AF can mediate left ventricular systolic dysfunction (LVSD) through a tachycardia-mediated cardiomyopathic process that may reverse with rate control alone. However, additional mechanisms contribute to AF-induced cardiomyopathy (AIC) that require rhythm control therapies. AIC can currently only be diagnosed retrospectively, as these component mechanisms are difficult to distinguish from each other and from other causes of LVSD prospectively. This narrative review considers the different potential mechanisms through which AF can impair ventricular function: rapid ventricular rate; irregularity of the ventricular rhythm; and impaired atrial contraction. How these features may exploit underlying structural vulnerability are considered and additional imaging-based parameters such as late gadolinium enhancement on cardiac MRI and contractile reserve during stress echocardiography are discussed. The limitations of existing parameters are discussed and a novel, non-parametric marker of ventricular rate with consideration of the inherent irregularity of AF - the Restitution Threshold Index (RTI) - is reviewed. Integrating RTI with these imaging-based measures may enhance clinical decision-making by more accurately identifying patients who would benefit from timely rhythm control. Further prospective validation is essential to develop accessible tools and an open-access RTI calculator has been made available (https://restitutionthreshold.com) to facilitate reproducibility and wider application.

Aims:Serial imaging demands precision-particularly for cardiotoxicity screening where small changes gatekeep major decisions. Automated measurement using artificial intelligence (AI)-based techniques should reduce variability and increase confidence for detection of true change. We directly compared the precision of fully automated AI vs. expert manual analysis of left ventricular function by echocardiography. Methods and results:Consecutive cancer patients referred for cardiotoxicity monitoring underwent same-day repeat 2D echocardiography [n = 60, 83% female, mean left ventricular ejection fraction (LVEF) 57 ± 7%], with 3D acquisition where feasible (n = 45). All 2D images underwent blinded analysis by a fully automated analysis software and four experts. Quantitative 2D LVEF measurement was feasible in 96% scans by both methods. Mean absolute difference (MAD) between repeat scans was significantly lower for AI than experts for both 2D LVEF {3.6% [confidence interval (CI) 2.8-4.4] vs. 6.6% [CI 5.3-7.9], P = 0.011} and global longitudinal strain [1.5% (CI 1.1-1.9) vs. 2.5% (CI 2.0-3.0), P = 0.006]. In participants with 3DE datasets, 3D LVEF MAD was lower than manual 2D LVEF [3.6% (CI 2.8-4.6) vs. 6.4% (CI 5.0-8.0), P = 0.006] but comparable to AI-derived 2D LVEF [3.5% (CI 2.9-4.2), P = 0.4]. In a subset (n = 48) also with same-day cardiovascular magnetic resonance (CMR) studies, AI 2DE analysis demonstrated stronger agreement with CMR than expert 2DE analysis [LVEF MAD 5.0% (CI 4.1-5.9) vs. 7.8% (CI 6.6-9.0) P = 0.006]. Conclusion:In cancer patients at risk of cardiotoxicity, the precision of 2D echocardiographic AI analysis exceeds that of experts, matching that of 3D LVEF assessment. Trial Registration:NCT06817044. Lay summary:Some cancer treatments may weaken the heart. As such, at-risk patients have repeat heart scans (echocardiograms) over the course of their cancer treatment. Doctors monitor these scans over time and watch closely for any change; even a small decline in heart function can trigger a major decision, such as pausing life-saving cancer therapy. It is therefore vital that these measurements are as consistent or 'precise' as possible.The problem is that measurements taken by hand can vary widely, and 'precision' may be low, even when performed by skilled experts. This makes it hard to know whether a change in heart function across follow-up scans is real or not and whether any action is therefore needed. We tested whether artificial intelligence (AI) software could measure heart function more precisely than experts.Sixty cancer patients each had two echocardiographic heart scans in close succession on the same day. This approach purposefully reduces the impact of other factors (such as differences in the person or equipment performing the heart scan) that might otherwise mean results differ. We then compared how closely the repeat measurements of heart function matched when performed by AI vs. four echocardiography experts. The AI was more precise, giving closer results between the two scans, whilst the experts' results varied more.In short, AI can measure heart function more precisely than experts in patients with cancer. This could give doctors greater confidence that any change seen on a scan is genuine, helping them make safer, better-informed decisions.

Importance:Patients undergoing aortic valve replacement (AVR) for chronic severe aortic regurgitation (AR) based on current guideline-based thresholds may have irreversible myocardial scarring. Objective:To quantify reverse remodeling, functional recovery, and symptomatic change after AVR and assess whether myocardial fibrosis is associated with incomplete recovery. Design, Setting, and Participants:In this prospective longitudinal observational study, patients with chronic severe AR referred for AVR by a cardiology team were included. Key exclusion criteria were previous valve surgery, moderate or greater valve disease, and other primary cardiomyopathies. Included patients underwent paired biomarkers, echocardiography, cardiopulmonary exercise testing, and cardiovascular magnetic resonance (CMR) at baseline and at a median of 7 months after AVR. The study took place at 2 tertiary cardiothoracic centers in London, United Kingdom, with enrollment from August 2021 to October 2023. Data were analyzed from January to April 2026. Exposure:AVR. Main Outcomes and Measures:Left ventricular (LV) reverse remodeling (change in LV end-diastolic volume [LVEDV] and LV mass) post-AVR and preoperative correlates of incomplete recovery, with prespecified focus on CMR fibrosis markers (late gadolinium enhancement [LGE] and extracellular volume [ECV]). Results:Seventy-two patients (median [IQR] age, 60 [6-70] years; 59 [82%] male, 35 [49%] with bicuspid aortic valve) completed paired studies. Median (IQR) regurgitant volume fell from 61 (38-83) mL to 5 (3-8) mL; median (IQR) LVEDV fell 44% from 273 (211-307) mL to 153 (130-177) mL; and median (IQR) LV mass fell 21% from 200 (159-226) g to 158 (137-184) g (all P < .001). Indexed intracellular volume declined 21% and indexed extracellular volume 15% (26 mL/m2 to 22 mL/m2; P < .001), raising extracellular volume fraction (ECV%) from 27.4% to 29.1% (P < .001). LGE as a percentage of LV mass was unchanged (2.3% to 2.4%; P = .36); baseline LGE burden was associated with less regression of LV mass (χ22 = 29.4; P < .001) and LVEDV at 7 months (χ21 = 7.9; P = .007). New York Heart Association class and quality of life improved (median [IQR] EQ-5D index improved from 0.89 [0.78-1.00] to 0.94 [0.81-1.00]; P < .001), but maximum oxygen consumption was unchanged (22.6 mL/kg/min to 21 mL/kg/min; P = .08). N-terminal pro-B-type natriuretic peptide decreased slightly (228 pg/mL to 198 pg/mL; P = .27), with a larger fall in patients with evidence of decompensation (n = 31; 469 pg/mL to 279 pg/mL; P = .02). Conclusions and Relevance:In this study, AVR was associated with substantial reverse remodeling at 7 months, including regression of hypertrophy and a fall in indexed extracellular (matrix) volume; the extracellular volume fraction rose, as cellular regression outpaced matrix regression. Focal scar, as a proportion of myocardium, was unchanged. Preoperative focal scar was independently associated with less recovery and may mark incomplete remodeling. Objective functional recovery did not improve at this time point.

With aging, left ventricular (LV) early diastolic lengthening declines. Delayed or dyssynchronous untwisting and relaxation may slow and reduce filling and contribute to elevated diastolic pressures. Segmental variations in the timing of early diastolic relaxation may impair LV suction during exercise and impact LV stroke volume reserve, especially in heart failure with preserved ejection fraction (HFpEF). To determine possible mechanisms causing dyspnea, we investigated 106 subjects aged ≥ 60 yr, including 38 patients with HFpEF, 26 breathless, 19 hypertensive, and 23 healthy controls, at rest and during submaximal exercise stress echocardiography. Global and regional early diastolic function were assessed by LV isovolumic relaxation time (IVRT), the deceleration time (DT) and propagation velocity of mitral inflow, and segmental variations in times-to-peak early diastolic myocardial velocity (e'). Global IVRT and DT were similar between groups at rest and during stress. During exercise, increments in mean segmental e' were similar between groups, whereas times-to-peak e' shortened variably, being 13%-20% longer in the midseptal and 30%-35% longer in the midlateral segments in HFpEF than in healthy or hypertensive subjects (P < 0.001). There were moderate inverse correlations between time-to-peak e' and LV inflow velocity, cardiac output on exercise, and 6-min walk distance (ρ -0.42, P < 0.001). Slower early diastolic relaxation on exercise is associated with less stroke volume reserve and reduced exercise capacity. Machine learning might be able to identify subtle changes in timing of relaxation as a diagnostic or therapeutic target in subjects with HFpEF.NEW & NOTEWORTHY Dyspnea in older subjects and patients with HFpEF is usually attributed to elevated LV filling pressures caused by reduced end-diastolic compliance. This study demonstrates that during exercise, slow early diastolic relaxation and reduced ventricular suction limit increments in early diastolic filling and impair stroke volume reserve, thereby reducing exercise capacity. Lowering late systolic pressure and augmenting early diastolic filling may be important targets for pharmacologic therapy to reduce dyspnea.

BACKGROUND:The coexistence of aortic stenosis (AS) and transthyretin cardiac amyloidosis (CA) is common. If treated with transcatheter aortic valve replacement (TAVR), patients with the combined phenotype (AS-CA) have a similar survival at 1 year compared to those with lone AS. This study aims to evaluate the long-term outcomes of AS-CA compared to lone AS. METHODS:Using a prospective, multicenter, observational, case-control design, we studied patients with severe AS referred for TAVR. All underwent bone scintigraphy to differentiate between AS-CA and lone AS. Outcomes were compared between the two cohorts. Mortality (all-cause and cardiovascular [CV]) and hospitalization for heart failure (HHF) were captured as clinical endpoints for long-term outcome. RESULTS:406 patients [84(80-88) years, 50 % female, EuroSCORE-II 4.2 (3.7-5.0)] were recruited, of which 47 (11.6 %) had AS-CA (all transthyretin). Over a follow-up of 5.4 (4.9-5.8) years, 244 (60.1 %) patients died. AS-CA was associated with higher all-cause mortality (crude HR 1.75, 95 % CI 1.24-2.46; log-rank, p = 0.001), which remained significant after multivariate adjustment for clinical confounders (EuroSCORE-II, valve replacement; adjusted HR 1.72, 95 % CI 1.22-2.42; p = 0.002). AS-CA was not associated with CV mortality (log-rank, p = 0.18) or time to first HHF (log-rank, p = 0.43), but the rate of HHF was significantly higher in AS-CA compared to lone AS (129 versus 65 per 1000 patient years, p = 0.022). CONCLUSION:AS-CA is associated with an increased long-term risk of all-cause mortality and rate of hospitalization for heart failure compared to patients with AS. Further studies evaluating the role of CA-specific therapies are warranted in this population.

BACKGROUND:Diffuse fibrosis is central to the pathophysiology of aortic stenosis (AS), can be assessed using cardiovascular magnetic resonance (CMR) with extracellular volume fraction (ECV%), and is associated with mortality. The relevance of this signal to long-term prognosis remains unclear. We aim to assess predictors of long-term mortality with focus on diffuse fibrosis. METHODS:Single-center prospective observational cohort study of patients with severe, symptomatic AS undergoing aortic valve replacement (AVR). Patients were assessed using echocardiography, high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and CMR, including T1 mapping for ECV% quantification. All-cause mortality was identified using the NHS National Spine Database. Univariable and multivariable Cox regression models were fitted to assess all-cause mortality associations. RESULT:One hundred and sixty-eight patients (age 72 [65-77] years, 55% [92/168] male) underwent CMR. Over a follow-up period of 9.7 (6.8-10.9) years, 76 deaths occurred. Patients who died had higher ECV% (29.9% vs 27.6%, p = 0.014) and greater late gadolinium enhancement (3.9% vs 2.0%, p = 0.013). Univariable predictors of mortality were age, atrial fibrillation (AF), left atrial area, left atrial volume, total cholesterol, triglycerides, HDL:LDL ratio, non-bicuspid aortic valve, hs-cTnT, NT-proBNP, EuroSCORE II and ECV%. On multivariable regression, age, AF and ECV% remained significant predictors of mortality, independently of sex. AIC indicated that the model with four covariates was preferable to the one also including EuroSCORE II and coronary artery disease, and this result was confirmed by a likelihood ratio test (p=0.387). CONCLUSIONS:In the longest follow-up cohort of T1 mapping in severe AS, we demonstrate diffuse fibrosis remains an independent predictor of long-term mortality. Integration of ECV% in baseline risk stratification should be explored further in patients with AS undergoing AVR.

AIMS:The prevalence of mitral valve prolapse (MVP) varies across populations and age groups; its natural history and clinical outcomes remain unclear. This meta-analysis established the prevalence of MVP in the general population, in associated syndromes and at different ages. It also determined the rate of progression and the incidence of adverse outcomes. METHODS AND RESULTS:A systematic search identified original reports on the prevalence of MVP and related outcomes. A total of 83 studies met inclusion: 47 (n = 992 944) non-syndrome associated; 31 (n = 3067) syndrome associated; and 5 (n = 1287) described mitral regurgitation (MR) progression or adverse outcomes. In the general population, the prevalence was 1.35% but higher in hospital cohorts (8.7%). Age-stratified prevalence was 0.5, 1.8, 2.7, and 2.0% in neonates, children, adolescents and adults, respectively. Meta-regression and subgroup analysis found no significant difference (P = 0.81) across ages but revealed a significantly higher prevalence in older compared to young adults (2.87% vs. 0.67%, P = 0.01). Prevalence rates were markedly higher in patients with genetic syndromes. MR progressed at 5.5 per 100 person-years, overall. Event rates for all-cause mortality, development of heart failure, and need for mitral valve intervention were 1.7, 1.0, and 1.2 per 100 person-years, respectively. CONCLUSION:MVP is common, with greater prevalence in syndromes. Although more common with age, MVP is observed in infants. MVP related MR is progressive, especially in moderate MR, and there is a signal of excess mortality for unclear reasons. Valve services must manage the whole life journey and the potential risks associated with MVP.

Background ORBITA-2 (The Placebo-Controlled Trial of Percutaneous Coronary Intervention for the Relief of Stable Angina) found that percutaneous coronary intervention (PCI) relieved angina in patients with single-vessel and multivessel stable coronary artery disease (CAD) on little or no antianginal medication. Whereas symptom characteristics and invasive physiological assessments can predict PCI efficacy, the role of noninvasive imaging with dobutamine stress echocardiography (DSE) remains unclear. Objectives This DSE-stratified secondary analysis of ORBITA-2 investigates the relationship between ischemia, assessed by DSE, and the placebo-controlled efficacy of PCI. Methods Participants with angina, single-vessel or multivessel CAD, and ischemia were enrolled. Following discontinuation of antianginal medications, patients were evaluated prerandomization using the ORBITA-app, questionnaires, DSE, and exercise treadmill testing. Stress echocardiography scores were calculated for each left ventricular segment at peak stress, with normal, hypokinetic, akinetic, dyskinetic, and aneurysmal segments scoring 0 to 4, respectively. Bayesian proportional odds modeling was used. Results Prerandomization DSE data were available for 262 patients. The median age was 65.5 years (Q1-Q3: 59-71 years), and 208 (79.4%) were male. At baseline, the median stress echocardiography score was 1.42 in the PCI group (n = 133) and 1.00 in the placebo group (n = 129), with an overall median score of 1.25 (Q1-Q3: 0.33-2.92). Higher stress echocardiography scores were strongly associated with greater placebo-controlled improvements in angina symptom score following PCI (OR: 1.23; 95% credible interval [CrI]: 1.13-1.35; Pr(interaction) > 99.9%). Higher scores also predicted significant reduction in daily angina episodes (OR: 1.36; 95% CrI: 1.24-1.49; Pr(interaction) > 99.9%), as well as improvement in the Seattle Angina Questionnaire angina frequency score (8.22; 95% CrI: 0.96-15.50; Pr(interaction) = 98.7%), and Seattle Angina Questionnaire quality of life score (8.95; 95% CrI: 2.05-16.00; Pr(interaction) = 99.3%). The relationship between stress echocardiography score and reduction in daily angina episodes remained consistent, irrespective of symptom characteristics. Conclusions In patients with single- and multivessel stable CAD on little or no antianginal medication, the placebo-controlled efficacy of PCI was predicted by the degree of ischemia detected on DSE. The greater the burden of baseline ischemia, the greater the improvement in symptoms and quality of life with PCI.

Background/Objectives: Early detection of familial dilated cardiomyopathy (DCM) is crucial for initiating timely interventions. Myocardial work (MW) analysis, which integrates strain imaging and blood pressure, shows promise in identifying subclinical disease. To assess the utility of MW in detecting early myocardial changes in relatives of DCM patients with a positive genotype (G+) compared to genotype-negative (G−) controls. Methods: This study involved asymptomatic relatives of DCM patients who underwent comprehensive echocardiographic evaluation, including MW analysis. Subjects (N = 77) were classified into G+ (n = 39) and (n = 38) groups based on genetic testing. Myocardial work parameters—myocardial global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE)—were measured. Statistical analyses compared these parameters between groups and assessed their predictive value for genotype status. Follow-up data were collected and analysed accordingly. Results: Among 77 participants (mean age 36 ± 14 years; 49% women), there were no significant differences in baseline characteristics between G+ and G− groups. S’ septal, s′ average, e′ lateral, E max and E/A were found to be significantly different between the two groups. G+ individuals had significantly reduced GWE (94% vs. 96%, p < 0.001) and increased GWW (113 mmHg% vs. 80 mmHg%, p = 0.001). After adjustment for significant echocardiographic parameters, GWE (OR = 0.746, 95% CI: 0.560–0.994, p = 0.045) and GWW (OR = 1.012, 95% CI: 1.002–1.024, p = 0.047) remained significant predictors of gene carrier status in multivariable analysis. The addition of GWE and GWW significantly increased the area under the curve of a model identifying G+ individuals (p < 0.05). During a median period of follow-up of 53 months, 16 (21%) individuals expressed a cardiomyopathy phenotype. There was a significant correlation between increased baseline GWW, reduced GWE, and the expression of cardiomyopathy phenotype. Conclusions: Myocardial work analysis, specifically GWE and GWW, identifies early myocardial dysfunction in asymptomatic carriers of genetic variants for DCM. These findings suggest that MW could complement traditional imaging in the early detection and management of familial DCM.

Patients with moderate aortic stenosis (AS) may experience symptoms and adverse outcomes. The aim of this study was to determine whether patients with moderate AS exhibited objective evidence of exercise limitation, compared with age and sex matched controls and if so, to determine which echocardiographic parameters predicted exercise ability. This was a prospective case control study of patients with moderate AS (peak velocity (Vmax) 3.0–3.9 m/s, mean gradient (MG) 20-39mmHg, aortic valve area (AVA)1.1-1.5cm2 ) and left ventricular ejection fraction (LVEF) ≥ 55

Abstract Introduction Advancements in cancer treatments are resulting in improved prognosis for patients. However, these therapies may cause cardiotoxicity, including left ventricular systolic dysfunction which may manifest years later. Echocardiographic monitoring frequency for cancer survivors, timing and role of initiation of cardioprotective medication to manage asymptomatic mild systolic dysfunction in this cohort is poorly understood. Aims To assess role of combined cardiopulmonary exercise test stress echo (CPET-SE) in providing additional benefit in monitoring patients at risk of cardiotoxicity. Methods Retrospective analysis of patients in the late effects clinic who were at higher risk of cardiotoxicity due to treatment received. Patients were referred for CPET-SE due to borderline reduced LVEF (<55%) with absence of heart failure symptoms. Results A total of 57 patients (mean age 32 years, 82% male, 70% receiving anthracycline treatment) were assessed between January 2019 and September 2022. Forty-nine (86%) patients performed a maximal exercise test, with all patients reporting fatigue as the reason to stop. 86% of patients showed appropriate contractile reserve with mean increase in LVEF of 9±6%. Mean resting and peak LVEF was 50 and 59% respectively (mean difference 9±5%). Only four patients saw no improvement in peak LVEF (3 of whom experienced a decrease with mean drop of -2%). There was improvement of longitudinal function: average resting and peak GLS were -14 and -17% respectively, with mean improvement of -3±2.1%. Average lateral S’ was 7.4 cm/s at rest and 12.5cm/s at peak exercise, mean increase was 5.1± 2.5cm/s. Despite improvement in cardiac function, all patients had reduced peak VO2 on CPET: average VO2 peak 26.8 ml/kg/min (69% target or moderately reduced). Mean peak O2 pulse was 11.5 ml/beat. VE/VCO2 was 25.5 suggesting there was no respiratory limitation, supported by normal spirometry, breathing reserve and oxygen saturations in all patients. Markers of contractile reserve and peak VO2/O2 pulse were significantly correlated (Figure 1): peak O2 pulse and peak EF r = 0.4 (P=0.004); between delta S’ and VO2 peak r = 0.3 (P=0.047), albeit relatively weak, indicating likely influence of non-cardiac causes on reduced peak VO2 / O2 pulse. Limitation in most patients was thought to be secondary to deconditioning. Conclusion Our data indicate that cancer survivors may demonstrate significant exercise limitation which remains underdiagnosed, and that non-cardiac factors likely contribute. CPET-SE differentiates cardiac dysfunction from other causes of exercise limitation and guide management focusing on rehabilitation programmes or early initiation of cardioprotective medication in patients with impaired contractile reserve.

Abstract Introduction Clinically significant valvular heart disease (VHD) affects 13.3% of individuals aged 75 and older, while left ventricular systolic dysfunction (LVSD) is seen in 2% of those aged 85 and older, and 3.5% of those aged 65 and older but most data comes from rural/suburban areas with predominantly Caucasian populations. Data on these diseases in urban, ethnically diverse areas with high migrant populations is lacking. Purpose This quality improvement project aimed to establish the prevalence of left-sided valve disease and LVSD by conducting community-based handheld echocardiography detection in an urban, multi-ethnic community. Methods Patients over 65 without known left-sided heart valve disease or heart failure, across four GP practices and one vaccination centre using handheld ultrasound device (Vscan Extend). The protocol included an abbreviated dataset with colour flow and three standard echocardiography views. All studies were reviewed and adjudicated by an independent expert. Those patients adjudicated to have important disease on handheld detection underwent subsequent comprehensive echocardiography. Results 518 patients were evaluated. Ethnic distribution: 14.4% Caucasian, 51.6% Indian, 0.2% Chinese, 14% Pakistani, 9.7% African, 9.1% other. New diagnoses of left-sided HVD or LVSD were identified in (n=166 ) 32% and (n=10) 2% respectively. Mitral Regurgitation (MR) was most common (n =100, 19.3%), followed by aortic regurgitation (AR) (n =30, 5.8%), aortic stenosis (AS) (n =13, 2.5%), and mitral stenosis (MS) (n =2, 0.4%). LVSD was found in (n=10, 2%). Comprehensive confirmatory echocardiograms were done in 73 patients. Of these mild VHD was observed in n =57 (78%), (mild AR n =27, 37%, mild MR n =31, 45%, and mild AS/aortic sclerosis n =12, 16%). Calcified mitral valve was found in n =3, (4%). Mild LVSD was in n =6, 8%. Moderate to severe HVD was found in n= 12 (16.4%), (MR in 8%, AR in 5% and AS in 2.7%) and moderate to severe LVSD in n =3, 4%. Age predicted HVD (OR 1.09, 95% CI 1.06-1.13, p <0.001) and LVSD (OR 1.07, 95% CI 1.01-1.13, p <0.05) while Type 2 diabetes (OR 3.47, 95% CI 0.13-0.83, p <0.05) and ischemic heart disease (IHD) (OR 5.41, 95% CI 2.26-13.11, p <0.001) were predictors for LVSD. There was no relationship between ethnic group and the presence of HVD or LVSD (p values >0.05). Conclusion(s) HVD and LVSD is common in this urban, multi-ethnic community. A Vscan based detection program found a prevalence of any VHD of 32% and LVSD of 2% . Of these 2.3% and 0.6% were moderate to severe (HVD and LVSD). Age was associated with both HVD and LVSD, while T2DM and IHD are associated with LVSD. There was no relationship between ethnicity and either HVD or LVSD. Severity of HVD Ethnicity Distribution

ABSTRACT Background Apical hypertrophic cardiomyopathy (ApHCM) patients can develop symptoms (chest pain, breathlessness), cardiac structural abnormalities (atrial dilatation, scar, apical aneurysm) and adverse outcomes despite preserved systolic function. Underlying mechanisms are poorly understood. We hypothesized that functional limitation in ApHCM may be associated with altered myocardial mechanics and myocardial perfusion. Methods We recruited 42 ApHCM patients and compared them with healthy controls (n=36). We assessed functional limitation (VO 2 <80% predicted) using cardiopulmonary exercise testing, stress apical myocardial blood flow (MBF) and scar using cardiovascular magnetic resonance, and echocardiography global longitudinal strain (GLS) and twist at rest and during exercise. Results Functional limitation occurred in 35% vs 6% of controls ( P <0.005) and was unrelated to wall thickness or ejection fraction. Myocardial mechanics were abnormal, with impaired GLS (−11.0% vs −18.3%, P<0.001), increased LV twist (22.6±9⸰ vs 16.6±4⸰, P<0.005) and delayed diastolic untwist (17.9% vs 9.2% of diastole, P<0.005). With exercise, GLS, twist and twist rate augmented but diastolic untwist delayed further. Stress apical MBF was reduced in all ApHCM patients and associated with mechanical abnormalities (GLS P<0.001, delayed diastolic untwist P=0.039). Percentage predicted peak VO 2 was worse with lower apical blood flow (P<0.005) and reduced GLS (P=0.017), but the best predictor was prolonged diastolic untwist (β-0.828, P<0.05). Conclusion One third of ApHCM patients have functional limitation - best predicted by delayed diastolic untwist. GLS, twist mechanics and apical MBF were abnormal in all subjects highlighting mechanical and perfusion abnormalities as hallmarks of the disease, but identifying diastolic impairment as the mechanistic link. Graphic Abstract Delayed myocardial untwist predicts functional limitation and is linked to microvascular ischemia in Apical HCM We postulate that increased left ventricular (LV) twist and delayed diastolic untwist results in prolonged systole and shortened diastole, which in turn reduces myocardial blood flow in a positive feedback loop. The net effect of mechanical and perfusion abnormalities is of functional limitation. CLINICAL PERSPECTIVES Apical hypertrophic cardiomyopathy (ApHCM) patients can develop symptoms, functional limitation, and adverse outcomes but the mechanisms underpinning this are unknown. Functional limitation is best assessed using cardiopulmonary exercise testing measuring peak VO 2 , whereby a value <80% predicted (based on age, sex and body size) is abnormal. Peak VO 2 is a known prognostic measure in hypertrophic cardiomyopathy. This multi-modality imaging study aimed to explore whether functional limitation associated with abnormal myocardial mechanics and myocardial perfusion. We found that 35% of ApHCM patients had functional limitation (vs 6% healthy controls), which was independent of wall thickness and ejection fraction. Percentage predicted peak VO 2 was worse with lower apical myocardial blood flow and reduced GLS, but was predicted by delayed diastolic untwist, implicating diastolic impairment as the mechanistic link. Understanding the abnormal mechano-structural and physiological features that contribute to, or predict functional limitation in apical hypertrophic cardiomyopathy strengthens our understanding of the disease and provides focus for future targeted research.

ABSTRACT Background Exercise Oscillatory Ventilation (EOV) and a steep ventilatory efficiency (VE/VCO2) slope are features of ventilatory inefficiency on cardiopulmonary exercise testing (CPET), both associated with poor prognosis in patients with heart failure (HF). The prevalence in patients with co‐existent atrial fibrillation (AF) and the impact of catheter ablation (CA) is unknown. Objectives To characterize ventilatory inefficiency in patients with persistent AF and Left Ventricular Systolic Dysfunction (LVSD) and assess the impact of CA. Methods Patients with persistent AF and Left Ventricular Ejection Fraction (LVEF) < 50% undergoing first‐time CA were prospectively enrolled. Echocardiography and CPET were performed at baseline and 6 months post‐CA. EOV was defined using the Kremser–Corrà criteria, and VE/VCO2 slope gradient > 30 was considered abnormal. Results A total of 53 participants were enrolled (mean LVEF of 34 ± 9%). A total of 10 (19.2%) exhibited EOV at baseline. These patients had larger indexed left atrial (41.6 ± 13.1 mL/m 2 vs. 33.3 ± 9.3 mL/m 2 , p = 0.03) and ventricular volumes [65.7 mL/m 2 (57.1, 89.0) vs. 46.7 mL/m 2 (39.8, 61.4), p = 0.03]. The partial pressure of end‐tidal carbon dioxide (P ET CO 2 ) at peak exercise increased (33.7 ± 6.1 mmHg to 41.2 ± 5.8 mmHg, p < 0.001) and correlated with improvement in HF symptoms ( p = −0.003) and objective HF markers. A total of 25 (48.1%) had an abnormal VE/VCO2 gradient. The EOV pattern resolved in eight (80%) participants due to a reduction in EOV burden (71.1 ± 11.9% vs. 48.8 ± 14.8%, p = 0.006) and the component amplitude of minute ventilation cycles (2.6 L/min (2.5,3.2) vs 2.2 L/min (1.8,2.6), p = 0.028). Fewer patients had an abnormal VE/VCO2 gradient after CA [25 (48.1%) vs. 16 (34.0%), p = 0.004]. Conclusions Ventilatory inefficiency is common in patients with AF and LVSD. CA improves both EOV and VE/VCO2 in AF‐induced cardiomyopathy. Improvement in P ET CO 2 is also seen and correlates with HF symptom burden.