BACKGROUND Fibrosis plays a central role in hypertrophic cardiomyopathy (HCM), contributing to symptoms via impaired systolic and diastolic function and ventricular arrhythmias. OBJECTIVES The aim of this study was to determine if eplerenone has an antifibrotic effect in nonobstructive HCM (resting left ventricular outflow tract gradient <30 mm Hg). METHODS This was a randomized, double-blind, placebo-controlled trial of eplerenone in 61 patients with nonobstructive HCM over 12 months. The primary endpoint was native T1 time on cardiac magnetic resonance as an index of diffuse fibrosis. Secondary endpoints included changes in diastolic function. RESULTS Thirty patients were randomized to 50 mg eplerenone and 31 to placebo. There was a reduction in native T1 time within the eplerenone group (1,315 f 134 ms at baseline vs 1,259 f 92 ms at 12 months; P = 0.041), with no significant change in the placebo group (1,234 f 28 ms at baseline vs 1,238 f 70 ms at 12 months; P = 0.854). This represents a 3.7% f 9% reduction in native T1 with eplerenone compared with a 1.1% f 9% increase with placebo (P = 0.07). There was no significant change in functional status or markers of diastolic function (such as E/e' ratio or mitral E/A ratio). CONCLUSIONS In patients with nonobstructive HCM, there was a reduction in myocardial T1 time with eplerenone, consistent with a reduction in diffuse myocardial fibrosis. Larger and longer trials are needed to confirm this finding and explore whether it translates into improved exercise capacity or a reduction in mortality over time. (Anti-fibrotic role of eplerenone on diffuse myocardial fibrosis and diastolic function in patients with hypertrophic cardiomyopathy; ACTRN12613000065796) (JACC Heart Fail. 2025;13:102415) (c) 2025 by the American College of Cardiology Foundation.

BACKGROUND:Fibrosis plays a central role in hypertrophic cardiomyopathy (HCM), contributing to symptoms via impaired systolic and diastolic function and ventricular arrhythmias. OBJECTIVES:The aim of this study was to determine if eplerenone has an antifibrotic effect in nonobstructive HCM (resting left ventricular outflow tract gradient <30 mm Hg). METHODS:This was a randomized, double-blind, placebo-controlled trial of eplerenone in 61 patients with nonobstructive HCM over 12 months. The primary endpoint was native T1 time on cardiac magnetic resonance as an index of diffuse fibrosis. Secondary endpoints included changes in diastolic function. RESULTS:Thirty patients were randomized to 50 mg eplerenone and 31 to placebo. There was a reduction in native T1 time within the eplerenone group (1,315 ± 134 ms at baseline vs 1,259 ± 92 ms at 12 months; P = 0.041), with no significant change in the placebo group (1,234 ± 28 ms at baseline vs 1,238 ± 70 ms at 12 months; P = 0.854). This represents a 3.7% ± 9% reduction in native T1 with eplerenone compared with a 1.1% ± 9% increase with placebo (P = 0.07). There was no significant change in functional status or markers of diastolic function (such as E/e' ratio or mitral E/A ratio). CONCLUSIONS:In patients with nonobstructive HCM, there was a reduction in myocardial T1 time with eplerenone, consistent with a reduction in diffuse myocardial fibrosis. Larger and longer trials are needed to confirm this finding and explore whether it translates into improved exercise capacity or a reduction in mortality over time. (Anti-fibrotic role of eplerenone on diffuse myocardial fibrosis and diastolic function in patients with hypertrophic cardiomyopathy; ACTRN12613000065796).

BACKGROUND:The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood.METHODS:Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1).RESULTS:There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE.CONCLUSION:An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.

Background Echocardiographic quantification of mitral regurgitation (MR) remains challenging, requiring dedicated image acquisition, and is limited by potential error from geometric assumptions of annular dimensions. Volume is a product of area and flow and assuming proportional mitral/aortic areas, an increased mitral-inflow volume compared to LV/RV-outflow semi-quantitatively represents greater MR regurgitant volume. Therefore, we investigated the feasibility and diagnostic performance of the mitral-aortic velocity-time integral(VTI) ratio in isolated MR. We also investigated the use of the mitral-pulmonary VTI ratio as an alternative in clinical situations where the LV outflow tract(LVOT) VTI could not be used. Methods We reviewed 166 consecutive patients (33%, n = 54 severe MR by multi-parameter integrated expert opinion)). Pulsed wave Doppler VTI at the mitral leaflet tips and the left ventricular outflow and continuous-wave Doppler of the RV outflow tract were measured individually and independently by blinded readers(expert and trainee status) to derive the ratio. Receiver operator characteristic area under the curve(AUC) comparison was calculated and compared with effective regurgitant orifice area(EROA > 40mm), regurgitant volume(RVol > 60mL), vena contracta(VC > 0.7cm), E-velocity > 1.2cm, systolic flow reversal(SFR), left atrial and ventricular dilatation. Results Increasing ratio was associated with severe MR(AUC 0.94) with optimal threshold defined at 1.3. This provided significant discrimination for severe MR(AUC 0.81) compared to EROA(0.68), VC(0.52), LV dilatation(0.69), LA dilatation(0.70), SFR(0.73), E-velocity(0.68) all p < 0.05, with sensitivity 82% and specificity 94%. The mitral-pulmonary VTI ratio demonstrated similar discrimination(AUC 0.92) with optimal threshold defined at 1.14. Excellent inter-observer reproducibility(intra-class correlation 0.97) was seen between trainee and expert readers. There was no difference in AUC comparison by MR mechanism or patient rhythm. Conclusions The mitral-aortic and mitral-pulmonary VTI ratios are simple, geometric-free parameters feasibly reproducible from routine echocardiographic datasets and are excellent discriminative tools for severe MR. Readers should consider integration of this parameter in routine reporting.

Transthoracic echocardiography (TTE) is the most widely available and utilised imaging modality for the screening, diagnosis, and serial monitoring of all abnormalities related to cardiac structure or function. The primary objectives of this document are to provide (1) a guiding framework for treating clinicians of the acceptable indications for the initial and serial TTE assessments of the commonly encountered cardiovascular conditions in adults, and (2) the minimum required standard for TTE examinations and reporting for imaging service providers. The main areas covered within this Position Statement pertain to the TTE assessment of the left and right ventricles, valvular heart diseases, pericardial diseases, aortic diseases, infective endocarditis, cardiac masses, pulmonary hypertension, and cardiovascular diseases associated with cancer treatments or cardio-oncology. Facilitating the optimal use and performance of high quality TTEs will prevent the over or under-utilisation of this resource and unnecessary downstream testing due to suboptimal or incomplete studies.

Abstract Background Detection of haemodynamically significant shunting from atrial septal defect (ASD) can be identified by using the pulmonary-systemic flow ratio (Qp/Qs). However, calculation of Qp/Qs by echocardiography relies on geometric assumptions that outflow tracts are circular, suffers from squared linear measures, and accurate measurement of right ventricular outflow tract (RVOT) diameter is challenging. Whilst adults with ASD should have overt right ventricular dilatation, RV sizing on echocardiography is often subjective and underappreciated. We evaluated whether a dimensionless index of flow (VTI) differences between the RVOT and left ventricular outflow tract (LVOT) could assist in identifying patients with ASD, and compared it with relative atrial index (RAI), a parameter previously assessed in identifying atrial shunting. Methods Data from 64 consecutive patients who underwent ASD closure and had no concomitant lesions, were compared with 63 normal controls. RVOT VTI, LVOT VTI, LVOT diameter, and atrial areas were measured. Results Between controls and ASD patients, there was no difference in LVOT VTI or forward stroke volume, but ASD patients had significantly higher RVOT VTI. The RVOT-LVOT VTI ratio was 1:1 in controls and 1.5:1 in ASD patients. Area under the ROC curve analysis of RVOT-LVOT VTI ratio was 0.83, and a ratio of 1.1:1 predicted patients with ASD with 86% sensitivity and 73% specificity. In comparison, the area under the ROC curve analysis of RAI was 0.70, and an RAI of 1.05:1 predicted patients with ASD with 77% sensitivity and 44% specificity. Conclusion Calculation of the dimensionless RVOT-LVOT VTI ratio is simple, and may be a useful additional semi-quantitative tool to assist cardiologists and sonographers in detecting atrial shunting, particularly in patients with borderline or overt right heart dilatation, and identify who patients should undergo further evaluation. Funding Acknowledgement Type of funding sources: None.

Background Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long-term cardiovascular outcomes in pre-transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long-term cardiovascular outcomes in kidney transplant candidates. Methods and Results We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom-limited exercise stress echocardiography for pre-transplant cardiovascular assessment. Exercise capacity was measured by age- and sex-predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time-varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow-up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29-0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30-0.91], P=0.02). Patients achieving predicted METs on pre-transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32-1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42-2.25], P=0.95). Conclusions Achievement of predicted METs on pre-transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

Global migration means rheumatic heart disease (RHD) and mitral stenosis (MS) remain important issues in Western health systems. Percutaneous mitral balloon valvuloplasty (PMBV) is a durable treatment strategy relying on suitable leaflet characteristics adjudged by a Wilkins score. Commissural calcification alone has been thought as reliable as Wilkins score. Timing PMBV is also important. Falling left atrial ejection fraction (LAEF) has been theorised to predict future MS intervention. This study compared Wilkins score and commissural calcification as predictors of procedural success and durability; and, observed if LAEF improved post-valvuloplasty. A retrospective case-note audit was conducted of patients undergoing PMBV at Monash Medical Centre, Victoria, between 1 June 2005 and 1 June 2020. Patients with echocardiograms performed before and after PMBV were included. Echocardiograms were examined by cardiologists with sub-specialty training. 89 patients were included (86.5% female, 84.3% born overseas). 25.6% of patients had commissural calcification. 44 patients had follow-up data (mean 4.4±3.8yrs), of whom 50.0% had event-free survival. Wilkins score <8 associated with better event-free survival compared to Wilkins score ≥8 (67.7% vs 7.7%, p<0.001), as did absence rather than presence of commissural calcification (70.4% vs 7.7%, p<0.001). Wilkins score <8 predicted lower mortality (0.0% vs 30.8%, p=0.003). Absent commissural calcification predicted procedural success (93.4% vs 76.2%, p=0.029) and durability (5.3±4.0yrs vs 2.4±2.6yrs, p=0.028). LAEF improved in patents with Wilkins score <8 compared to those ≥8 (6.3±10.9% vs -0.3±7.9%, p=0.034). Commissural calcification appears as reliable as Wilkins Score in predicting event-free survival and can predict procedural success and durability. Clinical significance of improving LAEF post-PMBV is unclear.

Computed tomography coronary angiography (CTCA) is well validated for the assessment of coronary artery disease; however, myocardial diseases are often not well delineated on standard CTCA. This report details a case of connective tissue disease myocarditis that was diagnosed on CTCA.

Importance:After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling.Objective:To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction.Design, Setting, and Participants:A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018.Interventions:Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo.Main Outcomes and Measures:The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed.Results:A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period.Conclusions and Relevance:Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated.Trial Registration:ClinicalTrials.gov Identifier: NCT02557217.

Abstract Background Pharmacological stress testing is commonly performed for cardiovascular risk stratification in potential renal transplant candidates due to a perceived inability for these patients to exercise. We have previously reported that exercise stress testing is feasible in renal transplant candidates but the prognostic utility of exercise capacity in this patient group is not known. Purpose This study prospectively evaluated the effect of exercise capacity on the risk of major adverse cardiovascular events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction, and stroke, in renal transplant candidates undergoing exercise stress echocardiography (ESE) for pre-transplant cardiovascular assessment. Methods We evaluated 898 consecutive patients with chronic kidney disease stage 4/5 who underwent symptom-limited treadmill ESE over 5-year mean follow-up. Exercise capacity was measured by age and sex predicted metabolic equivalents (METs). The primary outcome was achievement of predicted METs with first MACE. Cox proportional hazard multivariable modelling was used to determine MACE predictors with transplantation treated as a time-varying covariate. We also performed secondary analysis using a 7 MET threshold. Results There were 106 MACE with an annual cumulative risk of 2.4%. During follow-up, 525 (58%) received transplantation. Achievement of predicted METs (48%) (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.29–0.82, p=0.007) and transplantation (HR 0.52, 95% CI 0.30–0.91, p=0.02) were independently associated with reduced MACE. Similar results were observed using a 7 MET threshold achieved by 734 (82%) patients. Patients achieving predicted METs had no difference in MACE regardless of subsequent transplantation (HR 0.78, 95% CI 0.32–1.92, p=0.59). Patients who achieved predicted METs and did not receive transplantation had similar outcomes to those that did not achieve predicted METs and received transplantation (HR 0.97, 95% CI 0.42–2.25, p=0.95). Conclusions Exercise capacity is associated with reduced long-term MACE in renal transplant candidates undergoing ESE for pre-transplant cardiovascular assessment. Achievement of age and sex predicted METs confers excellent prognosis independent of subsequent transplantation. Funding Acknowledgement Type of funding sources: None.

Introduction: Pharmacological stress testing is routinely performed for cardiovascular assessment in kidney transplant candidates due to perceived poor exercise capacity in such patients. Although exercise stress testing is feasible, the prognostic utility of exercise capacity in this patient population has not been investigated. Hypothesis: We hypothesize that exercise capacity predicts long term cardiovascular risk in kidney transplant candidates undergoing exercise stress echocardiography (ESE) for pre-transplant cardiovascular assessment. Methods: We prospectively evaluated 898 patients with stage 4/5 chronic kidney disease from 2013 to 2020 who performed symptom limited treadmill ESE. Exercise capacity was calculated as age and sex predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction and stroke. Cox proportional hazard multivariable modelling was performed to identify predictors of MACE, with transplantation treated as a time-varying covariate. Results: There were 106 MACE. During follow up, 525 (58%) received a kidney transplant. Achievement of predicted METs (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.29-0.82, p=0.007) and transplantation (HR 0.52, 95% CI 0.30-0.91, p=0.02) were independently associated with less incident MACE. Patients who achieved predicted METs had similar rates of MACE irrespective of subsequent transplantation ( Figure 1 , HR 0.78, 95% CI 0.32-1.92, p=0.59). Patients who achieved predicted METs and were not transplanted had similar outcomes to those that did not achieve predicted METs and received a kidney transplant ( Figure 1 , HR 0.97, 95% CI 0.42-2.25, p=0.95). Conclusions: Exercise capacity is associated with reduced MACE in kidney transplant candidates. Achievement of predicted METs confers excellent prognosis independent of subsequent transplantation.

A 27-year-old lady presented to the emergency department with an acute episode of chest pain, on the background of a 6-year history of poorly controlled mixed connective tissue disease manifested by gastro-oesophageal reflux disease, digital ulceration, Raynaud’s phenomenon and interstitial lung disease (forced vital capacity 42% and diffusion capacity for carbon monoxide 27% of predicted). There were no preceding infective symptoms or fevers. Electrocardiogram demonstrated isolated non-dynamic q waves in aVL. High-sensitivity troponin I was elevated to 1,193 ng/L (reference <10 ng/L). Erythrocyte sedimentation rate was elevated at 74 mm/hr (reference <15 mm/hr) but C-reactive protein was normal. Transthoracic echocardiography demonstrated low-normal ejection fraction of 50% with mid posterolateral wall hypokinesis.

Background: Failure to increase left ventricular ejection fraction (LVEF) post-exercise may be seen in the absence of established causes in patients with suspected obstructive coronary artery disease (OCAD) investigated with exercise stress echocardiography. This is associated with long-axis left ventricular dysfunction, however, cardiovascular outcomes of patients with such an abnormal contractile response are unknown. Aim: To determine long-term major adverse cardiovascular events in patients with failure to increase LVEF post-exercise. Methods: Amongst 1275 patients with suspected obstructive coronary artery disease (OCAD) undergoing both exercise stress echocardiography and anatomic coronary imaging, failure to increase LVEF post-exercise was observed in 138 (11%) patients in the absence of established causes. The primary endpoint was defined as major adverse cardiovascular events (MACE: composite endpoint of cardiac mortality, acute myocardial infarction, new heart failure, life threatening ventricular arrhythmias, coronary artery revascularisation and stroke) at 5-year follow-up. Results: Twenty-eight percent experienced MACE (53% with OCAD). Patients in MACE group, compared to those without MACE, were older (72 ± 7 vs. 62 ± 10 years, P < 0.0001), predominantly male (47% vs. 24%, P = 0.016), and had higher prevalence of hypertension (90% vs. 61%, P = 0.003); diabetes (37% vs. 20%, P = 0.06) and dyslipidemia (60% vs. 42%, P = 0.09). On multivariate analysis, older age (OR = 1.12, 95% CI = 1.06–1.20, P < 0.0001) and hypertension (OR = 4.5, 1.16–17.5, P = 0.03), but not OCAD (OR = 1.25, 0.48–3.26, P = 0.647) were independent predictors of MACE. Conclusion: Patients with failure to increase LVEF post-exercise have a high incidence of MACE at 5-year follow-up. Older age and hypertension predicts MACE in this population independent of coronary anatomy. The study indicates that the clinical trajectory of patients with this abnormal response is not benign and warrants long-term surveillance.