Cardiomyopathy Patients Research Articles

Prevalence of transthyretin amyloid cardiomyopathy in patients hospitalised for heart failure with preserved ejection fraction in an LATAM center

Abstract Introduction Transthyretin Amyloid cardiomyopathy (ATTR-CM) usually presents as heart failure with preserved ejection fraction (HFpEF). Its diagnosis has a significant clinical impact, as specific treatment is currently available. Purpose To assess the prevalence of ATTR-CM in patients hospitalised for HFpEF and increased septal thickness in our institution of general community hospital in Latin America (LATAM). Methods Cross-sectional study. Patients hospitalised for HFpEF (>50%) and septal thickness ≥ 12 mm during the period from 8/2019 to 1/2023 were prospectively included. Patients with pacemaker, significant left valve disease and end-stage renal failure (creatinine clearance < 30 ml/min/BSA) were excluded. A pyrophosphate bone scintigraphy (PYP) was planned to be performed in order to assess ATTR-CM. The prevalence of ATTR-CM and its 95% confidence interval were calculated. Results A PYP was performed in 59/82 patients hospitalised for HFpEF. Median age was 85 [IQR 78-88] years, and 54% were women. At admission, 61% (n=36) had atrial fibrillation and the median NT Pro-Bnp was 3536 [1700-7748] pg/mL. The mean left ventricle ejection fraction was 57% (+/- 5%). The prevalence of ATTR-CM diagnosed by PYP was 19% (95% CI 9.7-30.1, n=11). There were no significant clinical differences between patients who performed a PYP and did not. Patients with ATTR-CM had lower blood pressure and higher septal thickness, NT Pro-Bnp and troponin levels compared to patients without ATTR-CM (TABLE). Conclusion In patients admitted for HFpEF and increased septal thickness, the diagnosis of ATTR-CM was relatively common (one of five had ATTR-CM) in our region (LATAM). We believe that systemic assessment with PYP should be performed in patients hospitalised with HFpEF and increased wall thickness.

MicroRNA-145-5p restricts cardiac scar resolution during cardiac regeneration

Abstract Background Human hearts have a very limited capacity to renew cardiomyocytes following injury. The lost myocardium is permanently replaced with noncontractile fibrotic tissue, consequently leading to heart failure. In contrast, zebrafish retain cardiac regenerative capacity during their lifetime. After injury, zebrafish hearts undergo transient fibrotic scarring that subsequently resolves and is replaced with new cardiomyocytes over time. Thus, understanding the molecular mechanisms governing cardiac scar resolution in zebrafish could offer insights into enhancing the regenerative capacities of human hearts. Objective We aimed to decipher the molecular pathways associated with zebrafish cardiac scar resolution. Methods We investigated the mRNA and miRNA responses to injury at 14 days post-injury by high-throughput transcriptome profiling of RNAs isolated from healthy or cryoinjured hearts. The prediction of miRNA-mRNA interactions was performed to identify the most differentially expressed miRNAs and their target genes. These miRNAs and genes were validated in zebrafish regenerating hearts and in the left ventricles of ischemic cardiomyopathy or dilated cardiomyopathy patients. The potential role of identified miRNAs in cardiac scar resolution was investigated in human cardiac fibroblasts. Results Principal component analyses identify two distinct clusters in both the mRNAome and miRNAome corresponding to healthy and injured hearts, indicating significant changes in transcriptome profiles during zebrafish cardiac regeneration. Gene set enrichment analyses indicate that molecular pathways involved in extracellular matrix organization and inflammatory response are markedly activated whereas genes associated with mitochondrial organization and oxidative phosphorylation are downregulated in injured hearts. We observed the downregulation of miR-145-5p and the upregulation of procollagen V in the injured hearts. In contrast to zebrafish, in the left ventricles of ischemic cardiomyopathy patients, miR-145-5p is significantly upregulated and procollagen V α1 is downregulated. Theoretical prediction of miRNA-mRNA interactions indicates procollagen V α1 is negatively correlated with miR-145-5p. Overexpression of miR-145-5p in human cardiac fibroblasts downregulates collagen V α1 and alpha smooth muscle actin, upregulates procollagen I and matrix metalloproteinase 9, and inhibits cell proliferation and migration. In contrast, inhibition of miR-145-5p upregulates collagen V α1 and alpha smooth muscle actin, downregulates procollagen I and matrix metalloproteinase 9, and stimulates cell proliferation and migration. Conclusion Our study suggests that miR-145-5p may play a role in the suppression of myofibroblast transdifferentiation via collagen V α1, which restricts scar resolution and cardiac repair.

Integrated plasma proteomics and myocardial tissue transcriptomics reveal elevated fibrosis markers in arrhythmogenic cardiomyopathy patients

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is characterized by myocardial fibrofatty replacement and ventricular arrhythmias, with potential progression to heart failure. This study aims to identify ACM-specific biomarkers for improved prognosis and possible treatment strategies. Methods RNA sequencing and transcriptome analyses were performed in cardiomyocytes of 10 ACM patients, 10 dilated cardiomyopathy patients and 10 healthy controls. Analyses were performed using liquid chromatography and mass spectrometry. Additionally, plasma protein expression was assessed in 38 ACM patients and 24 healthy controls using the Proximity Extension Assay (Olink®). A standardized bicycle exercise test was performed in 11 ACM patients and controls and blood was obtained before and after exercise. Results Myocardial tissue transcriptomics identified several upregulated molecules associated with extracellular matrix formation and immune response in ACM. Plasma protein sequencing revealed upregulation of proteins involved in metabolic pathways, inflammation, and fibrosis. Integration of these analyses identified key soluble profibrotic markers such as Fibulin-3, Endostatin and C-X-C motif chemokine 10 (CXCL10) in plasma of ACM patients. After exercise, Fibulin-3 levels increased in ACM patients compared to controls. These findings were further validated using enzyme-linked immunosorbent assay (ELISA). Conclusion This comprehensive analysis revealed distinct proteomic and transcriptomic signatures in ACM patients' plasma and cardiomyocytes. The integrative analysis identified several upregulated profibrotic markers in ACM. Our Findings may advance diagnostic and prognostic strategies and offer potential therapeutic targets.

Mitral regurgitation improvement following left bundle branch pacing versus right ventricular septum pacing: a dedication to postoperative amelioration of mitral regurgitation

Abstract Background Mitral regurgitation (MR) is correlated with left ventricular (LV) remodeling and LV function in patients. Left bundle branch pacing (LBBP) exhibits a significant decline in MR in left bundle branch block (LBBB) and cardiomyopathy patients. This research aims to evaluate the influence of LBBP on MR in comparison to right ventricular septal pacing (RVSP) in patients with atrioventricular block (AVB) or sick sinus syndrome (SSS). Methods Sixty consecutive patients with SSS or AVB were enrolled if they underwent pacemaker implantation via LBBP or RVSP. Patients with a history of mitral valve surgery were excluded. Echocardiogram parameters were assessed to measure MR and LV remodeling as well as LV function at baseline and follow-up. Results Thirty-six patients (60 %; mean age: 70.39 ± 14.80 years; 61.1 % male) underwent successful LBBP, and 24 patients (40 %; mean age: 71.58 ± 10.91 years; 66.7 % male) underwent RVSP. The average follow-up duration was relatively comparable between the two groups. In comparison to RVSP, LBBP demonstrated significant changes in MR area, and severity at baseline and follow-up (P<0.05). LBBP independently predicted MR amelioration in patients who underwent pacemaker implantation (HR=0.289, CI=0.087–0.9961; P=0.043). At follow-up, the LBBP subgroup with moderate/severe MR exhibited significantly shorter lead-TVA-dist, higher left atrium (LA) diameters, and mitral E/A ratio (P<0.05) compared to the none/mild MR subgroup. In LBBP with MR amelioration, LV remodeling (ΔLVEDD) was significantly enhanced compared to baseline (P=0.016). Additionally, a non-significant trend toward better improvement in LV function (ΔLVEF and ΔE/A) was observed in patients with MR amelioration. Conclusion LBBP, considered an optimal pacing technique for SSS or AVB patients, may substantially reduce MR and subsequently enhance LV remodeling and function compared to RVSP. This open, observational pilot study warrants confirmation through further investigations.Comparison between LBBP and RVSPKaplan-Meier curves for MR amelioration

The dynamic increment of epicardial adipose tissue is associated with reverse remodeling after guideline-directed medical treatment in dilated cardiomyopathy patients

Abstract Background/Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse prognosis in patients with HFpEF and a better prognosis in HFrEF patients. Whether EAT is playing a protective role in dilated cardiomyopathy (DCM) patients have been described sparingly. Purpose Aim to explore whether the epicardial fat would change along with the dynamic changes in cardiac function and volumes after receiving guideline-directed medical therapy (GDMT) in patients with DCM. Methods We prospectively enrolled 232 DCM patients who underwent complete baseline and follow-up Cardiac magnetic resonance (CMR) examinations. The measurement of the epicardial fat composition includes epicardial fat thickness, paracardial fat thickness, and paracardial fat volume, while the measurement of body fat composition includes subcutaneous and visceral abdominal fat, while We used univariable and multivariable logistic regression to evaluate the association between different body and cardiac fat depots with the changes in bi-ventricular structure (delta indexed EDV) and function (delta EF). Results The study included 232 patients (mean age 46.1±14.1 years, 157 (67.7%) males). After GDMT, we found that the visceral fat thickness and EAT (thickness and volume) tend to significantly increase. The increase in the (left ventricular reverse remodeling) LVRR group was significantly higher compared with the non-LVRR group. Independently with the changes of BMI and body fat depots, the increment of EAT was associated with the improvement in bi-ventricular function and volumes (significantly positively correlated with the improvement of LVEF (r = 0.499, p < 0.001), and RVEF (r = 0.482, p < 0.001), negatively correlated with delta LVEDVi (r = -0.407, p < 0.001), delta RVEDVi (r = -0.305, p < 0.001)). Conclusions After GDMT, the increment of EAT was positively correlated with the improvement of bi-ventricular structure and function, independent of the changes in BMI and body fat depots.Graphic Abstract

Left atrial strain differences between hypertensive and sarcomeric left ventricular hypertrophy: a sign of sarcomeric auricular myopathy?

Abstract Introduction In clinical practice, left ventricular (LV) hypertrophy is a common finding that can be caused by physiologic or pathologic conditions. An etiologic diagnosis is extremely important because it may change the prognosis and management of the patient and his family. Left atrial (LA) dysfunction is common due to diastolic dysfunction but, in patients with sarcomeric LV hypertrophy, primary cardiomyopathy disease could also be present. Purpose To evaluate if there are differences in LA function between arterial hypertension (HT) and hypertrophic cardiomyopathy (HCM) patients. Methods 73 patients with HCM (according to ESC guidelines criteria) and 82 patients with HT (under treatment with ≥1 hypertensive drug for ≥3 months) and ≥13mm of LV hypertrophy underwent an echocardiography to assess LA function with strain analysis and LV diastolic function. Continuous normally distributed variables were compared with T-student test and categoric variables with square-chi or exact Fisher test if required, accepting as significant a p-value <0.05. Results Globally, HCM patients showed thicker LV walls and larger LA indexed volumes (18.7±4.7 vs. 13.3±0,8 mm and 44.9±20.7 vs. 30.7±8.8 ml/m2, p<0.000 for both). Also, HCM patients presented diastolic dysfunction and atrial fibrillation history in a higher frequency (31 vs. 7.6% and 16.4% vs. 0%, p<0.000 for both). LA strain was significantly lower in HCM patients as compared to the HT group (LA contractile 11.5±5.8 vs. 17.2±4.4, p<0.000; LA conduit 12.2±5.4 vs. 13.3±3.8, p=0.041; and LA reservoir 23.9±8.7 vs. 31.1±5.9, p<0.000). In the subgroup of patients with moderate-severe LV hypertrophy (<17mm) and no significant mitral regurgitation (n=103; HCM=21, HT=82), LA contractile strain remained lower in HCM as compared to HT patients (13.2±4.8% vs. 17.2±4.4%, p<0.000) (figure 1); without differences in diastolic dysfunction, LA volumes, significant mitral regurgitation or atrial fibrillation history. Conclusions Our results show that LA strain is more impaired in HCM patients as compared to HT patients. Specifically, contractile LA strain remained lower even in those patients with moderate-severe LV hypertrophy, despite having similar LV diastolic function, LA indexed volumes, significant mitral regurgitation, or atrial fibrillation history. These findings could be caused by HCM involvement of the LA myocytes. In the context of moderate-severe hypertrophy of unknown origin with non-significant mitral regurgitation, the detection of abnormally reduced LA strain could indicate the presence of an HCM.Figure 1

Nationwide trends in utilization and safety of ventricular arrythmia ablation in patients with hypertrophic cardiomyopathy

Abstract Background Catheter ablation for ventricular arrhythmias, including ventricular tachycardia (VT) and premature ventricular complexes (PVC) is increasingly utilized across the nation, while data on its safety in Hypertrophic Cardiomyopathy (HCM) patients is sparse. Purpose To analyze the nationwide trends in utilization and complications of inpatient ventricular arrhythmia ablations in patients with HCM. Methods This study is a retrospective analysis of hospitalizations, in HCM patients 18 years of age and older, who underwent an inpatient VA ablation in the U.S., between 2016 and 2020. We drew data from the National Inpatient Sample (NIS) database. Patients without HCM undergoing the CA for VA were used as controls. Baseline sociodemographic and clinical data, procedural complications, mortality and length of stay were analyzed. Multivariable analysis was performed to identify independent predictors of procedural complications. Results Among a weighted total of 2880 patients hospitalized between 2016 and 2020, who underwent VA ablations, the median age was 67 years (IQR 56-74), 60% were male, and 73% were white. The HCM group had similar age distribution but more women (64.5% vs 33.6%, p<0.001) and more African Americans (13.2% vs. 7.3%, p=0.03). The non-HCM cohort had significantly higher rates of prior myocardial infarction (22% vs 12.4%, p=0.026), ischemic cardiomyopathy (30.1% vs 0.8%, p<0.001), heart failure (70.5% vs 39.7%, p<0.001), and peripheral vascular disease (PVD, 42.9% vs 18.2%, p<0.001). This was reflected in higher Deyo Comorbidity Index in the non-HCM cohort (score of ≥ 2 in 66.6% vs 43%, p<0.001). Overall, the real-world peri-procedural complication rate in the entire cohort was 15.3%, including 6.4% hemorrhagic, 4.5% pericardial, and 2.3% vascular complications. There was a trend for lower complication rate in the HCM group (9.9% vs. 16.7%, p = 0.08). The in-hospital mortality didn’t defer (1.7% vs. 4.2%, p=0.28) and the length of stay was shorter in the HCM group (3.5 vs. 6.4 days, p < 0.001). Multivariable logistic regression analysis showed obesity (OR 2.06; 95%CI: 1.59 - 2.67; p<0.001) and PVD (OR 2.19; 95%CI: 1.34-3.53; p=0.001) to be independent predictors of complications while HCM was not (OR 0.76, 95% CI 0.51-1.14, p = 0.195). Conclusion Real-world data from a nationwide inpatient database shows comparable safety for VA ablation in HCM patients with similar mortality and lower length of stay, compared to non-HCM patients.

Dynamic changes of excessive trabeculation in dilated cardiomyopathy: a longitudinal cardiovascular magnetic resonance study

Abstract Background A portion of dilated cardiomyopathy (DCM) patients present with left ventricular (LV) excessive trabeculation at diagnosis. It remains unknown if the extent of trabeculation would be reduced after guideline-directed medical therapy (GDMT). Purpose To investigate the dynamic change of excessive trabeculation after GDMT in patients with DCM, and its relationship with that in LV structure and function. Methods A group of DCM patients with baseline and follow-up cardiovascular magnetic resonance (CMR) examination after 1-2 years of GDMT were enrolled. Trabeculation was assessed by Petersen method as measuring the thickness of the most prominent non-compacted (NC) layer and the corresponding compacted (C) segment at the apical long-axis view at end-diastole. Excessive trabeculation was defined as the NC/C ratio > 2.3, and a regression was reached if it decreased to ≤ 2.3. Major adverse cardiovascular events (MACE) consisted of cardiovascular death, heart transplantation, and heart failure readmission. Results Among 218 DCM patients (45 ± 14 years, 67.4% male), 58 (26.6%) met the excessive trabeculation criteria at baseline. Despite a similar LV ejection fraction (LVEF), patients with excessive trabeculation had a higher LV end-diastolic dimension (73.3 ± 9.0 vs. 70.5 ± 8.0mm) and native T1 (1325.3 ± 71.2 vs. 1305.5 ± 65.9mm) (both p<0.05) with a trend of more late gadolinium enhancement (51.7% vs. 39.4% of patients). After 15 months of GDMT, patients with excessive trabeculation (n=58) showed a decreased NC layer (12.7 ± 3.4 vs. 11.3 ± 3.0 mm) and NC/C ratio (3.1 ± 0.9 vs. 2.7 ± 0.9) (both p < 0.05), 25.9% of whom showed a regression of trabeculation. Patients with the regression had a lower NC/C ratio (1.8 ± 0.4 vs. 3.0 ± 0.8, p < 0.001) and LV end-diastolic volume index (LVEDVi) (121.5 ± 40.5 ml/m2 vs. 165.9 ± 67.8ml/m2, p=0.004) compared with those without. The change of (△) NC/C ratio was associated with that of LVEDVi (r = 0.323), and LVEF as well (r = -0.254) (both p < 0.001). Excessive trabeculation at baseline did not differentiate patients with a higher risk of MACE by Kaplan-Meier survival curve (p= 0.208), but its persistent presence at follow-up did (p= 0.004). However, when put △NC/C ratio, △LVEDVi, △LVEF and In NT-proBNP into multivariate cox regression model, only the △LVEDVi (HR, 0.963; 95% CI: 0.942, 0.985; P = 0.001) and In NT-proBNP (HR, 2.016; 95% CI: 1.288, 3.157; P = 0.002) were independent predictors of MACE. Conclusions Regression of excessive trabeculation occurred after GDMT in DCM patients that was related somewhat to LV reverse remodeling and not an independent predictor of MACE. It may also indicate the interconnection between LV remodeling and trabeculation.

Polygenic risk score for prediction of atrial fibrillation according to presence of the hypertrophic cardiomyopathy

Abstract Background The significance of genetic predisposition in predicting atrial fibrillation (AF) is well recognized, yet its role in hypertrophic cardiomyopathy (HCM) patients remains less clear. Objective In this study, we aimed to elucidate the impact of genetic risk on the development of AF in both HCM and non-HCM patients. Methods This retrospective analysis examined 1,180 HCM patients (mean age 61.1±7.1, 63.0% male) and 476,238 non-HCM patients (mean age 57.0±8.1, 45.3% male) from the UK Biobank. Participants were stratified based on their validated polygenic risk score (PRS) for AF: the bottom 10% constituted the low genetic risk group, the top 10% comprised the high genetic risk group, and the remainder fell into the intermediate genetic risk group. We assessed the incidence of AF and major cardiovascular events and analyzed predictors, including genetic risk. Results Among HCM patients, no significant differences in baseline characteristics were observed based on genetic risk, except for the rate of CIED implantation (P=0.036). Conversely, among non-HCM patients, variations in age, gender, and comorbidities were noted according to genetic risk. The HCM patients were categorized into three groups based on risk, with respective AF incidence rates of 2.4, 3.6, and 5.4 events per 100 person-years, respectively. In non-HCM patients, the incidence of AF per 100 person-years was 0.2, 0.5, and 1.0, respectively. Genetic risk emerged as a significant predictor of AF in both HCM and non-HCM patients, although with a higher hazard ratio observed in non-HCM patient (HR, 2.51; 95% CI, 1.59–3.98 vs. HR, 4.77; 95% CI, 4.47–5.09) (P=0.003 for interaction). In non-HCM patients, predictors of AF included age, male sex, body mass index, smoking history, and a history of hypertension, diabetes, heart failure, stroke, and myocardial infarction, in addition to PRS. However, in HCM patients, only age, diabetes, and a history of stroke were identified as independent predictors of AF. Moreover, high genetic risk was significantly associated with the risk of major adverse cardiovascular events. Conclusions In conclusion, our study indicates associations between genetic predisposition and AF occurrence in both HCM and non-HCM patients.

Reverse remodelling and clinical outcomes in patients with chagas cardiomyopathy with reduced ejection fraction

Abstract Introduction Chagas disease affects around 8 million individuals globally and about 30% develop cardiac manifestations and, in time, heart failure with reduced ejection fraction (HFrEF). Chagas cardiomyopathy (CC) patients often have a poorer prognosis compared to other causes of HFrEF, owing to a higher rate of ventricular arrhythmias and thromboembolic conditions. Reverse remodelling (RR) has been linked to enhanced mortality and morbidity outcomes in HFrEF due to non-Chagas causes, but the effect of RR on CC prognosis is still unclear. Methods This retrospective study assessed 1043 patients diagnosed with CC via positive serology for Trypanosoma cruzi infection coupled with cardiopathy and ventricular dysfunction [left ventricular ejection fraction (LVEF) < 40%] during the follow-up period from January 2006 to September 2021. The primary outcome measured included overall mortality and heart transplantation in relation to RR status. Propensity score matching was utilised to adjust for confounding factors. Positive reverse remodelling (PRR) was characterised as patients displaying improved LVEF, and negative reverse remodelling (NRR) as those with persistent ventricular dysfunction during follow-up. Results Initially, 221 (21.2%) were categorised as PRR and 822 (78.8%) as NRR. Participants in the PRR group were predominantly female (51.6% versus 41.4%; p < 0.001), older [59 years (53 – 66) versus 56 years (47 – 64); p = 0.007], more prone to hypertension (43.4% versus 35.8%; p = 0.036), and presented with higher initial heart rates [70 bpm (60 – 80) versus 65 bpm (60 – 75); p = 0.002], systolic blood pressure [120 mmHg (110 – 130) versus 110 mmHg (100 – 120); p < 0.001], diastolic blood pressure [80 mmHg (69 – 82) versus 70 mmHg (60 – 80); p < 0.001], and LVEF [30.0% (26.0 – 35.0) versus 29% (25.0 – 34.0); p < 0.001] compared to the NRR group. Moreover, the PRR group had a lower intake of beta-blockers (BB) (76.6% versus 87.0%; p = 0.004), spironolactone (38.5% versus 59.5%; p < 0.001), and triple therapy (30.9% versus 50.4%; p < 0.001). Following propensity score matching, 200 patients remained for the final analysis, with 100 in each group. Cox proportional hazards model analysis revealed PRR as an independent predictor [hazard ratio (HR): 0.367; 95% confidence interval (CI) 0.218 – 0.616; p < 0.001] of mortality from all causes or heart transplantation. The PRR group exhibited a longer event-free survival duration than the NRR group (10.332 years; 95% CI 9.557 – 11.107 versus 7.348 years; 95% CI 6.606 – 8.089; p < 0.001). Discussion This study suggests a positive association between the PRR and increased survival in patients with CHD and HFrEF. Previously published studies didn’t demonstrate this association, possibly due to the small number of patients included. Conclusion PRR predicts a better long-term survival free from all-cause mortality and cardiac transplantation in Chagas cardiomyopathy with LVEF < 40%.Kaplan-Meier event-free survival curve

Identification and validation of ventricular rhythmic risk subgroups in hypertrophic cardiomyopathy by clustering analysis including left ventricular strain analysis

Abstract Background The excess mortality in hypertrophic cardiomyopathy (HCM) patients is mainly attributed to the occurrence of ventricular arrhythmia (VA).The prediction of VA remains challenging and could be improved. Purpose The study aimed to characterize the VA risk profile in HCM patients through clustering analysis combining conventional parameters with information derived from left ventricular longitudinal strain analysis (LV-LS). Methods 434 HCM patients (65% men, mean age 56 years) were retrospectively included from two referral centers and followed longitudinally (mean duration 6 years). The validation cohort included 177 HCM patients from an other tertiary French center. Mechanical and temporal parameters were automatically extracted from the LV-LS segmental curves of each patient in addition to conventional clinical and imaging data. A total of 287 features were analyzed using a clustering approach (k-means). The first endpoint for VA included suspected SCD, aborted cardiac arrest, appropriate ICD therapy (AIT), sustained ventricular tachycardia (SVT) and non-sustained ventricular tachycardia (NSVT) during follow-up. Results From the derivation cohort, 4 clusters were identified with a higher rhythmic risk for clusters 1 and 4 (VA rates of 26%(28/108), 13%(13/97), 12%(14/120), and 31%(34/109) for cluster 1,2,3 and 4 respectively) (Figure 1). These 4 clusters differed mainly by the LV mechanics. Patients from cluster 4 had a severe and homogeneous decrease of myocardial deformation (global longitudinal strain (GLS) -11%, normal value ≥ -20%) associated with LV and left atrium (LA) remodeling (left atrial volume index (LAVI) 46.6 vs. 41.5 ml/m², p=0.04 and LVEF 59.7 vs. 66.3%, p < 0.001) and impaired exercise capacity (% predicted peak work 58.6 vs. 69.5%; p= 0.025). Patients from cluster 1 showed a marked deformation delay and temporal dispersion on the segmental analysis associated with a moderate decrease of the GLS (-15.3%; p <0.0001 for GLS comparison between clusters). Patients from clusters 2 and 3 had a small GLS decrease (GLS -17.2 and -16.3%, respectively) with a less severe phenotype for cluster 2 and older patients for cluster 3 (mean age 62.1 vs. 54.1 years; p < 0.0001). The clustering analysis in the validation population resulted in the creation of 4 clusters overlapping the derivation cohort with similar characteristics (Figure 2). Clusters 1’ and 4’ had a higher incidence of ventricular arrhythmia with a VA rate of 22%(5/23), 18%(16/88), 0%(0/17), and 20%(10/49) for clusters 1’,2’,3’ and 4’ respectively. Conclusion Machine-learning-based cluster analysis processing LV-LS parameters in HCM patients identified 4 clusters with specific LV-strain patterns and different rhythmic risk levels. In the future, the automatic extraction and analysis of LV strain parameters could help to improve the risk stratification for SCD in HCM patients.Clustering analysisExternal validation

Ringlike late gadolinium enhancement: prevalence, association with cardiac phenotype, and patient outcome in an unselected cohort referred for cardiovascular magnetic resonance imaging

Abstract Background The identification of a non-ischemic ringlike enhancement in the left ventricular (LV) myocardium by cardiac magnetic resonance imaging (CMR) has emerged as a significant biomarker associated with arrhythmogenic cardiomyopathy (CMP) and adverse patient outcomes. Recently, the term "scarring CMP" has been also proposed to encompass various conditions characterized by a high burden of non-ischemic, often ring-like, myocardial scarring, including both genetic and acquired etiologies. Purpose To systematically evaluate CMR phenotypic traits and etiologic backgrounds in patients with ringlike enhancement and to assess the burden of adverse outcomes during follow-up (FU). Methods This is a single-center, retrospective analysis of prospectively enrolled patients undergoing CMR (from 2002 to 2024). Ringlike late gadolinium enhancement (LGE) was defined as continuous enhancement in three or more adjacent segments based on the AHA 17 segment model. Patients records were reviewed for etiologic classification and FU assessment. Results Among 23.472 patients, 19.696 (84%) underwent LGE assessment. In 152 patients (0.77%; 73% male; mean age 48.5 ± 17 years) a ringlike LGE was identified. The mean number of LV segments with LGE was 10 ± 3. Right ventricular (RV) LGE was present in 23% of subjects. LV fatty metaplasia was detected in 22%. Infero-lateral segments were most frequently affected. CMR showed the following morpho-functional features: LV dilatation (53%), LV hypokinesia (69%), LV hypertrophy (10.5%), LV non-compaction (11%), RV dilation (26%), and RV ejection fraction < 40% (21%). Phenotypic classification according to 2023 ESC guidelines identified dilated CMP phenotype (43%), non-dilated LV CMP phenotype (39%), predominant arrhythmogenic right ventricular phenotype (6%), hypertrophic phenotype (7%). 5% of cases remained unclassified, all of them showing LV dilated non-hypokinetic phenotype. Genetic analysis was performed in 101 patients (66%). Etiologic classification revealed non-desmosomal gene related CMP (24%), desmosomal gene related CMP (8%), inflammatory CMP (16%), genetic neuromuscular diseases (5%), congenital metabolic errors (3%), familiar gene elusive CMP (2%) and unknown etiology (45%). Notably, only 17% of patients classified as having inflammatory CMP and 66% of those with unknown etiology underwent genetic testing, with negative results. The median follow-up duration was 3 (IQR: 1-7) years. All-cause mortality occurred in 10.5% of patients, while 17% experienced sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapies, or sudden cardiac death. Heart transplantation or left ventricular assist device implantation was required in 8% of cases. Conclusion Ringlike LGE is a rare, non-disease-specific feature that can be found in different morpho-functional CMP phenotypes. It is associated with frequent genetic-determined etiology and high burden of arrhythmic and non-arrhythmic outcomes.

The added value of advanced echocardiography in dilated cardiomyopathy: looking at the right heart

Abstract Introduction and aims Right ventricular (RV) dilation and dysfunction significantly impact the prognosis of dilated cardiomyopathy (DCM) patients, and early detection of subclinical changes is mandatory. Furthermore, right atrial (RA) size and function are still often neglected in DCM patients. Accordingly, our aims were to evaluate (i) right heart chambers and tricuspid annulus (TA) subclinical remodeling, and (ii) the prognostic value of RA compared to left atrial (LA) size and function in patients with DCM without clinical RV involvement, RV pressure/volume overload or sustained atrial tachyarrhythmias by advanced echocardiography techniques. Materials and methods Sixty-eight patients out of a cohort of 106 patients with DCM (mean age 60 years, 35 men) were evaluated by comprehensive transthoracic two- (2DE) and three-dimensional (3DE) and speckle-tracking (2DSTE) echocardiography, were compared to 62 age- and sex-matched healthy controls (mean age 61 years, 32 men), and were followed-up for 37 ± 16.6 months. Results DCM patients have RV and RA global longitudinal dysfunction by 2DSTE, and higher RA minimum volumes (Vmin) and TA areas despite having normal RV volumes and ejection fraction (EF) and RA maximum volumes (Vmax) by 3DE compared to controls (Table). RA and RV strain correlate with each other (r=0.360, p=0.013 for RA reservoir and r=0.347, p=0.017 for conduit strain). TA area correlates with RA contractile strain (r=-.293, p=0.046) and RV free-wall strain (r=0.373, p=0.008), RA Vmax (r=0.513, p<0.001), RV (r=0.404, p=0.004 for end-diastolic and r=0.444, p=0.001 for end-systolic) and left ventricular (LV) volumes (r=0.394, p=0.016) and LV EF (r=-.361, p=0.028). RA reservoir strain (AUC=0.769) has higher value for outcome prediction compared to LA strain (p=0.02 between them). Conclusion Patients with DCM have RV longitudinal dysfunction and decreased RA function, in the absence of clinical RV involvement or atrial arrhythmias, and decreased RA strain is associated with an increased risk of hospitalization and cardiac death.Comparison of right heart parametersPrognostic value of atrial function

Prognostic impact of the concept of late gadolinium enhancement granularity in non-ischaemic dilated cardiomyopathy

Abstract Background The prognostic stratification of non-ischaemic dilated cardiomyopathy (DCM) to predict the risk of death is mainly driven by the left ventricular ejection fraction (LVEF). Indeed, LVEF<35% is currently the only indication for primary prevention with implantable cardioverter-defibrillator (ICD) in these patients. Beyond LVEF, several cardiac magnetic resonance imaging (MRI) studies have suggested the strong prgnostic impact of late gadolinium enhancement (LGE), and particularly its extent and location. Therefore, we assumed that a more granular approach combining detailed LGE findings including extent, location and pattern could improve risk stratification in this population. Purpose To assess the additional prognostic value of the concept of "Late Gadolinium Enhancement (LGE) Granularity" that includes extent, location, and pattern in non-ischaemic dilated cardiomyopathy (DCM) patients to predict all-cause death. Methods Between 2008-2021, all consecutive patients with DCM without ICD or history of sustained ventricular arrythmia referred for cardiac MRI were included in two French centres. In line with the current ESC and AHA guidelines, DCM was defined by the LV dilation and LVEF< 50% using cardiac MRI. All patients with history of coronary artery disease or clinical history of myocarditis were excluded. The primary outcome was all-cause death using the French National Registry of Death. Cox regressions were performed to determine the prognostic value of each LGE findings. The additional prognostic value of the LGE granularity was assessed by the C-statistic increment, the continuous net reclassification improvement (NRI), and the integrative discrimination index (IDI). Results Of 1,668 DCM patients (age 52±8 years, 54% males), 268 (16%) died after a median (interquartile range) follow-up of 9 (7-12) years. With a median LVEF value of 39% (30-46), 472 (28%) patients had non-ischemic LGE. Using survival curves, patients with LVEF>35% but the LGE septal location showed a higher risk of death compared to all patients with LVEF≤35% with or without LGE (except for the septal location, all p<0.001). In DCM patients with LGE (N=472), LGE extent (adjusted HR: 4.27, 95% CI: 2.22-8.22), septal location (HR: 5.74, 95% CI: 3.35-9.85) and multiple areas of LGE (HR: 4.38, 95% CI: 2.08-9.22; all p<0.001) were all independently associated with death after adjustment for prognosticators. The concept of "LGE granularity" combining all these LGE features showed the best improvement in model discrimination and reclassification over traditional prognosticators including LVEF (C-statistic improvement: 0.14; net reclassification improvement=64.3%; integrative discrimination index=29.0%; all p<0.05). Conclusion In a large cohort of DCM patients, the concept of "LGE granularity" combining LGE extent, location and the presence of multiple areas had an additional prognostic value above traditional prognosticators including LVEF to predict all-cause death.

Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: observations from a tertiary care center

Abstract Background In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system. Methods We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association [NYHA] class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks. Results At 261±143 days (range of 31-571 days), 69 (46%) patients had ≥1 NYHA class, 27 (18%) additional patients had ≥2 NYHA class improvement and 40 (27%) reported a no change in symptoms. The mean LVOT gradient at rest decreased from 41±33 mmHg at baseline to 16±17 mmHg at 4 weeks, 16±16 mmHg at 8 weeks and 15±16 mmHg at 12 weeks. The mean drop in resting LVOT gradient from baseline to last follow-up was 26±3 mmHg (p<0.0001). The mean Valsalva LVOT gradient decreased from 72±43 mmHg at baseline to 29±31 mmHg at 4 weeks, 29±28 mmHg at 8 weeks and 30±29 mmHg at 12 weeks (p<0.001). The mean reduction in post Valsalva LVOT gradient from baseline to last follow-up was 43±4 mmHg (p<0.0001). At baseline, 100% patients had Valsalva LVOT gradients ≥ 30 mm Hg and 142 (95%) had ≥ 50 mm Hg. After initiation of mavacamten therapy, Valsalva LVOT gradient ≥ 30 mm Hg was observed in 44/150 (29%) at 4 weeks, 40/141 (28%) at 8 weeks and 41/136 (30%) at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73±39 mmHg at baseline to 34± 27 mmHg at 4 weeks, 35±28 mmHg at 8 weeks and 30±24 mmHg at 12 weeks (P<0.001). The mean LVEF at baseline was 66±6% and changed to 64±5% at 4 weeks, 63±5% at 8 weeks and 62±7% at 12 weeks (p<0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF<50. During follow up, dose reduction or discontinuation of background HCM therapy (betablockers, calcium channel blockers and disopyramide) occurred in 33 (22%) patients. The breakdown of various drug doses of mavacamten, at last follow-up, is as follows: 2.5 mg (n=29, 19%), 5 mg (n=80, 53%), 10 mg (n=37, 25%) and 15 mg (n=3, 2%). Conclusions In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety of prescribing mavacamten under the REMS program.

From amoeboid myosin to unique targeted medicines for a genetic cardiac disease.

The importance of fundamental basic research in the quest for much needed clinical treatments is a story that constantly must be retold. Funding of basic science in the USA by the National Institutes of Health and other agencies is provided under the assumption that fundamental research eventually will lead to improvements in healthcare worldwide. Understanding how basic research is connected to clinical developments is important, but just part of the story. Many basic science discoveries never see the light of day in a clinical setting because academic scientists are not interested in or do not have the inclination and/or support for entering the world of biotechnology. Even if the interest and inclination are there, often the unknowns about how to enter that world inhibit taking the initial step. Young investigators often ask me how I incorporated biotech opportunities into my otherwise purely academic research endeavors. Here I tell the story of the foundational basic science and early events of my career that led to forming the biotech companies responsible for the development of unique cardiac drugs, including mavacamten, a first in class human β-cardiac myosin inhibitor that is changing the lives of hypertrophic cardiomyopathy patients.

Machine learning methods for diagnostic disease prediction and treatment decisions in parvovirus B19 positive viral cardiomyopathy

Abstract Background Parvovirus B19 (B19V) is the most common type of virus found in endomyocardial biopsies (EMB) from patients with inflammatory heart disease. However, the detection of genomic B19V-DNA appears to have little clinical significance and is often considered an incidental finding. Recent analyses of a large cohort of B19V-positive patients revealed that the detection of RNA transcripts rather than DNA is of clinical importance, as B19V-RNA-positive patients have a significantly worse cardiovascular outcome. Here, we applied machine learning (ML) methods to assess the impact of B19V transcriptional activity on cardiac inflammation and patient clinical outcome. Methods and results A total of 305 patients with a known clinical course and a positive endomyocardial B19V-DNA test were included in this study. Follow-up measurements of the B19V-specific transcripts VP1/2 and NS1 revealed significantly worse clinical courses than in patients without B19V-RNA detection (P=0.019, hazard ratio (95% CI)=1.62 (1.10-2.57)). LVEF at follow-up was significantly lower in patients with detected B19V-RNA (P=0.007), and adverse events such as worsening LV function (P=0.003) or stable systolic dysfunction (P=0.013) were more frequent in this group. Importantly, analysis of inflammatory markers in EMB showed no difference in patients with and without RNA detection (P=0.432), suggesting that the deterioration in clinical outcome was related to B19V transcriptional activity rather than an increase in inflammation. The analysis of area under the receiver operating characteristic curve (AUROC) of B19V-RNA-negative patients revealed that the macrophage marker MAC-1 (AUROC=0.66, P=0.002) was the single most prognostically relevant parameter, while the T cell marker CD3 (AUROC=0.73, P<0.001) was identified as the most prognostically relevant marker in B19V-RNA-positive patients. The linear combination of several inflammatory markers increased the AUROC value to 0.67 in B19V-RNA-negative patients and to 0.74 in B19V-RNA-positive patients. To further increase prognostic accuracy, we trained ML models on features derived from EMB inflammatory markers. For the prediction of major adverse cardiac events within 60 months, the best ML-models achieved an AUROC of 0.87 in B19V-RNA-positive and of 0.86 in B19V-RNA-negative patients, while models that neglect the differentiation of patients with regard to the presence of B19V RNA transcripts only achieved an AUROC of up to 0.76. Conclusions These results show that B19V transcriptional activity is an independent risk marker for adverse cardiac events in patients with viral cardiomyopathy and thus confirm the clinical-therapeutic importance of myocardial biopsy. Furthermore, we present an ML-based algorithm that accurately indicates disease progression in B19V-positive cardiomyopathy patients and is thus helpful for appropriate therapy recommendation.

Anderson-Fabry disease patients with anatomical heart hypertrophy express a higher degree of electrocardiographic hypertrophy compared to hypertrophic cardiomyopathy patients

Abstract Background Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease that has progressively gained attention due to the availability of specific therapeutic options. Heart involvement is of critical prognostic significance and differential diagnosis with Hypertrophic Cardiomyopathy (HCM) is as challenging as it is crucial to provide the patient with the appropiate treatment. Purpose To describe ECG features in AFD patients according to the presence of anatomical hypertrophy and compare them with matched HCM patients. Methods One-hundred-sixty-two AFD patients were recruited in the present multicentre study cohort and divided into 2 groups according to the presence (Group A, n=111) or the absence (Group B, n=51) of anatomical hypertrophy. Group A patients were then compared with a matched cohort of HCM patients (n=111) with the use of Propensity Score Martching relatively to sex, age and maximal wall thickness. Results AFD patients with cardiac hypertrophy, compared with matched HCM patients with the same indexed cardiac mass at echocardiography [151 (124-211) vs 145 (123-182) g/m2; p=0.1675], showed on the surface electrocardiogram a higher degree of electrical hypertrophy expressed as increased total QRS score [204 (158-271) vs 177 (138-221) mm; p=0.0004] and R wave amplitude in aVL ≥ 11 mm [51 (45.9%) vs 25 (22.5%); p<0.0001], whereas they did not differ with respect to Sokolow-Lyon index [31 (18-44) vs 32 (22-40) mm; p=0.518] and Cornell index [19 (12-25) vs 17 (12-24) mm; p=0.5]. Furthermore, AFD patients featured wider QRS complexes [110 (100-134) vs 100 (90-106) ms; p<0.0001] and a higher prevalence of Right Bundle Branch Block (RBBB), both complete [25 (22.5%) vs 3 (2.7%); p<0.0001] and incomplete [17 (15.4%) vs 2 (1.8); p<0.0001], as well as non specific intraventricular block [14 (12.6%) vs 4 (3.6%); p<0.0001]. Conclusions Our cohort of Anderson-Fabry patients, compared with HCM patients with the same indexed cardiac mass at echocardiography matched by age, sex and wall thickness, featured a higher degree of electrocardiographic hypertrophy expressed as increased total QRS score and R wave amplitude in aVL, whereas it did not differ with respect to Sokolow-Lyon and Cornell indexes. These findings may prove beneficial in achieving earlier the diagnosis of AFD, enabling clinicians to initiate swiftly and without delay the specific disease modifying therapies available.Electrocardiographic differencesTotal QRS Score AFD vs HCM

Assessment of coronary blood volume to left ventricular mass ratio: a comparative study among endurance athletes, hypertrophic cardiomyopathy patients and healthy controls

Abstract Background Pathologic left ventricular hypertrophy (LVH) may lead to a mismatch between left ventricular mass (LVM) and blood supply, potentially reducing coronary flowreserve. Typically, assessing this involves complex or invasive methods. Objective We assessed epicardial coronary blood volume (CBV) to LVM ratio (V/M) using coronary computed tomography (CT) angiography in athletes, HCM patients, and healthy controls. Methods A total of 169 individuals without obstructive coronary artery disease were included, comprising 39 endurance athletes, 55 HCM patients, and 79 healthy controls. Automated detection of the epicardial coronary tree facilitated the calculation of CBV, enabling the assessment of LVM and subsequent comparison of the V/M ratio. Results HCM patients had the highest LVM (242g ±115), followed by athletes (145g ±33.35) and healthy controls (106g ±22.53), the corresponding CBV were: (7ml ±2.09 ml), (6.35±1.68 ml), and (4.43±0.93 ml); respectively. V/M ratios were similar in athletes (0.04 ±0.01 ml/m2), and controls (0.04 ±0.01, P= 0.298 ml/m2), but were significantly lower in HCM patients (0.03 ±0.01, P<0.001 ml/m2). CBV and LVM significantly corelated among the three group (Figure). Conclusions Contrast CT findings reveal that unlike HCM patients with pathological LVH, athletes exhibit sufficient increase in CBV relative to LVM thereby maintaining normal V/M ratio.

ECGWiz: a unified and generalizable AI model for comprehensive ECG diagnosis

Abstract Background Deep learning has demonstrated diagnostic performance in electrocardiogram (ECG) analysis comparable to that of clinicians. However, existing models primarily excel in diagnosing common conditions such as arrhythmias and heart blocks, which are easily identifiable using standard predictor variables. Conversely, models aiming to uncover novel insights, such as detecting structural changes or the presence of myocardial scar, often lack generalizability due to insufficient data, model architecture limitations, and other factors. Moreover, these models frequently encounter challenges, such as a decline in performance when applied to external datasets. To address these issues comprehensively, we propose the ECGWiz — a unified model capable of tackling diverse ECG-related problems with consistently high performance. Objective To develop a generalizable Foundation AI model for ECG diagnosis capable of detecting diverse cardiac abnormalities and diseases using few training samples. Methods We utilized publicly available datasets like PTB-XL, CPSC, etc. To build our model, totaling approximately 80,000 ECGs. These 12 lead ECGs are scaled and filtered before using them for training. The AI model is pretrained using Self Supervised Learning and Contrastive Learning strategies. Further, the model undergoes supervised training using a hierarchy of labels that increase in granularity, encompassing arrhythmias, heart blocks, other cardiac abnormalities, heart failure, sudden cardiac death and more. Lastly, the model is prepared for Few-Shot Learning — where the model learns from a minimal set of samples (5 to 10 ECGs) of the target disease. For testing the model, we are using unique datasets like PROSE which consists of non-ischemic cardiomyopathy patients with and without myocardial scaring detected using cardiac MRI imaging at the Johns Hopkins University. Results Our model, trained on a dataset of only 5 ECG recordings, demonstrated a 74% accuracy in identifying myocardial scarring as detected by LGE MRI, utilizing a standard 12-lead ECG. This performance is comparable to that of conventional deep learning methods, which necessitate datasets containing upwards of 120 ECG recordings. Conclusion Our model represents a promising stride in creating a unified and adaptable foundation AI model for comprehensive ECG-based diagnosis. Its capacity to learn from a minimal set of examples signifies a robust framework that can evolve and adapt to new challenges in ECG diagnosis. Ongoing improvements, particularly through dataset expansion, underscore its potential to enhance cardiovascular diagnostics, offering precise and efficient patient care.