BACKGROUND AND AIMS:The prediction of the first major arrhythmic event (MAE) is still an unmet need in the recently defined scenario of non-dilated left ventricular cardiomyopathy (NDLVC). METHODS:A cohort of 337 patients with NDLVC and no history of MAE was retrospectively identified at two large centres. Patient-tailored diagnostic workup included cardiac magnetic resonance (CMR), endomyocardial biopsy, and genetic testing. The primary endpoint was the occurrence of the first MAE, including sustained ventricular tachycardia (VT), ventricular fibrillation, or appropriate implantable cardioverter-defibrillator therapy, by 60-month follow-up. A pool of 216 NDLVC patients from 11 European centres served as a validation cohort. RESULTS:In the study cohort (mean age 37 ± 15 years, 62% male), the mean left ventricular ejection fraction (LVEF) was 52 ± 8%, and 79% of patients had late gadolinium enhancement (LGE) at baseline CMR. By 60-month follow-up, 51 patients (15%) experienced a MAE. The primary endpoint was predicted by male sex [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.3-4.4, P = .007], baseline non-sustained VT (HR 3.1, 95% CI 1.7-5.6, P < .001), LVEF < 45% (HR 5.5, 95% CI 2.7-11.0, P < .001), septal (HR 2.0, 95% CI 1.0-4.0, P = .046) and ring-like pattern of LGE (HR 1.3, 95% CI .6-2.6, P = .54), pathogenic/likely pathogenic variants in guideline-defined high-risk genes (HR 4.6, 95% CI 2.3-9.1, P < .001), and biopsy/CMR-proven myocardial inflammation (HR 15.7, 95% CI 6.1-40.3, P < .001). The results were confirmed in the validation cohort (Uno's C-index 0.81, 95% CI .75-.88). A novel risk score was subsequently derived. CONCLUSIONS:In NDLVC, male sex, non-sustained VT, LVEF < 45%, septal and ring-like LGE, high-risk genotypes, and myocardial inflammation predicted the first episode of MAE by 60 months.

Dilated cardiomyopathy (DCM) is associated with shifts in cardiac metabolism. Those shifts are inconsistent between patients, possibly due to heterogeneity in DCM etiologies. Identifying metabolic subtypes, or metabotypes, in DCM patients may open personalized treatment opportunities. Developing a methodology to identify metabotypes would be a boon in this regard. Here, we describe a metabotyping pipeline, integrating advanced metabolic modeling methods optimized for cardiac research, to uncover these subtypes using widely available transcriptomics data. We applied our method to publicly available cardiac data of end-stage DCM patients and non-failing controls, identifying two metabotypes in the DCM group. These metabotypes are characterized by unique metabolic alterations, notably in calcium handling, amino-acid oxidation, and the pentose phosphate pathway. Strikingly, one metabotype exhibited a greater deviation from healthy controls, suggesting a greater metabolic contribution to its underlying etiology. Further transcriptome-wide analysis revealed immune-related differences between metabotypes, suggesting an interplay between inflammation, immune response and metabolism in these DCM subtypes. Our study uncovers cardiometabolic heterogeneity in DCM and underscores the potential of transcriptome-derived metabotyping in cardiovascular research. ### Competing Interest Statement The authors have declared no competing interest.

Background: Atrial fibrillation (AF) is the most common arrhythmia in dilated cardiomyopathy (DCM) and is associated with adverse outcomes. Characterization of AF in DCM by genotype and clinical features remains limited. Aims: To describe AF prevalence and incidence in DCM stratified by genotype and disease gene, and to identify clinical and genetic predictors of incident AF. Methods: Using the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), we included 3117 DCM patients who had genetic testing. AF prevalence, incidence, clinical characteristics and genotype (genotype-positive [G+], defined by the presence of a pathogenic/likely pathogenic [P/LP] variant in a DCM gene or genotype-negative [G-]) were assessed and further stratified by disease gene. Predictors of incident AF were identified with uni- and multivariable analyses. Covariates for the multivariable model were selected based on clinical relevance and discriminative performance (C-index 0.74), and included age at first site visit, sex, genotype, prior heart failure (HF) hospitalization and left atrial (LA) diameter. Results: Of 3117 patients with DCM (mean age 48±15 years, 39% female, 35% G+), 12.3% (n=384) had prevalent AF. Among 2491 patients without prevalent AF, 12.5% (n=312) developed incident AF during a median follow-up of 4.5 years (IQR 1.6-9.0). AF burden varied by disease gene (Figure 1). Patients with P/LP LMNA variants had the highest AF prevalence (56.7%) and incidence (7.6/100 patient-years), with AF typically preceding left ventricular systolic dysfunction, and LMNA was the only gene independently associated with incident AF in multivariable analysis (HR 7.10, 95% CI 4.44-11.36; p<0.001). In contrast, those with P/LP TTN variants had lower AF burden (prevalence 24.4%, incidence 2.1/100 patient-years), comparable to G- patients, despite having the largest LA diameter (41±7mm). Patients with P/LP DSP variants were the 3 rd largest gene group (n=156) but had the lowest AF prevalence (7.4%) and incidence (0.8/100 patient-years). Additional independent predictors of incident AF included male sex, prior HF hospitalization, older age at first visit, and larger LA diameter (Table 1). Conclusion: In this multicenter cohort study of genotyped patients with DCM, LMNA had the strongest genetic association with AF, while TTN had lower AF rates despite larger LA diameter. Genotype-based risk stratification may help guide AF surveillance and management in DCM patients.

Dilated cardiomyopathy (DCM) comes with an estimated societal cost of above €10,000 per patient per year and a lower quality of life (QoL). However, DCM represents a heterogeneous disease with different aetiologies that can be combined in subgroups. Insight in QoL and societal costs per DCM subgroup may guide resource allocation, research focus areas, and tailored patient management. We investigated subgroup-specific costs and QoL in patients with DCM. Patients with DCM (n = 550) were included, all phenotyped by endomyocardial biopsy and genetic testing besides routine cardiac evaluation. Patients were classified as chemotherapy-induced DCM (n = 27), genetic DCM (n = 91), inflammatory DCM (n = 53), systemic immune-mediated disease (SID)-associated DCM (n = 83), alcohol-induced DCM (n = 40), and idiopathic DCM (n = 280). QoL and societal costs were cross-sectionally evaluated using the EQ-5D-5 L and the iMTA medical and productivity cost questionnaires, sent at 8 [IQR 5; 12] years after cardiomyopathy diagnosis. Compared to other subgroups, QoL was lower for inflammatory DCM (-0.053 [-0.106; -0.003], p = 0.04), SID-associated DCM (-0.078 [-0.126; -0.031], p < 0.01), and alcohol-induced DCM (-0.079 [-0.141; -0.017], p = 0.01). Societal costs were higher for patients with inflammatory DCM (19,197€ [13,703 − 27,211]; log-transformed change + 0.862 [0.103; 1.621], p = 0.03), and SID-associated DCM (19,197€ [8,494 − 25,623]; log-transformed change + 0.804 0.104; 1.505], p = 0.03). Healthcare costs were highest for patients with inflammatory DCM (6,198€ [4,083 − 8,626], log-transformed change + 0.614 [0.039; 1.189] p = 0.049). Patients with DCM due to chronic myocarditis or a SID have lower QoL and higher societal costs due to higher healthcare costs, compared to patients with DCM and other etiologies. These findings may guide resource allocation, research focus areas, and tailored management such as patient education, financial counseling, and psychological support. Dilated cardiomyopathy comes with a staggering societal cost of > 10.000€ per patient per year while impacting quality of life. Dilated cardiomyopathy is a heterogeneous disease with diverse aetiologies. Understanding underlying the impact of each aetiology on costs and quality of life may further guide resource allocation and patient management. Aetologies of dilated cardiomyopathy come with their own societal cost characteristics and quality of life impact. Inflammatory, systemic immune disease-associated, and alcohol-induced dilated cardiomyopathy have a worse quality of life, while the former two come with higher societal costs. These findings help us in tailoring patient management such as in patient education, financial counseling, and psychological support.

Coronary artery disease (CAD) and diabetes mellitus (DM) can induce changes in myocardial structure and function, thereby increasing the risk of heart failure (HF). We aimed to identify the alterations in echocardiographic variables and circulating biomarkers associated with DM, CAD, or both and to assess the effect of spironolactone on them. The “Heart OMics in AGEing” (HOMAGE) trial evaluated the effect of spironolactone on circulating markers of fibrosis over 9 months of follow-up in people at risk for HF. From the initial population (N = 527) of the HOMAGE trial, a total of 495 participants (mean age 74 years, 25

Aims In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice.Methods and results Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin-cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling.Conclusion Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.

Clonal hematopoiesis of indeterminate potential (CHIP) is a well-studied phenomenon in hematologic malignancies. With advancements in gene sampling and analysis and the use of large cohort studies, CHIP has recently been linked to cardiovascular disease (CVD). The relationship between CHIP and CVD appears to be bidirectional, with traditional risk factors for cardiovascular disease increasing the mutation burden in CHIP, and CHIP itself effecting the incidence or prognosis of a variety of CVD. The purpose of this review is to understand the epidemiology, risk factors, and pathogenesis of CHIP in the context of various CVD conditions.

AimsHigh left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables.Methods and resultsIn the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population‐based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase‐2 (MMP‐2), insulin‐like growth factor binding protein‐2 (IGFBP‐2) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP‐2 and NT‐proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C‐terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10).ConclusionIn individuals without heart failure, LAVi was associated with MMP‐2, IGFBP‐2 and NT‐proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

The increased sensitivity of novel DNA sequencing techniques has made it possible to identify somatic mutations in small circulating clones of haematopoietic stem cells. When the mutation affects a 'driver' gene, the mutant clone gains a competitive advantage and has the potential to expand over time, a phenomenon referred to as clonal haematopoiesis (CH), which is emerging as a new risk factor for various non-haematological conditions, most notably cardiovascular disease (e.g. heart failure). Dilated cardiomyopathy (DCM) is a form of non-ischaemic heart failure that is characterized by a heterogeneous aetiology. The first evidence is arising that CH plays an important role in the disease course in patients with DCM, and a strong association of CH with multiple aetiologies of DCM has been described (e.g. inflammation, chemotherapy, and atrial fibrillation). The myocardial inflammation induced by CH may be an important trigger for DCM development for an already susceptible heart, e.g. in the presence of genetic variants, environmental triggers, and comorbidities. Studies investigating the role of CH in the pathogenesis of DCM are expected to increase rapidly. To move the field forward, it will be important to report the methodology and results in a standardized manner, so results can be combined and compared. The accurate measurement of CH in patients with DCM can provide guidance of specific (anti-inflammatory) therapies, as mutations in the CH driver genes prime the inflammasome pathway.

BACKGROUND:Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team.METHODS:All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion.RESULTS:Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT.CONCLUSIONS:The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.

BACKGROUND:Systemic immune-mediated diseases (SIDs) are a well-known cause of dilated cardiomyopathy (DCM), a cardiac phenotype influenced by genetic predispositions and environmental factors. OBJECTIVES:This study sought to examine if an underlying genetic predisposition is present in patients with DCM and SID. METHODS:Genotyped DCM-SID patients (n = 183) were enrolled at 3 European centers. Genetic variants were compared with healthy control subjects (n = 20,917), DCM patients without SID (n = 560), and individuals with a suspicion of an SID (n = 1,333). Clinical outcomes included all-cause mortality, heart failure hospitalization, and life-threatening arrhythmias. RESULTS:The SID diagnosis preceded the DCM diagnosis by 4.8 months (Q1-Q3: -68.4 to +2.4 months). The prevalence of pathogenic/likely pathogenic (P/LP) variants in DCM patients with an SID from the Maastricht cohort was 17.1%, compared with 1.9% in healthy control subjects (P < 0.001). In the Madrid/Trieste cohort, the prevalence was 20.5% (P < 0.001). Truncating variants showed the strongest enrichment (10.7% [OR: 24.5] (Maastricht) and 16% [OR: 116.6 (Madrid/Trieste); both P < 0.001), with truncating TTN (titin) variant (TTNtv) being the most prevalent. Left ventricular ejection fraction at presentation was reduced in TTNtv-SID patients compared with DCM patients with SID without a P/LP (P = 0.016). The presence of a P/LP variant in DCM-SID had no impact on clinical outcomes over a median follow-up of 8.4 years (Q1-Q3: 4.9-12.1 years). CONCLUSIONS:One in 6 DCM patients with an SID has an underlying P/LP variant in a DCM-associated gene. This highlights the role of genetic testing in those patients with immune-mediated DCM, and supports the concept that autoimmunity may play a role in unveiling a DCM phenotype in genotype-positive individuals.

In the past decade, genetic testing for cardiac disease has become part of routine clinical care. A genetic diagnosis provides the possibility to clarify risk for relatives. For family planning, a genetic diagnosis provides reproductive options, including prenatal diagnosis and preimplantation genetic testing, that can prevent an affected parent from having a child with the genetic predisposition. Owing to the complex genetic architecture of cardiac diseases, characterized by incomplete disease penetrance and the interplay between monogenic and polygenic variants, the risk reduction that can be achieved using reproductive genetic testing varies among individuals. Globally, disparities, including regulatory and financial barriers, in access to reproductive genetic tests exist. Although reproductive options are gaining a prominent position in the management of patients with inherited cardiac diseases, specific policies and guidance are lacking. Guidelines recommend that prenatal diagnosis and preimplantation genetic testing are options that should be discussed with families. Health-care professionals should, therefore, be aware of the possibilities and feel confident to discuss the benefits and challenges. In this Review, we provide an overview of the reproductive options in the context of inherited cardiac diseases, covering the genetic, technical, psychosocial and equity considerations, to prepare health-care professionals for discussions with their patients.

AIMS:Dilated cardiomyopathy (DCM) is a major cause of heart failure impairing patient wellbeing and imposing a substantial economic burden on society, but respective data are missing. This study aims to measure the quality of life (QoL) and societal costs of DCM patients. METHODS AND RESULTS:A cross-sectional evaluation of QoL and societal costs of DCM patients was performed through the 5-level EuroQol and the Medical Consumption Questionnaire and Productivity Cost Questionnaire, respectively. QoL was translated into numerical values (i.e. utilities). Costs were measured from a Dutch societal perspective. Final costs were extrapolated to 1 year, reported in 2022 Euros, and compared between DCM severity according to NYHA classes. A total of 550 DCM patients from the Maastricht cardiomyopathy registry were included. Mean age was 61 years, and 34% were women. Overall utility was slightly lower for DCM patients than the population mean (0.840 vs. 0.869, P = 0.225). Among EQ-5D dimensions, DCM patients scored lowest in 'usual activities'. Total societal DCM costs were €14 843 per patient per year. Cost drivers were productivity losses (€7037) and medical costs (€4621). Patients with more symptomatic DCM (i.e. NYHA class III or IV) had significantly higher average DCM costs per year compared to less symptomatic DCM (€31 099 vs. €11 446, P < 0.001) and significantly lower utilities (0.631 vs. 0.883, P < 0.001). CONCLUSION:DCM is associated with high societal costs and reduced QoL, in particular with high DCM severity.

Figure 1 The clinical presentation and outcome of DCM or NDLVC are determined by the common co-existence of both genetic -mono and polygenic risk-and acquired factors (such as toxins, viruses, and auto-immune diseases), disease modifiers (such as pregnancy), or co-morbidities (diabetes, hypertension, endocrinopathies, and renal, hepatic or (micro)-vascular disease).

BACKGROUND Papillary muscle-delayed hyperenhancement (papHE) at cardiac magnetic resonance indicates fibrotic or infiltrative processes. Contrary to myocardial HE, the prevalence and prognostic implications of papHE in patients with nonischemic dilated cardiomyopathy are unclear. OBJECTIVES The purpose of this study was to determine the prevalence of papHE and describe its association with adverse clinical outcomes. METHODS This prospective cohort study included 528 patients who underwent late gadolinium enhancement cardiac magnetic resonance. The primary outcomes were all-cause mortality, sudden cardiac death, life-threatening arrhythmia, and hospitalization for heart failure. Patients were allocated into 4 categories: the first without papHE and without myocardial HE, the second with papHE, the third with myocardial HE, and the fourth with papHE and myocardial HE. The hazards of the primary outcomes for each category were compared using multivariable Cox regression. RESULTS papHE was present in 131 patients (25%). The median follow-up duration was 6.1 years (IQR: 3.7-9.7 years). Isolated papHE and isolated myocardial HE were not significantly associated with any of the prespecified outcomes. Patients who had both myocardial HE and papHE were at an increased risk of all-cause mortality (HR: 2.33, 95% CI: 1.26-4.30), sudden cardiac death (HR: 3.77, 95% CI: 1.59-8.94), life-threatening arrhythmia (HR: 3.94, 95% CI: 1.34-11.58), and hospitalization for heart failure (HR: 2.97, 95% CI: 1.30-6.80). CONCLUSIONS The combined presence of myocardial and papHE was independently associated with adverse outcomes. Future studies should investigate if the incorporation of papHE and myocardial HE may improve clinical decision-making strategies to select dilated cardiomyopathy patients who would benefit the most from ICD implantation. (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

AbstractAimsFew randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial.MethodsIn HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25–50 mg/day). The current sub‐study included 113 controls and 114 patients assigned spironolactone (~70% on beta‐blockers), who all completed the ISWT at baseline and at Months 1 and 9. Within‐group changes over time (follow‐up minus baseline) and between‐group differences at each time point (spironolactone minus control) were analysed by repeated measures ANOVA, unadjusted or adjusted for sex, age and body mass index, and additionally for baseline for testing 1 and 9 month data.ResultsIrrespective of randomization, the resting HR and CHR did not change from baseline to follow‐up, with the exception of a small decrease in the HR immediately post‐exercise (−3.11 b.p.m.) in controls at Month 9. In within‐group analyses, HR decline over the 5 min post‐exercise followed a slightly lower course at the 1 month visit in controls and at the 9 month visits in both groups, but not at the 1 month visit in the spironolactone group. Compared with baseline, EE increased by two to three shuttles at Months 1 and 9 in the spironolactone group but remained unchanged in the control group. In the between‐group analyses, irrespective of adjustment, there were no HR differences at any time point from rest up to 5 min post‐exercise or in EE. Subgroup analyses by sex or categorized by the medians of age, left ventricular ejection fraction or glomerular filtration rate were confirmatory. Combining baseline and Months 1 and 9 data in both treatment groups, the resting HR, CHR and HRR at 1 and 5 min averaged 61.5, 20.0, 9.07 and 13.8 b.p.m. and EE 48.3 shuttles.ConclusionsSpironolactone on top of usual treatment compared with usual treatment alone did not change resting HR, CHR, HRR and EE in response to ISWT. Beta‐blockade might have concealed the effects of spironolactone. The current findings demonstrate that the ISWT, already used in a wide variety of pathological conditions, is a practical instrument to measure symptom‐limited exercise capacity in patients prone to developing heart failure because of coronary heart disease.

None of the spironolactone trials in heart failure (HF) assessed the blood pressure (BP) responses to exercise, while conflicting results were reported for exercise capacity. In the HOMAGE trial, 527 patients at increased HF risk were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current substudy included 113 controls and 114 patients assigned spironolactone, who all completed the incremental shuttle walk test at baseline and months 1 and 9. Quality of life (QoL) was assessed by EQ5D questionnaire. Between-group differences (spironolactone minus control [Δs]) were analyzed by repeated measures ANOVA with adjustment for baseline and, if appropriate, additionally for sex, age and body mass index. Δs in the pre-exercise systolic/diastolic BP were -8.00 mm Hg (95% CI, -11.6 to -4.43)/-0.85 mm Hg (-2.96 to 1.26) at month 1 and -9.58 mm Hg (-14.0 to -5.19)/-3.84 mm Hg (-6.22 to -1.47) at month 9. Δs in the post-exercise systolic/diastolic BP were -8.08 mm Hg (-14.2 to -2.01)/-2.07 mm Hg (-5.79 to 1.65) and -13.3 mm Hg (-19.9 to -6.75)/-4.62 mm Hg (-8.07 to -1.17), respectively. For completed shuttles, Δs at months 1 and 9 were 2.15 (-0.10 to 4.40) and 2.49 (-0.79 to 5.67), respectively. Δs in QoL were not significant. The correlations between the exercise-induced BP increases and the number of completed shuttles were similar in both groups. In conclusion, in patients at increased risk of developing HF, spironolactone reduced the pre- and post-exercise BP, but did not improve exercise capacity or QoL.