Percent Predicted Peak Exercise Oxygen Pulse Provides Insights Into Ventricular-Vascular Response and Prognosticates HFpEF.

Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredO2P) and ventricular-vascular response (VVR) and the association of %PredO2P with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients. Objectives: The authors investigated the association between: 1) CPET measures of %PredO2P and VVR; and 2) %PredO2P and all-cause mortality in HFpEF patients. Methods: Our cohort of 154 HFpEF patients underwent invasive CPET and were grouped into %PredO2P tertiles. The association between percent predicted Fick components and markers of VVR (ie, proportionate pulse pressure, effective arterial elastance) was determined with correlation analysis. The Cox proportional hazards model was used to identify predictors of mortality. Results: The participants' mean age was 57 ± 15 years. Higher %PredO2P correlated with higher exercise capacity. In terms of VVR, higher %PredO2P correlated with a lower pressure for a given preload (effective arterial elastance r = -0.45, P < 0.001 and proportionate pulse pressure r = -0.22, P = 0.008). %PredO2P distinguished normal and abnormal percent predicted peak stroke volume and correlated positively with %PredVO2 (r = 0.61, P < 0.001). Participants had a median follow-up time of 5.6 years and 15% death. Adjusted for age and body mass index, there was a 5% relative reduction in mortality (HR: 0.95, 95% CI: 0.92-0.98, P = 0.003) for every percent increase in %PredO2P. Conclusions: In HFpEF, %PredO2P is a VVR marker that can stratify invasive parameters such as percent predicted peak stroke volume. %PredO2P is an independent prognostic marker for all-cause mortality and those with higher %PredO2P exhibited longer survival.

Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial.

Importance: Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors' knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF. Objective: To investigate the efficacy and safety of the novel urate transporter-1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level. Design, Setting, and Participants: This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024. Interventions: Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization. Main Outcomes and Measures: Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events). Results: Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro-brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, -59.6%; 95% CI, -64.4% to -54.2%) lowered SUA level to a greater extent than allopurinol (mean change, -37.6%; 95% CI, -45.3% to -28.9%) or placebo (mean change, 0.8%; 95% CI, -11.8% to 15.2%; P < .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, -0.56 to 1.10 mL/kg/min; allopurinol, -0.17 mL/kg/min; 95% CI, -1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, -0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, -3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group. Conclusions and Relevance: Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT04327024.

Newton-Krylov continuation of amplitude-modulated rotating waves in sheared annular electroconvection.

We present an approach for studying the primary, secondary, and tertiary flow transitions in sheared annular electroconvection. In particular, we describe a Newton-Krylov method based on time integration for the computation of rotating waves and amplitude-modulated rotating waves, and for the continuation of these flows as a parameter of the system is varied. The method exploits the rotational nature of the flows and requires only a time-stepping code of the model differential equations, i.e., it does not require an explicit code for the discretization of the linearized equations. The linear stability of the solutions is computed to identify the parameter values at which the transitions occur. We apply the method to a model of electroconvection that simulates the flow of a liquid crystal film in the smectic A phase suspended between two annular electrodes and subjected to an electric potential difference and a radial shear. Due to the layered structure of the smectic A phase, the fluid can be treated as two-dimensional (2D) and is modeled using the 2D incompressible Navier-Stokes equations coupled with an equation for charge continuity. The system is a close analog to laboratory-scale geophysical fluid experiments and thus represents an ideal system in which to apply the method before its application to these other systems that exhibit similar flow transitions. In the model for electroconvection, we identify the parameter values at which the primary transition from steady axisymmetric flow to rotating waves occurs, as well as at which the secondary transition from the rotating waves to amplitude-modulated rotating waves occurs. In addition, we locate the tertiary transition, which corresponds to a transition from the amplitude-modulated waves to a three-frequency flow. Of particular interest is that the method also finds a period-doubling bifurcation from the amplitude-modulated rotating waves and a subsequent transition from the flow resulting from this bifurcation.

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Association of Smartwatch-Based Heart Rate and Physical Activity With Cardiorespiratory Fitness Measures in the Community: Cohort Study.

BACKGROUND: Resting heart rate (HR) and routine physical activity are associated with cardiorespiratory fitness levels. Commercial smartwatches permit remote HR monitoring and step count recording in real-world settings over long periods of time, but the relationship between smartwatch-measured HR and daily steps to cardiorespiratory fitness remains incompletely characterized in the community. OBJECTIVE: This study aimed to examine the association of nonactive HR and daily steps measured by a smartwatch with a multidimensional fitness assessment via cardiopulmonary exercise testing (CPET) among participants in the electronic Framingham Heart Study. METHODS: Electronic Framingham Heart Study participants were enrolled in a research examination (2016-2019) and provided with a study smartwatch that collected longitudinal HR and physical activity data for up to 3 years. At the same examination, the participants underwent CPET on a cycle ergometer. Multivariable linear models were used to test the association of CPET indices with nonactive HR and daily steps from the smartwatch. RESULTS: We included 662 participants (mean age 53, SD 9 years; n=391, 59% women, n=599, 91% White; mean nonactive HR 73, SD 6 beats per minute) with a median of 1836 (IQR 889-3559) HR records and a median of 128 (IQR 65-227) watch-wearing days for each individual. In multivariable-adjusted models, lower nonactive HR and higher daily steps were associated with higher peak oxygen uptake (VO2), % predicted peak VO2, and VO2 at the ventilatory anaerobic threshold, with false discovery rate (FDR)-adjusted P values <.001 for all. Reductions of 2.4 beats per minute in nonactive HR, or increases of nearly 1000 daily steps, corresponded to a 1.3 mL/kg/min higher peak VO2. In addition, ventilatory efficiency (VE/VCO2; FDR-adjusted P=.009), % predicted maximum HR (FDR-adjusted P<.001), and systolic blood pressure-to-workload slope (FDR-adjusted P=.01) were associated with nonactive HR but not associated with daily steps. CONCLUSIONS: Our findings suggest that smartwatch-based assessments are associated with a broad array of cardiorespiratory fitness responses in the community, including measures of global fitness (peak VO2), ventilatory efficiency, and blood pressure response to exercise. Metrics captured by wearable devices offer a valuable opportunity to use extensive data on health factors and behaviors to provide a window into individual cardiovascular fitness levels.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.

AIMS: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose. METHODS: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials. CONCLUSIONS: HuMAIN will test a promising novel agent for obesity-related HFpEF.

Cannulated screws versus nitinol staple for tarsometatarsal fusion: A cadaveric biomechanical comparison model.

BACKGROUND: The objective of this study was to evaluate the biomechanical stability of a medially placed nitinol staple compared to two crossed-screws in the first TMT-1 joint fusion in a cadaveric cyclic loading model. METHODS: Seven matched pairs (N = 7) of lower limb cadaveric specimens were utilized. TMT-1 joints from each donor were fixed with a medially placed nitinol staple or dorsally placed two 3.5 mm partially threaded cannulated crossed-screws. Specimens were tested in a 4-point bending setting with increasing cyclic forces. RESULTS: The mean plantar gapping was not significantly different between the two groups at any loading stage below 200 N. Specimens fixed with a nitinol staple failed at a mean load of 305 ± 57 N. Conversely, those fixed with crossed-screws failed at 373 ± 86 N. (P = .09). CONCLUSION: There was no statistical difference between a medially placed nitinol staple and dorsally placed crossed-screws in failure loads and plantar gapping under cyclic loads at the TMT-1 joint, however, the staple fixation was much more variable. LEVEL OF EVIDENCE: Level V, basic science study, biomechanics.

Clusters of multidimensional exercise response patterns and estimated heart failure risk in the Framingham Heart Study.

AIMS: New tools are needed to identify heart failure (HF) risk earlier in its course. We evaluated the association of multidimensional cardiopulmonary exercise testing (CPET) phenotypes with subclinical risk markers and predicted long-term HF risk in a large community-based cohort. METHODS AND RESULTS: We studied 2532 Framingham Heart Study participants [age 53 ± 9 years, 52% women, body mass index (BMI) 28.0 ± 5.3 kg/m2, peak oxygen uptake (VO2) 21.1 ± 5.9 kg/m2 in women, 26.4 ± 6.7 kg/m2 in men] who underwent maximum effort CPET and were not taking atrioventricular nodal blocking agents. Higher peak VO2 was associated with a lower estimated HF risk score (Spearman correlation r: -0.60 in men and -0.55 in women, P < 0.0001), with an observed overlap of estimated risk across peak VO2 categories. Hierarchical clustering of 26 separate CPET phenotypes (values residualized on age, sex, and BMI to provide uniformity across these variables) identified three clusters with distinct exercise physiologies: Cluster 1-impaired oxygen kinetics; Cluster 2-impaired vascular; and Cluster 3-favourable exercise response. These clusters were similar in age, sex distribution, and BMI but displayed distinct associations with relevant subclinical phenotypes [Cluster 1-higher subcutaneous and visceral fat and lower pulmonary function; Cluster 2-higher carotid-femoral pulse wave velocity (CFPWV); and Cluster 3-lower CFPWV, C-reactive protein, fat volumes, and higher lung function; all false discovery rate < 5%]. Cluster membership provided incremental variance explained (adjusted R2 increment of 0.10 in women and men, P < 0.0001 for both) when compared with peak VO2 alone in association with predicted HF risk. CONCLUSIONS: Integrated CPET response patterns identify physiologically relevant profiles with distinct associations to subclinical phenotypes that are largely independent of standard risk factor-based assessment, which may suggest alternate pathways for prevention.

Observation-Based Diagnostics of Reactive Nitrogen Recycling through HONO Heterogenous Production: Divergent Implications for Ozone Production and Emission Control.

Understanding of nitrous acid (HONO) production is crucial to photochemical studies, especially in polluted environments like eastern China. In-situ measurements of gaseous and particulate compositions were conducted at a rural coastal site during the 2018 spring Ozone Photochemistry and Export from China Experiment (OPECE). This data set was applied to investigate the recycling of reactive nitrogen through daytime heterogeneous HONO production. Although HONO levels increase during agricultural burning, analysis of the observation data does not indicate more efficient HONO production by agricultural burning aerosols than other anthropogenic aerosols. Box and 1-D modeling analyses reveal the intrinsic relationships between nitrogen dioxide (NO2), particulate nitrate (pNO3), and nitric acid (HNO3), resulting in comparable agreement between observed and simulated HONO concentrations with any one of the three heterogeneous HONO production mechanisms, photosensitized NO2 conversion on aerosols, photolysis of pNO3, and conversion from HNO3. This finding underscores the uncertainties in the mechanistic understanding and quantitative parametrizations of daytime heterogeneous HONO production pathways. Furthermore, the implications for reactive nitrogen recycling, ozone (O3) production, and O3 control strategies vary greatly depending on the HONO production mechanism. On a regional scale, the conversion of HONO from pNO3 can drastically enhance O3 production, while the conversion from NO2 can reduce O3 sensitivity to NOx changes in polluted eastern China.

Characterization of serum phosphate levels over time with intravenous ferric carboxymaltose versus placebo as treatment for heart failure with reduced ejection fraction and iron deficiency: An exploratory prospective substudy from HEART-FID.

AIMS: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. METHODS AND RESULTS: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. CONCLUSIONS: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF.

Cardiorespiratory Fitness Is Associated with Decreased Platelet Reactivity.

PURPOSE: Platelets are key mediators in cardiovascular disease (CVD). Low cardiorespiratory fitness (CRF) is a risk factor for CVD. The purpose of our study was to assess if CRF associates with platelet function. METHODS: Platelet assays and cardiopulmonary exercise testing were conducted in the Framingham Heart Study (n = 3,014). Linear mixed effects models estimated associations between CRF (assessed by peak oxygen uptake [VO2]), and multiple platelet reactivity assays. Models were adjusted for multiple medications, risk factors, relatedness and prevalent CVD. RESULTS: Nineteen associations passed the significance threshold in the fully adjusted models, all indicating higher CRF associated with decreased platelet reactivity. Significant traits spanned multiple platelet agonists. Strongest associations were observed in Multiplate whole blood testing after TRAP-6 (e.g., velocity, beta = -0.563, 95% CI [-0.735,-0.391], p = 1.38E-10), ADP (e.g., velocity, beta = -0.514, 95% CI [-0.681,-0348], p = 1.41E-09), collagen (e.g., velocity, beta = -0.387, 95% CI [-0.549,-0.224], p = 3.01E-06), ristocetin (e.g., AUC, beta = -0.365, 95% CI [-0.522,-0.208], p = 5.17E-06) and arachidonic acid stimulation of platelets (e.g., velocity, beta = -0.298, 95% CI [-0.435,-0.162], p = 3.39E-04), and light transmission aggregometry (LTA) after ristocetin stimulation (e.g., max aggregation, beta = -0.362, 95% CI [-0.540,-0.184], p = 6.64E-05). One trait passed significance threshold in the aspirin sub-sample (LTA ristocetin primary slope, beta = -0.733, 95% CI [-1.134,-0.333], p = 3.30E-04), and another in a model including von Willebrand Factor levels as a covariate (U46619, a thromboxane receptor mimetic, AUC in the Optimul assay, beta = -0.36, 95%CI [-0.551,-0.168], p = 2.35E-04). No strong interactions were observed between the associations and sex, age or body mass index in formal interaction analyses. CONCLUSIONS: Our findings build on past work that shows CRF to be associated with reduced CVD by suggesting decreased platelet reactivity may play a mechanistic role. We found significant associations with multiple platelet agonists, indicating higher CRF may globally inhibit platelets; however, given multiple strong associations after TRAP-6 and ADP stimulation, PAR-1 and purinergic signaling may be most heavily involved. This is notable since each of these receptor pathways are tied to anti-coagulant (DOACs/thrombin inhibitors) and anti-platelet therapies (P2Y12/PAR1/PAR4 inhibitors) for CVD prevention.

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Uncovering Unrecognized Heart Failure With Preserved Ejection Fraction Among Individuals With Obesity and Dyspnea.

BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community. METHODS: Research volunteers with dyspnea and obesity underwent resting echocardiography; participants with possible pulmonary hypertension qualified for invasive cardiopulmonary exercise testing. HFpEF was defined using rest or exercise pulmonary capillary wedge pressure criteria (≥15 mm Hg or Δpulmonary capillary wedge pressure/Δcardiac output slope, >2.0 mm Hg·L-1·min-1). RESULTS: Among n=78 participants (age, 53±13 years; 65% women; body mass index, 37.3±6.8 kg/m2), 40 (51%) met echocardiographic criteria to undergo invasive cardiopulmonary exercise testing. In total, 24 participants (60% among the cardiopulmonary exercise testing group, 31% among the total sample) were diagnosed with HFpEF by rest or exercise pulmonary capillary wedge pressure (n=12) or exercise criteria (n=12). There were no differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide; 79 [62-104] versus 73 [57-121] pg/mL) or resting echocardiography (mitral E/e' ratio, 9.1±3.1 versus 8.0±2.7) among those with versus without HFpEF (P>0.05 for all). Distributions of HFpEF diagnostic scores were similar, with the majority classified as intermediate risk (100% versus 93.75% [H2FPEF] and 87.5% versus 68.75% [HFA-PEFF (Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing, and final etiology)] in those with versus without HFpEF). CONCLUSIONS: Among adults with obesity and dyspnea without known cardiovascular disease, at least a third had clinically unrecognized HFpEF uncovered on invasive cardiopulmonary exercise testing. Clinical, biomarker, resting echocardiography, and diagnostic scores were similar among those with and without HFpEF. These results suggest clinical underdiagnosis of HFpEF among individuals with obesity and dyspnea and highlight limitations of noninvasive testing in the identification of HFpEF.

Life's Essential 8 Cardiovascular Health Score and Cardiorespiratory Fitness in the Community.

BACKGROUND: The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community-dwelling adults. METHODS AND RESULTS: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O2). A 100-point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O2 (log-transformed) and complementary CRF measures. In age- and sex-adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O2, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all P<0.0001). A clinically meaningful 5-point higher LE8 score was associated with a 6.0% greater peak V̇O2 (≈1.4 mL/kg per minute at sample mean). All LE8 components were significantly associated with peak V̇O2 in models adjusted for age and sex, but blood lipids, diet, and sleep health were no longer statistically significant after adjustment for all LE8 components. Over an ≈8-year interval, a 5-unit increase in LE8 score was associated with a 3.7% higher peak V̇O2 (P<0.0001). CONCLUSIONS: Higher LE8 score and improvement in LE8 over time was associated with greater CRF, highlighting the importance of the LE8 factors in maintaining CRF.

Level of autistic traits in neurotypical adults predicts kinematic idiosyncrasies in their biological movements.

Introduction: Over the last decade of research, a notable connection between autism spectrum disorder (ASD) and unique motor system characteristics has been identified, which may influence social communication through distinct movement patterns. In this study, we investigated the potential for features of the broader autism phenotype to account for kinematic idiosyncrasies in social movements expressed by neurotypical individuals. Methods: Fifty-eight participants provided recordings of point-light displays expressing three basic emotions and completed the Autism Spectrum Quotient (AQ). We extracted kinematic metrics from the biological movements using computer vision and applied linear mixed-effects modeling to analyze the relationship between these kinematic metrics and AQ scores. Results: Our results revealed that individual differences in the total AQ scores, and the sub-scale scores, significantly predicted variations in kinematic metrics representing order, volume, and magnitude. Discussion: The results of this study suggest that autistic traits may intricately influence the movement expressions at the microlevel, highlighting the need for a more nuanced understanding of the potential endophenotypic characteristics associated with social movements in neurotypical individuals.

A second chance for a new heart? The role of metabolic and bariatric surgery in patients with end-stage heart failure.

BACKGROUND: Obesity is an independent risk factor for heart failure (HF). Substantial weight loss has been shown to reverse obesity-related cardiomyopathy. This study aimed to report our institution's experience with laparoscopic sleeve gastrectomy (LSG) in patients with morbid obesity and end-stage HF. METHODS: Between 2018 and 2022, 26 patients with end-stage HF were referred for LSG. Of 26 patients, 16 underwent an operation, and 10 did not. After institutional review board approval, a retrospective electronic medical record review was performed to evaluate (i) age, (ii) preoperative weight, (iii) decrease in body mass index (BMI) score, (iv) whether the patient underwent heart transplantation, and (v) mortality. Data analysis was performed using Stata/SE (version 17.0; StataCorp). The Wilcoxon rank-sum test was used to compare continuous variables between the cohorts, and the Pearson chi-square test was used for binary variables with Bonferroni correction applied. RESULTS: The LSG and non-LSG cohorts had comparable ages (P = .088) and starting BMI score (P = .918), and a proportion of patients had a ventricular assist device (P = .191). Patients who underwent LSG lost significantly more weight than the patients who did not, with an average decrease in BMI score of 8.9 kg/m2 (SD, ±6.13) and 1.1 kg/m2 (SD, ±4.10), respectively (P = .040). Of note, 6 patients (37.5%) who underwent LSG eventually underwent transplantation, compared with 2 patients (20.0%) from the matched cohort (P = .884). Of the 26 patients, there were 6 deaths: 2 (12.5%) in the LSG cohort and 4 (40.0%) in the non-LSG cohort (P = .525). CONCLUSION: LSG may be safe and effective for weight loss in patients with HF. This operation may provide patients affected by obesity with end-stage HF the lifesaving opportunity to achieve transplant candidacy.

Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy.

BACKGROUND: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity. OBJECTIVES: This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2). METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10). CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. OBJECTIVES: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. METHODS: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. RESULTS: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). CONCLUSIONS: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Transverse patella fracture fixation: A cadaveric biomechanical comparison of cannulated screws and anterior tension band versus low-profile, multiplanar mesh plating.

INTRODUCTION: Multiplanar mesh plating of patella fractures has become more popular in recent years. It was the goal of this study to compare the biomechanical stability of cannulated screw with anterior tension band to multiplanar mesh plating for fixation of transverse patella fractures in cadaver specimens. MATERIALS AND METHODS: Eight matched pairs of fresh frozen cadaveric knees were obtained and soft tissues dissected leaving the extensor mechanism, joint capsule, and retinaculum intact. Transverse fractures were created at the mid-portion of the patella. For each pair, one specimen was repaired using cannulated screws with anterior tension band, and the second was repaired using multiplanar mesh plating. Each specimen underwent cyclic extension loading with loads increasing by 1.1 kg after every 50 cycles. Interfragmentary displacement was measured at the end of each interval at both 5° and 45° of knee flexion angle, with fixation failure defined by >2 mm displacement. RESULTS: The specimens fixed with multiplanar mesh plating survived more cycles and higher loads than the specimens fixed with cannulated screws with anterior tension band (p = 0.011 comparing survival plots). After 150 cycles of extension loading, 3 of 8 of the specimens fixed with screws/tension band had failed, whereas none of the mesh plated specimens had failed. After 400 cycles, 7 of 8 of the screws/tension band had failed, whereas half of the mesh plated specimens had failed. CONCLUSIONS: While a more technically challenging and expensive technique, mesh plating for patella fractures appears to offer greater durability than traditional cannulated screw with tension banding.