results: A prospective observational analysis of 183 patients in an advanced HF clinic stratified at baseline by diuretic dose (low dose ≤ 80 mg, high dose > 80 mg furosemide equivalent) was performed. All patients were followed for 1 year, and the primary outcome was a combined HF event of admission for HF, cardiac transplant, mechanical cardiac support, or death. Compared with patients taking low-dose diuretics (n = 113), patients taking high-dose diuretics (n = 70) had more markers of increased cardiovascular risk and were more likely to have a history of recent instability (33% vs 4.4% in low dose, P < .001). High doses of diuretics were a strong univariate predictor of subsequent HF events (hazard ratio 3.83, 95% confidence interval 1.82–8.54); however, after adjustment for clinical stability, diuretic dose no longer remained significant (hazard ratio 1.53, 95% confidence interval 0.58–4.03). Conclusion: High-dose diuretics may be more of a marker than a cause of instability. A history of HF stability during the past 6 months is associated with an 80% lower risk of an HF event during the next year, independently of baseline diuretic dose. [Copyright &y& Elsevier]

Objectives: We explored the incidence and predictors of hyperkalemia in a broad population of heart failure patients. Background: When used in optimal doses to treat patients with heart failure, renin-angiotensin-aldosterone system (RAAS) inhibitors improve clinical outcomes but can cause hyperkalemia. Methods: Participants in the CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) (n = 7,599) Program were randomized to standard heart failure therapy plus candesartan or placebo, titrated as tolerated to a target of 32 mg once daily with recommended monitoring of serum potassium and creatinine. We assessed the incidence and predictors of hyperkalemia associated with dose reduction, study drug discontinuation, hospitalization, or death over the median 3.2 years of follow-up. Results: Independent of treatment assignment, the risk of hyperkalemia increased with age ≥75 years, male gender, diabetes, creatinine ≥2.0 mg/dl, K+ ≥5.0 mmol/l, and background use of angiotensin-converting enzyme inhibitors or spironolactone. Candesartan increased the rate of aggregate hyperkalemia from 1.8% to 5.2% (difference 3.4%, p < 0.0001) and serious hyperkalemia (associated with death or hospitalization) from 1.1% to 1.8% (difference 0.7%, p < 0.001), with hyperkalemia associated with death reported in 2 (0.05%) candesartan patients and 1 (0.03%) placebo patient. The benefit of candesartan in reducing cardiovascular death or heart failure hospitalization (relative risk reduction 16%, p < 0.0001) was uniform in these subgroups, as was the incremental risk of hyperkalemia. Conclusions: The risk of hyperkalemia is increased in symptomatic heart failure patients with advanced age, male gender, baseline hyperkalemia, renal failure, diabetes, or combined RAAS blockade. Although these groups derive incremental clinical benefit from candesartan, careful surveillance of serum potassium and creatinine is particularly important. [Copyright &y& Elsevier]

Heart Failure (HF) undermines daily quality of life even when not severe enough to warrant hospitalization. Ambulatory pulmonary pressure-guided management decreases hospitalizations across all ranges of EF. This management improves HF symptom scores, but it is not known whether it improves health expectations and perceptions of disease control as reported directly by patients. Patients with prior HF hospitalization and NYHA class III symptoms will report improved health expectations and an increased sense of control over their HF disease progression. Patient-reported outcomes were explored in a substudy of 286 class III CHF patients during the post-approval study for the implanted pulmonary artery pressure sensor. Patients completed validated measures of key appraisals of their cardiac disease and health expectations (e.g. 8-item Brief Illness Perception Questionnaire (BIPQ)) and the 24-item Cardiac Health Security Survey (CHSS) at baseline, 6 months and 12-month timepoints. All patients continued to receive optimal guideline directed medical therapy during ambulatory hemodynamic monitoring with a target PAD pressure of 8-20 mmHg. In this substudy, age was 69 ± 11 years and 62% were male, 53% with preserved ejection fraction. From the Baseline BIPQ of 46 ± 10.5, illness perception was reduced by 3.3 and 4.4 points at 6 and 12 months, respectively (p< 0.0001 both). Individual item analysis indicated significant benefits across perceptions of disease control, symptom reduction, and emotional and disease concerns (p<.05). Health expectations scores from the CHSS were not significantly different at any timepoint. Subjects' perceptions about the use of the CardioMEMS™ system from the CHSS after both 6 and 12 months of use indicated high levels of satisfaction, security, and ease of use of the hemodynamic monitoring system. Patient management guided by ambulatory pulmonary pressure monitoring was associated with improved patient perception of illness spanning sense of control, symptom reduction, and reduced concerns about their illness over time. The lack of change in health expectations likely reflects patient understanding regarding chronicity of HF on recommended therapies. Patients reported high levels of end user satisfaction and benefit with the hemodynamic monitoring system itself. This technology offers sustained benefits to patients beyond reduction of hospitalizations. [ABSTRACT FROM AUTHOR]

Abstract: This clinical perspective addresses the practical aspects of the decision to implant an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden death in patients with symptomatic heart failure and reduced left ventricular ejection fraction, based on a distillation of recent trial experience. Potentially eligible patients are selected on the basis of left ventricular ejection fraction <30% to 35% and anticipated survival with good functional capacity beyond 1 year. Communication with these patients focuses on a horizon of 5 years, during which for every 100 patients receiving devices, approximately 30 patients are predicted to die with or without an ICD, while 7 to 8 lives may be saved with the ICD. These estimates are presented in the context of adverse events, including unnecessary shocks, and the possibility that circumstances may arise for which the defibrillator may be inactivated to allow natural death. [Copyright &y& Elsevier]

In low- and intermediate-risk patients with unstable angina pectoris (UAP) and non–ST-elevation acute myocardial infarction (NSTEAMI), routine early invasive management with coronary angiography does not decrease the risk of death or AMI. The economic consequences of this strategy in low- and intermediate-risk patients are unknown. We applied a risk prediction rule to a multihospital practice database and to the population of the Thrombolysis In Myocardial Ischemia trial, phase IIIB (TIMI 3B), which compared early invasive with conservative therapy for UAP and NSTEAMI. We then analyzed the effect of an early invasive strategy with regard to the composite end point of death, AMI, or rehospitalization for ischemia at rest. A logistic regression model was used to compare outcomes in patients with high versus low or intermediate risk scores. The costs and benefits of early invasive management in low- or intermediate-risk patients were assessed. In the practice database, 56% of patients with UAP and NSTEAMI who had low or intermediate risk scores underwent early cardiac catheterization, although early invasive management of these lower risk patients has not been associated with a reduction in the rate of death or MI. In TIMI 3B, when rehospitalization for ischemia at rest was added to the composite end point, invasive management was superior to conservative management at 42 days (p = 0.005) and at 1 year (p = 0.03). If all low- or intermediate-risk patients randomized to conservative therapy in that trial had been treated instead with an early invasive strategy, an estimated 5.4% of rehospitalizations would have been avoided. Within TIMI 3B, such a routine invasive strategy would have resulted in an additional cost of $2,695,700 with no effect on death or AMI, but it would have led to 34 fewer rehospitalizations. This expenditure of $79,285 per hospitalization prevented far exceeds the monetary cost of rehospitalization ($14,000). Although common in clinical practice, routine early invasive management of low- or intermediate-risk patients with UAP generates substantial health-care costs without a mortality benefit or decrease in the risk of AMI. Unless the incremental benefit in quality of life from prevented rehospitalizations for UAP is judged to be worth the large incremental cost ($79,285 per hospitalization prevented), such a strategy is unlikely to be cost effective. [Copyright &y& Elsevier]

Hemodynamic monitoring has been shown to reduce admissions for heart failure in both the large randomized CHAMPION Trial (CHMP) and a 1200 patient Post Approval Study registry (PAS). A persistent observation in heart failure (HF) studies is that trial patient populations differ from patients who are treated in clinical practice. After identifying patients who could be propensity matched to the CHMP trial patients, we studied the characteristics and outcomes of the patients who could not be matched. PAS was an FDA mandated registry to determine if results of the CHMP trial could be replicated in clinical practice, as reported previously. Propensity matching was done between CHMP Control and PAS patients. 387 PAS patients could be propensity matched and can be considered "Trial-Type" patients (TT) and 813 were not match able (NM). For each patient group heart failure (HFH) and all-cause (ACH) hospitalization rates at 1 year were compared to the rate in the year prior to enrollment. Compared to CHMP Treatment patients, NM patients were older 61.3 vs 71.8, more likely to be female (18.1% vs 39.6%) and have heart failure with normal ejection fraction (HFpEF) (23% vs 55.9%), p < 0.001 for all. Wedge pressure was higher (17.5 vs 20.0 mmHg) and GFR was lower (60.4 vs 50.5 mL/min/1.73 m2), p < 0.001 for both. Although ACH and HFH were higher in NM patients before and during PA pressure guided management, there was a significant decline in both after implantation of the CardioMEMS™ monitor (Figure 1). Of the 1200 patients in the PAS, 67% (813/1200) patients were not match able to typical trial subjects. Nonetheless, these patients with older age, worse renal function, and more hospitalizations still had significant reduction in rates of HFH and ACH during ambulatory hemodynamic monitoring. [ABSTRACT FROM AUTHOR]