Search

This study aimed to evaluate hemodynamic correlates of inducible blood pressure (BP) pulsatility with exercise in heart failure with preserved ejection fraction (HFpEF), to identify relationships to outcomes, and to compare this with heart failure with reduced ejection fraction (HFrEF).In HFpEF, determinants and consequences of exercise BP pulsatility are not well understood.We measured exercise BP in 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Pulsatile BP was evaluated as proportionate pulse pressure (PrPP), the ratio of pulse pressure to systolic pressure. We measured pulmonary arterial catheter pressures, Fick cardiac output, respiratory gas exchange, and arterial stiffness. We correlated BP changes to central hemodynamics and cardiovascular outcome (nonelective cardiovascular hospitalization) and compared findings with 57 patients with HFrEF from the same referral population.In HFpEF, only age (standardized beta = 0.593; P 0.001), exercise stroke volume (standardized beta = 0.349; P 0.001), and baseline arterial stiffness (standardized beta = 0.182; P = 0.02) were significant predictors of peak exercise PrPP in multivariable analysis (R = 0.661). In HFpEF, lower PrPP was associated with lower risk of cardiovascular events, despite adjustment for confounders (HR:0.53 for PrPP below median; 95% CI: 0.28-0.98; P = 0.043). In HFrEF, lower exercise PrPP was not associated with arterial stiffness but was associated with lower peak exercise stroke volume (P = 0.013) and higher risk of adverse cardiovascular outcomes (P = 0.004).In HFpEF, greater inducible BP pulsatility measured using exercise PrPP reflects greater arterial stiffness and higher risk of adverse cardiovascular outcomes, in contrast to HFrEF where inducible exercise BP pulsatility relates to stroke volume reserve and favorable outcome.

Mechanisms underlying sex differences in heart failure with preserved ejection fraction (HFpEF) are poorly understood. We sought to examine sex differences in measures of arterial stiffness and the association of arterial stiffness measures with left ventricular hemodynamic responses to exercise in men and women.We studied 83 men (mean age 62 years) and 107 women (mean age 59 years) with HFpEF who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial stiffness measurement (augmentation pressure [AP], augmentation index [AIx], and aortic pulse pressure [AoPP]). Sex differences were compared using multivariable linear regression. We examined the association of arterial stiffness with abnormal left ventricular diastolic response to exercise, defined as a rise in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO) ≥ 2 mmHg/L/min by using logistic regression models.Women with HFpEF had increased arterial stiffness compared with men. AP was nearly 10 mmHg higher, and AIx was more than 10% higher in women compared with men (P0.0001 for both). Arterial stiffness measures were associated with a greater pulmonary capillary wedge pressure response to exercise, particularly among women. A 1-standard deviation higher AP was associated with3-fold increased odds of abnormal diastolic exercise response (AP: OR 3.16, 95% CI 1.34-7.42; P = 0.008 [women] vs OR 2.07, 95% CI 0.95-5.49; P = 0.15 [men]) with similar findings for AIx and AoPP.Arterial stiffness measures are significantly higher in women with HFpEF than in men and are associated with abnormally steep increases in pulmonary capillary wedge pressure with exercise, particularly in women. Arterial stiffness may preferentially contribute to abnormal diastolic function during exercise in women with HFpEF compared with men.

Aims To evaluate the associations of dietary indices and quantitative cardiorespiratory fitness (CRF) measures in a large, community-based sample harnessing metabolomic profiling to interrogate shared biology. Methods and results Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise tests for CRF quantification (via peak VO2) and completed semi-quantitative food frequency questionnaires. Dietary quality was assessed by the Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS), and fasting blood concentrations of 201 metabolites were quantified. In 2380 FHS participants (54 ± 9 years, 54% female, body mass index 28 ± 5 kg/m2), 1 SD higher AHEI and MDS were associated with 5.2% (1.2 mL/kg/min, 95% CI 4.3–6.0%, P < 0.0001) and 4.5% (1.0 mL/kg/min, 95% CI 3.6–5.3%, P < 0.0001) greater peak VO2 in linear models adjusted for age, sex, total daily energy intake, cardiovascular risk factors, and physical activity. In participants with metabolite profiling (N = 1154), 24 metabolites were concordantly associated with both dietary indices and peak VO2 in multivariable-adjusted linear models (FDR < 5%). Metabolites that were associated with lower CRF and poorer dietary quality included C6 and C7 carnitines, C16:0 ceramide, and dimethylguanidino valeric acid, and metabolites that were positively associated with higher CRF and favourable dietary quality included C38:7 phosphatidylcholine plasmalogen and C38:7 and C40:7 phosphatidylethanolamine plasmalogens. Conclusion Higher diet quality is associated with greater CRF cross-sectionally in a middle-aged community-dwelling sample, and metabolites highlight potential shared favourable effects on cardiometabolic health.

International audience; Background: Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF).Methods: Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers.Results: The ARISE-HF Trial is fully enrolled.Conclusions: This report describes the rationale and study design of ARISE-HF.

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3–9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0–9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7–10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6–34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1–7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05–2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01–1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF., In a multicenter, randomized trial, the SGLT2 inhibitor dapagliflozin improved the health status and exercise function of patients with heart failure with preserved ejection fraction (HFpEF), a condition for which effective treatments are lacking.

Preformed donor-specific antibodies are associated with a higher risk of rejection and worse graft survival in organ transplantation. However, in heart transplantation, the risk and benefit balance between high mortality on the waiting list and graft survival may allow the acceptance of higher immunologic risk donors in broadly sensitized recipients. Transplanting donor-recipient pairs with a positive complement dependent cytotoxic (CDC) crossmatch carries the highest risk of hyperacute rejection and immediate graft loss and is usually avoided in kidney transplantation. Herein we report the first successful simultaneous heart-kidney transplant with a T- and B-cell CDC crossmatch positive donor using a combination of rituximab, intravenous immunoglobulin, plasmapheresis, bortezomib and rabbit anti-thymocyte globulin induction followed by eculizumab therapy for two months post-transplant. In the year following transplantation, both allografts maintained stable graft function (all echocardiographic left ventricular ejection fractions ≥ 65%, eGFR>60) and showed no histologic evidence of antibody-mediated rejection. In addition, the patient has not developed any severe infections including cytomegalovirus or BK virus infection. In conclusion, a multitarget immunosuppressive regimen can allow for combined heart/kidney transplantation across positive CDC crossmatches without evidence of antibody-mediated rejection or significant infection. Longer follow-up will be needed to further support this conclusion.

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Aims While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory fitness are incompletely understood. Methods and results Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures [sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA)] via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants [age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min]. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate Conclusions Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.

Background Cardiorespiratory fitness is a powerful predictor of health outcomes that is currently underused in primary prevention, especially in young adults. We sought to develop a blood‐based biomarker of cardiorespiratory fitness that is easily translatable across populations. Methods and Results Maximal effort cardiopulmonary exercise testing for quantification of cardiorespiratory fitness (by peak oxygen uptake) and profiling of >200 metabolites at rest were performed in the FHS (Framingham Heart Study; 2016–2019). A metabolomic fitness score was derived/validated in the FHS and was associated with long‐term outcomes in the younger CARDIA (Coronary Artery Risk Development in Young Adults) study. In the FHS (derivation, N=451; validation, N=914; age 54±8 years, 53% women, body mass index 27.7±5.3 kg/m 2 ), we used LASSO (least absolute shrinkage and selection operator) regression to develop a multimetabolite score to predict peak oxygen uptake (correlation with peak oxygen uptake r =0.77 in derivation, 0.61 in validation; both P P P =0.0003) in models adjusted for age, sex, and race, which remained robust with adjustment for clinical risk factors. Conclusions A blood‐based biomarker of cardiorespiratory fitness largely independent of traditional risk factors is associated with long‐term risk of cardiovascular disease and mortality in young adults.

Objectives The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF). Background There are no proven effective treatments for patients with PH-HFpEF. Methods Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages. Results Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (−1.4 mm Hg; 95% confidence interval [CI]: −7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (−3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo. Conclusions Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603 )

AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

ImportanceAdding a sodium-glucose cotransporter-2 inhibitor (SGLT2-I) to standard-of-care treatment in patients with heart failure with preserved ejection fraction (HFpEF) reduces the risk of a composite outcome of worsening heart failure or cardiovascular mortality, but the cost-effectiveness in US patients with HFpEF is uncertain.ObjectiveTo evaluate the lifetime cost-effectiveness of standard therapy plus an SGLT2-I compared with standard therapy in individuals with HFpEF.Design, Setting, and ParticipantsIn this economic evaluation conducted from September 8, 2021, to December 12, 2022, a state-transition Markov model simulated monthly health outcomes and direct medical costs. Input parameters including hospitalization rates, mortality rates, costs, and utilities were extracted from HFpEF trials, published literature, and publicly available data sets. The base-case annual cost of SGLT2-I was $4506. A simulated cohort with similar characteristics as participants of the Empagliflozin in Heart Failure With a Preserved Ejection Fraction (EMPEROR-Preserved) and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction (DELIVER) trials was used.ExposuresStandard of care plus SGLT2-I vs standard of care.Main Outcomes and MeasuresThe model simulated hospitalizations, urgent care visits, and cardiovascular and noncardiovascular death. Future medical costs and benefits were discounted by 3% per year. Main outcomes were quality-adjusted life-years (QALYs), direct medical costs (2022 US dollars), and incremental cost-effectiveness ratio (ICER) of SGLT2-I therapy from a US health care sector perspective. The ICER of SGLT2-I therapy was evaluated according to the American College of Cardiology/American Heart Association value framework (high value: ResultsThe simulated cohort had a mean (SD) age of 71.7 (9.5) years and 6828 of 12 251 participants (55.7%) were male. Standard of care plus SGLT2-I increased quality-adjusted survival by 0.19 QALYs at an increased cost of $26 300 compared with standard of care. The resulting ICER was $141 200 per QALY gained, with 59.1% of 1000 probabilistic iterations indicating intermediate value and 40.9% indicating low value. The ICER was most sensitive to SGLT2-I costs and effect of SGLT2-I therapy on cardiovascular death (eg, increasing to $373 400 per QALY gained if SGLT2-I therapy was assumed to have no effect on mortality).Conclusions and RelevanceResults of this economic evaluation suggest that at 2022 drug prices, adding an SGLT2-I to standard of care was of intermediate or low economic value compared with standard of care in US adults with HFpEF. Efforts to expand access to SGLT2-I for individuals with HFpEF should be coupled with efforts to lower the cost of SGLT2-I therapy.

Background Heart failure with preserved ejection fraction (HFpEF) is characterized by left ventricular hypertrophy and decreased exercise capacity. Fibroblast growth factor 23 (FGF23), a hormone involved in phosphate, vitamin D, and iron homeostasis, is linked to left ventricular hypertrophy and HF. We measured c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels and examined their associations with exercise capacity in patients with HFpEF. Methods and Results Using multivariable linear regression and linear mixed models, we studied the associations of cFGF23 and iFGF23 with baseline and mean weekly change over 24 weeks in peak oxygen consumption and 6-minute walk distance in individuals enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial. Our study population included 172 individuals with available plasma for cFGF23 and iFGF23 measurements. Median (25th–75th percentile) baseline cFGF23 and iFGF23 levels were 208.7 RU/mL (132.1–379.5 RU/mL) and 90.3 pg/mL (68.6–128.5 pg/mL), respectively. After adjustment for cardiovascular disease and hematologic and kidney parameters, higher cFGF23 was independently associated with a lower peak oxygen consumption at baseline. Higher iFGF23 was independently associated with shorter 6-minute walk distance at baseline. No significant associations were appreciated with the longitudinal outcomes. Conclusions In patients with HFpEF, higher FGF23 levels are independently associated with decreased exercise capacity at baseline.

There have been nearly 70 million cases of COVID‐19 worldwide, with over 1.5 million deaths at the time of this publication. This global pandemic has mandated dramatic changes in healthcare delivery with a particular focus on social distancing in order to reduce viral transmission. Heart failure patients are among the highest utilizers of health care and are at increased risk for COVID‐related vulnerabilities. Effectively managing this complex and resource‐intensive patient population from a distance presents new and unique challenges. Here, we review relevant data on telemedicine and remote monitoring strategies for heart failure patients and provide a framework to help providers treat this population during the COVID‐19 pandemic. This includes (i) dedicated pre‐visit contact and planning (i.e. confirm clinical appropriateness, presence of compatible technology, and patient comfort); (ii) utilization of virtual clinic visits (use of telehealth platforms, a video‐assisted exam, self‐reported vital signs, and weights); and (iii) use of existing remote heart failure monitoring sensors when applicable (CardioMEMS, Optivol, and HeartLogic). While telemedicine and remote monitoring strategies are not new, these technologies are emerging as an important tool for the effective management of heart failure patients during the COVID‐19 pandemic. In general, these strategies appear to be safe; however, additional data will be needed to determine their effectiveness with respect to both process and outcomes measures.

Donor organ demand continues to outpace supply in heart transplantation. Utilization of donation after circulatory death (DCD) hearts could significantly increase heart donor availability for patients with advanced heart failure.The purpose of this study was to describe hemodynamic and clinical profiles of DCD hearts in comparison to standard of care (SOC) hearts donated after brain death (DBD).This single-center retrospective cohort study of consecutive heart transplant recipients analyzed right heart catheterization measurements, inotrope scores, echocardiograms, and clinical outcomes between DCD and DBD heart recipients.Between April 2016 and February 2022, 47 DCD and 166 SOC hearts were transplanted. Median time from DCD consent to transplant was significantly shorter compared with SOC waiting list time (17 days [6-28 days] vs 70 days [23-240 days]; P 0.001). Right heart function was significantly impaired in DCD recipients compared with SOC recipients 1 week post-transplant (higher median right atrial pressure (10 mm Hg [8-13 mm Hg] vs 7 mm Hg [5-11 mm Hg]; P 0.001), higher right atrial pressure to pulmonary capillary wedge pressure ratio (0.64 [0.54-0.82] vs 0.57 [0.43-0.73]; P = 0.016), and lower pulmonary arterial pulsatility index (1.66 [1.27-2.50] vs 2.52 [1.63-3.82]; P 0.001), but was similar between groups by 3 weeks post-transplant. DCD and SOC recipient mortality was similar at 30 days (DCD 0 vs SOC 2%; P = 0.29) and 1 year post-transplant (DCD 3% vs SOC 8%; P = 0.16).DCD heart utilization is associated with transient post-transplant right heart dysfunction and short-term clinical outcomes otherwise similar to transplantation using DBD hearts.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.

Across differing spectrums of cardiac function and cardiac pathologies, there are strong associations between measures of cardiorespiratory fitness and burden of symptoms, quality of life, and prognosis. In this part 2 of a 4-part series, we contend that there is a strong association among physical activity, cardiorespiratory fitness, and cardiac function. We argue that a chronic lack of exercise is a major risk factor for heart failure with preserved ejection fraction in some patients. In support of this hypothesis, increasing physical activity is associated with greater cardiac mass, greater stroke volumes, greater cardiac output and peak oxygen consumption, and fewer clinical events. Conversely, physical inactivity results in cardiac atrophy, reduced output, reduced chamber size, and decreased ability to augment cardiac performance with exercise. Moreover, physical inactivity is a strong predictor of heart failure risk and death. In sum, exercise deficiency should be considered part of the broad heart failure with preserved ejection fraction phenotype.

Background: Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking. Methods: We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study. Results: In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin–angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50–0.92]; P =0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45–0.80]; P =0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome ( P interaction =0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction ( P =0.0004 for a combined myocardial–vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD. Conclusions: Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.

Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Mor...

Exercise intolerance is a principal feature of heart failure with preserved ejection fraction (HFpEF), whether or not there is evidence of congestion at rest. The degree of functional limitation observed in HFpEF is comparable to patients with advanced heart failure and reduced ejection fraction. Exercise intolerance in HFpEF is characterized by impairments in the physiological reserve capacity of multiple organ systems, but the relative cardiac and extracardiac deficits vary among individuals. Detailed measurements made during exercise are necessary to identify and rank-order the multiorgan system limitations in reserve capacity that culminate in exertional intolerance in a given person. We use a case-based approach to comprehensively review mechanisms of exercise intolerance and optimal approaches to evaluate exercise capacity in HFpEF. We also summarize recent and ongoing trials of novel devices, drugs, and behavioral interventions that aim to improve specific exercise measures such as peak oxygen uptake, 6-min walk distance, heart rate, and hemodynamic profiles in HFpEF. Evaluation during the clinically relevant physiological perturbation of exercise holds promise to improve the precision with which HFpEF is defined and therapeutically targeted.

Background The United Network of Organ Sharing (UNOS) heart allocation policy designates patients on ECMO or with nondischargeable, surgically implanted, nonendovascular support devices (TCS-VAD) to higher listing statuses. Objectives This study aimed to explore whether temporary circulatory support-ventricular assist devices (TCS-VAD) have a survival advantage over extracorporeal membrane oxygenation (ECMO) as a bridge to transplant. Methods The UNOS database was used to conduct a retrospective analysis of adult heart transplants performed in the United States between 2005 and 2017. Survival analysis was performed to compare patients bridged to transplant with different modalities. Results Of the 24,905 adult transplants performed, 7,904 (32%) were bridged with durable left ventricular assist devices (LVADs), 177 (0.7%) with ECMO, 203 (0.8%) with TCS-VAD, 44 (0.2%) with percutaneous endovascular devices, and 8 (0.03%) with TandemHeart (LivaNova, London, United Kingdom). Unadjusted survival at 1 and 5 years post-transplant was 90 ± 0.4% and 77 ± 0.7% for durable LVAD, 84 ± 3% and 71 ± 4% for all TCS-VAD types, 79 ± 9% and 73 ± 14% for biventricular TCS-VAD, and 68 ± 3% and 61 ± 8% for ECMO. After propensity-matched pairwise comparisons were made, survival after all TCS-VAD types continued to be superior to ECMO (p = 0.019) and similar to LVAD (p = 0.380). ECMO was a predictor of post-transplant mortality in the Cox analysis compared with TCS-VAD (hazard ratio 2.40; 95% confidence interval: 1.44 to 4.01; p = 0.001). Conclusions Post-transplant survival with TCS-VAD is superior to ECMO and similar to LVAD in a national database.

Background Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear. Objectives This study sought to investigate the association of exPH with clinical determinants and outcomes. Methods The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality. Results Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p Conclusions Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.

Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp +/− mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp +/− mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. Conclusions: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT03759392.

Importance The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures The area under the curve (AUC) for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08;P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non–life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%];P = .04), there were no observed safety concerns. Conclusions and Relevance The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration ClinicalTrials.gov Identifier:NCT02816736

Fournier's gangrene (FG) is a perineal and abdominal necrotizing infection. It is most commonly found in middle-aged men with comorbidities such as diabetes mellitus. Initial symptoms are often indistinct and can rapidly progress to overwhelming infections with a relatively high mortality rate. It is crucial to make a prompt diagnosis so that the patient receives appropriate treatment. Given the importance of the identification of FG, we explored what were the most common signs and symptoms associated with FG, as well as distinguished the gold standard treatment. This systematic review utilized articles identified exclusively through PubMed using key terms such as Fournier's gangrene, signs, symptoms, and treatment. A total of 37 studies, including a total of 3,224 patients (3,093 males and 131 females), fit our inclusion parameters for relevance that included either the most identifiable presentation of FG or the most effective treatment. From our search, the most common clinical presentation was scrotal and labial pain, fever, abscesses, crepitus, erythema, and cellulitis. Diagnosis is made from clinical findings in conjunction with imaging. The gold standard for treatment was found to be a combination of surgical debridement, broad-spectrum antibiotics, and the administration of intravenous fluids. Further, patient survival was found to be directly related to the time from diagnosis to treatment when they underwent surgical debridement. The importance of early identification for improved outcomes or survival highlights the need for further studies or measures to enhance the identification of the signs and symptoms of FG.

Supplemental Digital Content is available in the text.