Borlaug, Barry A.

BACKGROUND: The right ventricular (RV) response to pressure overload is a crucial determinant of outcomes in pulmonary arterial (PA) hypertension. Sotatercept improves clinical outcomes, but its effects on the right ventricle have been inconsistent. We evaluated the effects of sotatercept on load-independent measures of RV contractility, RV–PA coupling, and right heart deformation at rest and exertion in patients with PA hypertension. METHODS: In this prospective trial among participants with PA hypertension recruited between July 2024 and May 2025, we performed simultaneous echocardiography and invasive pressure measurements during rest and exercise to evaluate changes in RV contractility (end-systolic elastance [Ees]), afterload (PA elastance [Ea]), RV–PA coupling (ratio of arterial Ea to Ees), and right heart deformation, including RV and right atrial strain, before and after 24 weeks of sotatercept using mixed models. RESULTS: Among 30 participants (n=21; 70% female; mean age, 49.3 years [SD 13.5]), sotatercept decreased PA Ea. These changes were associated with reduced RV contractility, PA pulsatility index, and the maximal rate of RV pressure increase over time (dP/dt max ; P <0.001 for all). The decrease in Ees was associated with a decrease in PA Ea (r=+0.70 [95% CI, +0.44 to +0.85]; P <0.0001) with preserved RV–PA coupling (mean difference, +0.08 [95% CI, −0.11 to +0.26]; P =0.42). Although systolic indices measured at the base of the right ventricle (tricuspid annular plane systolic excursion and systolic velocity of the lateral tricuspid annulus) decreased after sotatercept use, there was an increase in RV free wall–dependent systolic indices, including resting and exercise RV free wall strain (mean difference, +6.2% [95% CI, +4.5 to +7.8]; P <0.0001) and fractional area change ( P =0.0001). Beyond the right ventricle, there was also improved right atrial filling and contractile performance across rest and exercise ( P <0.0001 for all). CONCLUSIONS: Sotatercept decreases RV contractility in proportion to reduced afterload, while preserving the RV–PA coupling relationship. Despite decreased RV contractility, global measures of right heart performance, such as RV free wall strain and RA strain, improve, alongside redistribution of RV deformation from annular motion to free wall shortening. These data suggest that sotatercept causes an energetically favorable reduction in resting RV contractility to match the lower afterload, which does not appear physiologically detrimental when considering the concurrent improvement in RV free wall contractile mechanics and exertional right heart reserve. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06409026.

Abstract Background and Aims Exercise stress echocardiography is recommended as an alternative to invasive testing for diagnosing heart failure with preserved ejection fraction (HFpEF), but an evidence-based operational framework guiding its application is lacking. Methods Patients with chronic unexplained dyspnoea underwent invasive haemodynamic exercise testing with simultaneous echocardiography to test the hypotheses that (i) the current diagnostic algorithms (H2FPEF, HFA-PEFF, and HFpEF-ABA scores) could be enhanced when combined with exercise echocardiography; and (ii) incorporating resting left atrial (LA) compliance (LA reservoir strain divided by E/e′) could further improve diagnostic triage, using separate cut points optimizing sensitivity and specificity. Findings were then validated in an international multicentre cohort. Results Of 482 patients, HFpEF was present in 386 and non-cardiac dyspnoea in 96. Sensitivity to detect HFpEF was only 55%–60% and accuracy 61%–67% using individual diagnostic scores with currently recommended exercise echocardiography. Addition of abnormal resting LA compliance to exercise echocardiography increased sensitivity to 84%–85% but increased the false-positive rate to 31%–43%. Applying separate cut points that optimize specificity and sensitivity (either exercise E/e′ ≥ 13.8 or resting LA compliance ≤1.6% to rule-in HFpEF; both exercise E/e′ &lt; 7.2 and resting LA compliance &gt;4.4% to rule-out HFpEF, remaining patients indeterminate who require invasive testing) improved sensitivity to 95%–99% among definitively classified patients and reduced the number of patients that require invasive exercise testing from ∼60% to ∼30%. Findings were replicated in a multicentre, international validation cohort of patients undergoing rest–exercise echocardiography and invasive exercise testing. Conclusions Currently used non-invasive approaches to HFpEF diagnosis have inadequate sensitivity, indicating that exercise echocardiography cannot supplant invasive testing. Addition of LA strain imaging with optimized rule-in or rule-out values improves diagnostic triage by expanding non-invasive rule-in/rule-out classifications while identifying patients who still require invasive testing in the evaluation of HFpEF.

Background We examined the relationship between infection‐related hospitalization (IRH) and heart failure (HF) in a large clinical health system and assessed whether IRH improved prediction beyond HF risk equations. Methods We studied 80 880 adults (14 150 with IRH and 66 730 age‐ and sex‐matched comparators) aged ≥18 years without HF in the Rochester Epidemiology Project from 1/1/2005–12/31/2019. IRH was identified using International Classification of Diseases ( ICD ) codes. HF incidence was defined as ≥1 HF‐related ICD code. Multivariable Cox models assessed the association between IRH and incident HF. Among 29 219 adults aged 30 to 79 years without baseline cardiovascular disease in the Rochester Epidemiology Project, Harrell's concordance statistic assessed whether IRH improved discrimination of the Predicting Risk of Cardiovascular Disease EVENTs–Heart Failure (PREVENT‐HF) equations. Results Participants were 53.3% women, 85.6% White individuals, and 95.1% non‐Hispanic individuals, with a mean age of 56.0±20.0 years. Median follow‐up time was 6.2 years. Among the IRH group, 2729 developed incident HF (2.75/100 person‐years) versus 4854 (1.00/100 person‐years) in the comparator. The multivariable adjusted hazard ratio for incident HF among participants with versus without an IRH was 1.85 (95% CI, 1.76, 1.94). In a separate cohort, incorporating IRH into PREVENT‐HF increased the concordance statistic from 0.776 to 0.779 (change, 0.003 [95% CI, 0.001–0.004]). The PREVENT‐HF risk score underestimated the 10‐year risk of HF by up to 9% among participants with an IRH. Conclusions IRH was associated with incident HF but provided negligible change to 10‐year HF risk discrimination. However, among individuals with an IRH, incorporating this information meaningfully improved 10‐year HF risk prediction. Severe infections may serve as a risk‐enhancing factor warranting enhanced preventive measures, particularly in populations where IRH is more common.

Left atrial (LA) myopathy plays a critical role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate LA function in a murine model of hypertension-induced HFpEF, with and without obesity, by analyzing left ventricular (LV) pressure signals to quantify the contribution of LA systole to total LV volume. HFpEF was induced in C57BL/6J mice using the SAUNA model, which involves uninephrectomy, chronic aldosterone infusion, and high-salt drinking water for four weeks. To model obesity-associated HFpEF, a high-fat diet (HFD) was added to the SAUNA protocol. Invasive hemodynamic measurements were obtained, and a novel method was developed to assess atrial systole using the second-order derivative of the LV pressure signal during diastolic filling. SAUNA HFpEF mice exhibited preserved LVEF, moderate hypertension, pulmonary congestion, and diastolic dysfunction as evidenced by a prolonged time constant of relaxation (Tau). In sham control mice, atrial systole accounted for 23.0 ± 2.4% of LV volume, whereas this contribution was significantly reduced to 13.9 ± 2.3% in SAUNA HFpEF mice ( P &lt; 0.01). In obese sham controls, atrial systole contributed 53.1 ± 2.2%, which was markedly decreased to 36.8 ± 3.6% in obese-SAUNA HFpEF mice ( P &lt; 0.003). This novel method enables precise quantification of LA systolic contribution to LV filling in mice and highlights the pathophysiological effects of hypertension and obesity on LA function in HFpEF.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure (HF) cases and remains diagnostically challenging due to nonspecific symptoms and a lack of accessible noninvasive screening tools, leading to widespread underdiagnosis and delayed treatment. The electrocardiogram (ECG) is a low-cost, widely available tool that reflects myocardial electrical remodeling. We previously developed and externally validated an ECG-based artificial intelligence (ECG-AI) model capable of classifying ECGs into four categories: reduced ejection fraction (rEF), mid-range ejection fraction (mEF), HFpEF, and controls. In this study, we evaluate the ability of this ECG-AI model to predict future HFpEF diagnosis using real-world data from a large integrated health system. Methods: We applied the validated ECG-AI model to an independent cohort of 7713 patients from Wake Forest Baptist Health (WFBH), using one ECG per patient recorded before the clinical diagnosis of HFpEF. Model discrimination was evaluated across multiple prediction windows from six months up to ten years before diagnosis using the area under the receiver operating characteristic curve (AUC), with comparisons performed using DeLong’s test. Performance was also compared head-to-head with the H2FPEF score, a validated clinical score for HFpEF, in the subset of patients with complete data for score calculation. ECG-AI outputs were stratified into quartiles and evaluated using Kaplan–Meier survival analysis and multivariable Cox proportional hazards regression adjusted for demographics and major comorbidities. Results: Of the 7713 patients, 283 (3.7%) were subsequently diagnosed with HFpEF. The ECG-AI model achieved an AUC of 0.79 (95% CI, 0.72–0.86) using ECGs recorded within six months before diagnosis. Discrimination remained stable across prediction windows extending up to ten years before diagnosis (AUC range, 0.78–0.80; all DeLong p > 0.01 vs. the six-month window). Compared with the H2FPEF score, ECG-AI demonstrated superior discrimination, improving the AUC by 0.06–0.07 across the evaluated prediction windows. Patients in the highest ECG-AI risk quartile had an unadjusted hazard ratio (HR) of 11.18 (95% CI, 7.27–17.21; C-index, 0.75) and an adjusted HR of 6.60 (95% CI, 4.24–10.28; C-index, 0.82). Adding clinical covariates to ECG-AI improved the C-index by 0.07 and 0.09 for the five- and ten-year prediction windows, respectively. Conclusions: An independently validated ECG-AI model predicted incident HFpEF up to ten years before clinical diagnosis and outperformed the H2FPEF score using ECG alone, indicating that ECG-derived signatures precede clinical recognition of the syndrome. ECG-AI shows promise as a prognostic, risk-stratification tool to prioritize further evaluation; prospective validation and single-lead assessment are needed before screening or wearable deployment.

Abstract Aims Cardiogenic shock (CS) is characterized by impaired left ventricular (LV) mechanical performance and adverse remodelling. We evaluated whether transthoracic echocardiography (TTE)-derived modified cardiac efficiency (mCE), integrating stroke work and residual LV volume, is associated with short- and long-term mortality in CS and whether its prognostic value differs by shock aetiology. Methods and results In this retrospective cohort study, consecutive adults admitted with CS to the cardiac intensive care unit at Mayo Clinic (2007–2018) were included if TTE was performed within 24 h. mCE was calculated as (stroke volume × estimated LV end-systolic pressure) divided by LV end-systolic volume and categorized into quartiles. Primary outcome was in-hospital mortality; secondary outcome was 1-year mortality. Multivariable logistic and Cox models adjusted for illness severity, comorbidity burden, shock aetiology, cardiac arrest, vasoactive therapy, and mechanical circulatory support. Among 667 patients, median mCE was 48 mmHg (IQR 32–74). In-hospital mortality was 28% and increased stepwise across decreasing mCE quartiles. The lowest quartile had a 2.5-fold higher adjusted odds of in-hospital death (OR 2.53; 95%CI: 1.49–4.37; P &lt; 0.001). One-year mortality was 41%; the lowest quartile had a two-fold higher adjusted hazard of death (HR 2.05; 95%CI: 1.45–2.89; P &lt; 0.001). Associations were stronger in acute coronary syndrome-related CS (interaction P = 0.035 for in-hospital; P = 0.015 for 1-year). Within the lowest quartile, reduced systolic pressure further amplified mortality risk. Conclusion Early TTE-derived mCE was independently associated with short- and long-term mortality in CS, particularly in acute coronary syndrome-related CS, and captured the interaction between ventricular remodelling and mechanical performance underlying high-risk phenotypes.

At a time when there was no unifying hypothesis and no broadly effective treatments for heart failure with a preserved ejection fraction (HFpEF), it was proposed that HFpEF represented a multitude of different disorders. Accordingly, characterization of phenotypic heterogeneity was envisioned as a means of identifying novel causal pathways that could lead to new treatments while simultaneously discerning patients who would selectively benefit from a specific therapy. However, efforts over the past decade to characterize phenotypic diversity in diverse and complex ways have not achieved these goals. Subgroup analyses of neutral HFpEF trials have failed to reliably identify responders to treatments. Neither proteomics nor unsupervised cluster analysis across multiple phenotypic domains has yielded reproducible results (even in the same dataset), elucidated novel mechanistic pathways for new drug development, or identified patients most likely to benefit from treatment. In marked contrast to these efforts to characterize phenotypic heterogeneity, large-scale trials in HFpEF enrolled patients using broad eligibility criteria, and they established the benefits of sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists without evidence for subgroup effects. However, it is noteworthy that patients enrolled in recent large-scale HFpEF trials were characterized by general uniformity with respect to the presence of excess adiposity, with central obesity being a feature of the vast majority of enrolled participants. Of note, patients with obesity showed particularly large benefits when treated with effective drugs for HFpEF. These observations raise the possibility that, if these trials had permitted the participation of patients with class III obesity or with lower natriuretic peptide levels, the magnitude of the observed treatment effects might have been greater than originally reported. These findings are consistent with a central role for visceral adiposity (and the secretion of an altered suite of adipokines) in the pathogenesis of HFpEF. Therefore, because the field of HFpEF has a unifying hypothesis (applicable to the large majority of patients), enrolled a broad population of patients in large-scale trials without subgroup interactions, and has several broadly applicable effective treatments (as is true for heart failure with a reduced ejection fraction), the motivation to characterize phenotypic heterogeneity in HFpEF in complex ways may no longer be supported or needed.

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance, with respiratory muscle dysfunction as a contributing factor. Patients with HFpEF have exaggerated cardiovascular responses to respiratory muscle metaboreflex activation. In this study, we determined the impact of inspiratory muscle training (IMT) on the respiratory muscle metaboreflex in HFpEF. We found that 8 wk of IMT improved inspiratory muscle strength and attenuated the respiratory muscle metaboreflex-mediated cardiovascular responses in patients with HFpEF.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract