Left Ventricular Hypertrophy Research Articles

Gene-echocardiography: unmasking the covert role of fatty acid metabolism gene mutations in adult cardiomyopathy

Abstract Background Although the role of fatty acid metabolic deficiencies in cardiomyopathy is established, the precise identity of causative genes and their respective phenotypes in adult cardiomyopathy remains unclear. Methods We implemented a combination of echocardiography and whole exome sequencing in clinically diagnosed cardiomyopathy patients to uncover this relationship. This involved recording cardiac phenotypes, identifying genes associated with disrupted fatty acid metabolism, and subsequently followed up with these patients. Results Out of 802 cardiomyopathy patients, 27 exhibited mutations in genes tied to fatty acid metabolism. Specifically, 16 patients demonstrated a hypertrophic cardiomyopathy (HCM) phenotype, and 11 showed a dilated cardiomyopathy (DCM) phenotype. The implicated genes were SLC22A5 (n=7), ACADVL (n=6), ACADS (n=4), ACADM (n=3), SLC25A20 (n=3), ACADL (n=2), HADH (n=1), and AGK (n=1), with a higher prevalence in males. Among these, the SLC22A5 mutation was predominant and correlated with HCM phenotype. Notably, compound mutations were frequently observed (16/27), leading to earlier disease onset and diminished aortic sinus dimension. Further investigation showed that smaller aortic sinus dimensions resulted from abnormal left ventricular myocardial work. HCM phenotype mutation carriers showed more consistent left ventricular hypertrophy and a higher probability of right ventricular hypertrophy, while DCM phenotype mutation carriers exhibited impaired contractile function across all left ventricle segments. After a 24-month follow-up, the DCM phenotype group demonstrated higher cardiovascular risk, including two fatalities. Conclusion Our investigation highlights the significant prevalence of mutations related to abnormal fatty acid metabolism in adult cardiomyopathy patients, underscoring the utility of a gene-echocardiography approach for diagnosis.

High-intensity exercise-related sudden cardiac death in hypertrophy cardiomyopathy

Abstract Background Whether exercise provokes sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM) is uncertain. Current European guidelines recommend against high-intensity exercise in individuals with high SCD risk or obstructive physiology. Purpose We investigated the factors associated with exercise-related SCD in HCM. Methods We retrospectively analyzed of 2,844 consecutive patients with HCM who underwent evaluation between 2005 and 2023 at a high-volume tertiary center. SCD events were defined as a composite of aborted SCD, appropriate implantable cardioverter-defibrillator (ICD) shock, and SCD. Among 80 first SCD events (2.8%), 75 events had a description of the physical activity at the time of the event. Patients were classified into two groups according to physical activity level at the time of the SCD event. Group 1 included patients with high-intensity exercise-related SCD events, defined as happening during or immediately after high-intensity exercise or physical activity, while Group 2 included patients with SCD events happening at rest or during light or moderate physical activity. Results The 75 first SCD events included 44 aborted SCD, 22 appropriate ICD shocks, and 9 SCD. Median age at SCD event was 54 (IQR 39.5–62.5) years and 60 (80%) were men. Patients in Group 1 (n=14) were younger than patients in Group 2 (n=61) (23.5 [IQR 16–48] vs. 55 [IQR 44–64] years, p<0.001), and most patients in group 1 (92.9%) were under the age of 60 years. Patients in Group 1 had slightly smaller left ventricular (LV) end-diastolic dimension and had higher ESC SCD risk scores (3.6 [IQR 2.5–6.7] vs. 2.4 [IQR 1.7–4.8], p=0.044) than patients in Group 2; however, there were no significant differences in the proportion of high-risk patients (28.6% vs. 14.8%, p=0.396) or patients with AHA major SCD risk factors (57.1% vs. 55.7%, p=0.999). Otherwise, there were no significant differences in the presence of obstructive physiology, apical HCM, and apical aneurysm, LV systolic and diastolic function, and comorbidities between the two groups. Furthermore, of the 29 patients who underwent genetic testing, there was no difference in the proportion of patients with pathogenic sarcomeric variants according to exercise-related SCD (50.0% vs. 65.2%, p=0.683). To note, there was a non-significant tendency towards higher proportion of thin filament variants in Group 1 than Group 2 among those with pathogenic sarcomeric variants (100% [3/3] vs 26.7% [4/15], p=0.084). Conclusions Most high-intensity exercise-related SCD events happened under the age of 60. The ESC SCD risk score was higher in patients with high-intensity exercise-related SCD events, although the SCD risk categories or AHA risk factors could not discriminate patients at higher risk of events. These results suggest that exercise recommendations should not be based on SCD risk category, presence of obstruction, or degree of LV hypertrophy.

Long-term changes in cardiac geometry and mechanics after bariatric surgery- insights from the FatWest study

Abstract Background Patients with severe obesity have a high prevalence of subclinical cardiac organ damage including impaired longitudinal and radial cardiac mechanics. Previous studies on the impact of bariatric surgery on cardiac remodeling, most of them with short patient follow-up, have yielded inconsistent results. Purpose To assess progressive changes in cardiac geometry and mechanics up to five years following bariatric surgery. Methods In the prospective Bariatric Surgery on the West Coast of Norway (FatWest) study, cardiac remodeling was assessed by 2D echocardiography preoperatively and at six months, one year and five years after Roux-en-Y gastric bypass in a cohort of 97 patients (44±10 years, 72% women, body mass index [BMI] 41.8±4.8 kg/m²). Excess weight loss (EWL) was calculated as: absolute weight loss/(initial weight-ideal weight)x100. Left ventricular (LV) size was assessed by the LV mass/ height^2.7, LV longitudinal mechanics by the peak global longitudinal strain (GLS) and radial mechanics by the midwall shortening (MWS). LV myocardial oxygen demand was estimated from the LV mass-wall stress-heart rate product. Right ventricular diameter was measured in the basal one-third of the ventricular cavity. Left atrial (LA) reservoir function was assessed by the LA emptying fraction. Results After a mean follow-up of 63±13 months, the average postoperative EWL was 66%. Overall, both right ventricular diameter, LV mass index, LV GLS, myocardial oxygen demand and LAEF (68% vs. 64%) improved significantly at the 5-year follow-up (all p<0.05), while MWS remained unchanged (Figure). Prevalence of normal LV geometry increased gradually from 56% to 80%, while that of LV hypertrophy fell from 36% to 16% (p<0.001). Analyses of temporal trends showed that improvement in BMI, LV mass and LV GLS occurred during the first postoperative year (Figure). In Cox regression analysis, a low 5-year GLS was associated with preoperative hypertension after adjustment for age, sex, preoperative diabetes mellitus, and postoperative changes in BMI, mean blood pressure and myocardial oxygen demand (p<0.01). In a similar linear model, after adjustment for the same covariates, LV mass index at the 5-year follow-up was independently related to the magnitude of the postoperative BMI reduction (R² = 0.58, p<0.001). Conclusion Ventricular size and longitudinal mechanics are significantly improved 5 years after bariatric surgery, with the reverse remodeling occurring during the first postoperative year. Residual abnormal 5-year LV geometry and mechanics are related to preoperative hypertension and suboptimal BMI reduction.Figure

Cardiac structural, functional remodelling, and perfusion impairments across the spectrum of aortic stenosis

Abstract Background Aortic stenosis (AS) accounts for substantial global morbidity and premature mortality even in moderate AS (Mod-AS). Whilst myocardial remodeling response is considered critical in the adverse prognosis of Mod-AS, the precise mechanisms remain poorly understood. We aimed to prospectively assess myocardial remodeling, perfusion and energetics differences in Mod-AS and severe AS (Severe-AS). Methods Fifty-two Severe-AS and 25 Mod-AS patients and 18 demographically-matched controls underwent cardiovascular magnetic resonance and phosphorus-magnetic resonance spectroscopy to define left ventricular (LV) mass and function, global longitudinal shortening (GLS), rest and adenosine-stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR), layer-specific perfusion metrics (subendocardial [Endo], subepicardial [Epi] MBF and MPR, and Endo-Epi-MBF ratio [Endo/Epi]), myocardial scar on late gadolinium enhancement (LGE) imaging, and myocardial energetics (phosphocreatine:ATP ratio [PCr/ATP]). Results Compared to controls, with increasing AS severity, there was progressive increase in LV concentricity (LV mass-index (controls: 46[40,51],Mod-AS:58[51,65],Severe-AS: 70[65,75]g/m2; P<0.0001), and stepwise decline in GLS (controls:19.9[17.6,22.2], Mod-AS:17.7[16.6,18.8], Severe-AS:13.4[12.5,14.4]%; P<0.0001) with significant differences between Mod-AS and Severe-AS in all three comparisons. Both stress MBF(controls:2.1[1.9,2.3],Mod-AS:1.9[1.6,2.2],Severe-AS:1.3[1.2,1.5]ml/min/g; P<0.0001) and MPR(controls:3.3[2.8,3.6],Mod-AS:2.8[2.4,3.2], Severe-AS:1.9[1.8,2.1]; P<0.0001) were only significantly reduced in Severe-AS compared to controls, with significant differences also detected between Mod-AS and Severe-AS. However, stress-endo-MBF (controls:2.0[1.8,2.3], Mod-AS:1.7[1.5,2.0], Severe-AS:1.2[1.1,1.3]ml/min/g; P<0.0001), stress-Endo/Epi(controls:1.00[0.93,1.07],Mod-AS:0.87[0.80,0.94],Severe-AS:0.81[0.75,0.82];P<0.0001), rest-Endo/Epi (controls:1.12[1.10,1.14], Mod-AS:1.06[1.03,1.09], Severe-AS:1.03[1.02,1.06]; P<0.0001) and endo-MPR (controls:3.2[2.7,3.6],Mod-AS:2.5[2.1,2.9],Severe-AS:1.7[1.5,1.8]; P<0.0001) were all significantly reduced in both Mod-AS and Severe-AS. Compared to controls, both AS groups showed significantly lower PCr/ATP (controls:2.2[2.0,2.3],Mod-AS:1.8[1.6,2.0],Severe-AS:1.7[1.6,1.8]; P<0.0001). Only the Severe-AS group had evidence of non-ischemic myocardial scarring on LGE (2.9[0.0,6.2]%), which was detected in 65%(n=34) of patients. AS severity (peak aortic valve velocity) correlated with stress-MBF (r=-0.45, P=0.0003), MPR (r=-0.44, P=0.0005) and GLS (r=-0.47, P=0.0001). Conclusions Moderate and severe-AS are both associated with cardiac concentric hypertrophy, reductions in myocardial energetics, and subendocardial hypoperfusion. Patients with Severe-AS exhibit a more pronounced phenotype with worse LV hypertrophy, contractile dysfunction and myocardial scarring compared to Mod-AS patients.

Exaggerated blood pressure response to submaximal exercise must be considered relative to fitness: strong associations with hypertensive target organ damage

Abstract Exaggerated systolic blood pressure (SBP) during submaximal exercise is associated with increased cardiovascular (CV) risk. However, findings are mixed and new evidence indicates that cardiorespiratory fitness should be considered for proper clinical interpretation of exercise SBP responses. This study aimed to determine the relationship between SBP response to submaximal effort corrected for fitness and abnormalities of cardiac structure and function. Methods Each of 231 participants (age 54±12 years; 53% females) with controlled clinic BP, no evidence for ischemic heart disease, valvular heart disease or heart failure underwent cardiopulmonary exercise testing (Bruce protocol), resting and exercise echocardiography and 24h ABPM. Submaximal exercise SBP (measured at the 2nd stage of Bruce protocol) was corrected for two fitness variables: 1) peak VO2 and 2) maximal workload in METs (SBP/peakVO2 and SBP/METs). Results There were no, or weak, associations with exercise SBP and target organ damage. However, there was a progressive deterioration of cardiac function and structure parameters across the exercise SBP tertiles corrected for fitness (Table 1). Both SBP/peakVO2 and SBP/METs significantly correlated with left ventricular (LV) mass, LV diastolic and systolic, and left atrial parameters (Table 2). ROC analysis revealed good performance of corrected SBP response to submaximal exercise in detection of LV hypertrophy and diastolic dysfunction (AUC 0.792 and 0.808, and 0.771 and 0.802 for SBP/peakVO2 and SBP/METs, respectively; Figure). Conclusions Fitness-corrected SBP responses to submaximal exercise can identify more profound target organ damage with respect to cardiac function and structure even among patients with controlled clinic BP. Exaggerated BP response to exercise must be considered relative to fitness for proper clinical interpretation of BP responses to exercise testing.Figure

The BET inhibitor Apabetalone protects against heart failure with preserved ejection fraction by suppressing myocardial inflammation

Abstract Background Posttranslational histone modifications, play a major role in cardiac hypertrophy and dysfunction. Apabetalone (APA), a selective inhibitor of bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. Purpose We sought to investigate whether APA could be beneficial in cardiometabolic heart failure with preserved ejection fraction (cHFpEF). Methods Mice were subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Histology, mouse echocardiography (Vevo3100) and Treadmill exhaustion test were performed. Unbiased gene expression profiling by PCR array and proteomics analysis (Olink) was employed in left ventricular (LV) myocardial specimens from HFpEF mice and control animals. Cultured cardiomyocytes (CMs) treated with palmitic acid (PA) were used as an in vitro model of metabolic stress. cHFpEF mice were chronically treated with the BET inhibitor APA (150mg/kg/day) or vehicle (DMSO). In order to translate our findings to the human setting, passive stiffness of skinned CMs collected from cHFpEF patients was assessed before and after APA treatment. Results HFpEF mice displayed LV hypertrophy, diastolic dysfunction, myocardial fibrosis, lung congestion and impaired exercise tolerance as compared to controls. Interestingly, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) - and lung congestion were significantly reduced in HFpEF mice treated with APA, while exercise tolerance was improved. Transcriptomic analysis in PA-treated CMs and LV mouse specimens from cHFpEF mice showed a profound deregulation of genes controlling inflammation, namely IL-6, TNF-alpha, and IL-1beta. ChIP assays showed BRD4 occupancy on the promoter of several inflammatory genes, including IL6. Treatment with APA suppressed most of inflammatory genes, with a pronounced effect on IL6 expression. Moreover, APA reduced circulating levels of several inflammatory chemokines. The beneficial effects of APA were explained by modulation of IL-6/CaMKII/STAT3 pathway both in cHFpEF hearts and PA-treated CMs. In skinned CMs from cHFpEF patients, both APA and IL6 blockade were able to attenuate passive stiffness. Conclusions Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF.

Nicorandil activates lkb1-ampk signaling pathway to ameliorate cardiac remodeling after myocardial ischemia/reperfusion injury by upregulating mt2

Abstract Background Cardiomyocyte apoptosis is a crucial event underlying the development of cardiac abnormalities and dysfunction after myocardial ischemia reperfusion (MI/R) injury. A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI/R. Nicorandil, an ATP-sensitive potassium channel opener, could improve mitochondrial damage and reduce oxidative stress，which reduce cardiomyocyte apoptosis. Metallothionein (Mt), reactive oxygen species (ROS) scavenger, which can reduce oxidative stress, also attenuated MI/R-induced autophagy and cell apoptosis. Except as a potassium channel opener, nicorandil may play a cardioprotective role by regulating metallothionein, and its specific mechanism remains to be elucidated. Objective To clarify the protective effect of nicorandil in myocardial ischemia/reperfusion injury, and elucidate the specific mechanism which nicorandil regulate the expression of metallothiosin to reduce myocardial ischemia/reperfusion injury, so as to provide new drug targets or new measures for clinical prevention and treatment of MI/R. Methods A cardiac MI/R injury model was constructed by the ligation of the left anterior descending coronary artery to investigate the underlying molecular mechanisms. The apoptosis of myocardial tissue cells was detected by TUNEL staining. The ultrastructural changes of myocardial tissue were observed by transmission electron microscopy. The expressions of Mt family, mitochondrial dynamics and Glucose metabolism-associated genes were measured by Western blotting and qPCR. The content of ATP was determined by ELISA in heart tissue. AutodockVina was used to evaluate binding energy and interaction patterns between drug candidates and their targets. The protein-protein interaction model was predicted by ZDOCK software. Results Treatment with nicorandil mitigated left ventricular enlargement, improved cardiac dysfunction,reduced myocardial infarcation area and decreased cardiomyocyte apoptosis after I/R. Nicorandil up-regulated the expression of Mt2 and decreased the expressions of Drp-1,p-Drp-1(ser616), while enhanced the expression of Mfn1/2,GLUT4,HK II and MPC II in myocardium. Knockdown of Mt2 decreased the effects of nicorandil on apoptosis and mitochondrial dysfunction after I/R. Mechanistically, nicorandil significantly upregulated the expression of Mt2, which could bound to LKB1 and cause phosphorylation of LKB1, resulting in AMPK-dependent activation. Conclusions Nicorandil significantly upregulated the expression of Mt2, which interacted with LKB1 to promote LKB1 protein phosphorylation, resulting in AMPK-dependent activation and subsequently alleviating I/R-induced mitochondrial dysfunction and energy metabolism disorder, and thereby reducing cardiomyocyte apoptosis, eventually improving I/ R-induced cardiac remodeling and dysfunction.

Sex differences in left ventricular dilatation in patients with significant aortic regurgitation: prognostic implications

Abstract Background Left ventricular (LV) dilatation is a strong indicator of adverse outcome in patients with aortic regurgitation (AR). Accordingly, current guidelines recommend the use of LV end-systolic diameter index (LVESDi) as one of the criteria to trigger aortic valve surgery (AVS) in patients with severe AR, but with the same threshold regardless of gender. Purpose To assess sex differences in LV remodeling using both volumetric and linear measurements in a large cohort of patients with significant AR (moderate or greater) and to investigate their prognostic implications. Methods A total of 1070 patients (56 ± 18 years, 691 men) were included. The primary outcome was all-cause mortality. Results Women presented with older age (58 ± 19 vs. 55 ± 17, p=0.023) and more advanced heart failure (HF) symptoms than men (NYHA class III-IV 12% vs. 9%, p=0.017). Men showed significantly larger LVESDi (21 ± 5 vs. 20 ± 5 mm/m2, p=0.013) and LV end-systolic volume index (LVESVi 37 ± 28 vs. 26 ± 17 ml/m2 p<0.001). During a median follow-up of 89 (IQR, 54-132) months, 168 patients died. Women had lower survival rates at 3, 5, and 10 years of follow-up compared to men (92% vs. 94.3%; 85% vs. 89.7% and 75.3% vs. 84.1%, p=0.005) (Figure 1). Spline curve analysis revealed that the threshold of LVESDi associated with an increased risk of mortality was 20 mm/m2 for both sexes. In turn, the threshold for LVESVi was 40 ml/m2 for women and 45 ml/m2 for men. Univariable Cox regression models were constructed separately for men and women. The variables associated with all-cause mortality were age, NYHA class III-IV, and AVS as time-dependent covariate in women, and age, diabetes, AVS as time-dependent covariate, and LAVI (left atrial volume index) in men. These parameters were used as a basal multivariable Cox regression model on top of which LVESDi >20 mm/m2 (Model 1), LVESVi >40 ml/m2 for women and 45 ml/m2 for men (Model 2) were added (Table 1A). LVESVi >40 ml/m2 was not a significant univariate predictor in men. In women, LVESDi >20 mm/m2 (HR: 2.046, 95%CI 1.244-3.419; p=0.006) and LVESVi >40 ml/m2 (HR 1.758, CI 1.095-2.825; p=0.020) showed an independent association with all-cause mortality among other factors (Table 1A). In men, death was independently associated with LVESDi >20 mm/m2 (HR 1.979, 95%CI 1.255-3.121; p=0.003) and LVESVi >45 ml/m2 (HR 2.388, 1.522-3.746; p<0.001), among other factors (Table 1A). Moreover, when added to a basal model that included clinical and echocardiographic variables associated with prognosis, LV dilatation based on volumetric LV enlargement resulted in a greater discriminatory power for both genders (Table 1B). Conclusion Men and women have a similar LVESDi threshold of 20 mm/m2, which is associated with an increased risk of death. However, their respective cut-off values for LVESVi differ, with the optimal threshold for women being 40 ml/m2 and for men 45 ml/m2.

Association between impaired left ventricular global longitudinal strain and B-type natriuretic peptide in obstructive hypertrophic cardiomyopathy

Abstract Background Left ventricular global longitudinal strain (LV-GLS) is considered valuable in explaining impaired left ventricular contractility in hypertrophic cardiomyopathy (HCM) with preserved ejection fraction and is associated with worse outcome. Elevated B-type natriuretic peptide (BNP) is a biomarker of increased LV wall stretch and a risk factor of heart failure, mortality, and other adverse cardiovascular events. However, relationship between GLS and BNP has not received sufficient attention in the obstructive variant of HCM. Purpose This study aimed to determine the association between echocardiographic LV-GLS and plasma BNP in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods A total of 145 consecutive patients (32% females) with symptomatic HOCM were enrolled in the retrospective study. HOCM was defined with a maximum end-diastolic wall thickness ≥15mm without other etiologies for LV hypertrophy, and peak LV outflow tract (LVOT) gradient ≥30mmHg. The echocardiographic parameters regarding LV geometry, loading conditions, and GLS were evaluated according to guidelines. Patients were divided into two groups according to absolute GLS values (greater or lower than median LV-GLS). Patient baseline clinical data, echocardiographic parameters, and BNP were compared. Univariate and multivariable regression analysis were applied to identify the independent determinator of LV-GLS. Results The median value of LV-GLS of this study cohort was -13.4%. Eighty-one patients (47.6±13.4 years-old) had a |GLS|≥13.4% and 64 individuals (48.7±12.6 years-old) had a |GLS|<13.4%. No differences were found in age, gender, physical examinations, LVEF, cardiovascular comorbidities, or active medications between the two groups, except for body mass index (BMI). Patients with |GLS|≥13.4% had statistically lower BMI (24.58±2.42 vs. 26.00±3.12kg/m², p=0.030). BNP was found significantly elevated in patients with |GLS|<13.4% when compared with individuals with |GLS|≥13.4% {median (IQR); 550.05 (214.50, 899.35) vs. 182.40 (78.90, 479.90)pg/mL, p=0.004}. In univariate regression analysis, decreased |GLS| was associated with male gender, maximum and mean LV wall thickness, peak LVOT gradient, reduced mitral annular e’ velocity, elevated BNP and cardiac troponin I. In multivariable regression analysis, GLS was found independently associated with mean LV wall thickness and BNP. Conclusions In patients with symptomatic HOCM with preserved ejection fraction, impaired LV-GLS was found to be associated with plasma BNP and mean LV wall thickness, independent of gender, age, loading conditions, LVEF, or LVOT gradient. Reduced GLS may be a more sensitive surrogate in assessing increased myocardial wall tension or stretch, rather than LV contractility in these patients. Therefore, the interpretation of GLS in HOCM should shift away from systolic interest toward emphasizing its potential value in risk stratification of diastolic heart failure with preserved LVEF.Figure 1

Diversity of heart failure phenotypes in transthyretin amyloid cardiomyopathy. More than just heart failure with preserved ejection fraction

Introduction Current guidelines recommend suspecting transthyretin amyloid cardiomyopathy (ATTR-CM) in patients over 65 years of age with unexplained left ventricular (LV) hypertrophy in a non-dilated LV, heart failure (HF) and preserved ejection fraction (HFpEF), hypertrophic cardiomyopathy or severe aortic stenosis. However, there is evidence indicating a high prevalence of ATTR-CM in other HF phenotypes. As such, this study aimed to characterize the diversity of HF phenotypes of ATTR-CM by examining the LV ejection fraction and LV dilatation using echocardiography. Methods This multicentre, retrospective observational study included patients diagnosed with ATTR-CM between 2015–2023. The diagnosis was based on a positive cardiac biopsy or positive bone scintigraphy without monoclonal gammopathy. Echocardiographic measurements were categorized according to LV ejection fraction (LVEF) into HFpEF (LVEF ≥50%), HF with mildly reduced EF (HFmrEF, LVEF 40–49%), and HF with reduced EF (HFrEF, LVEF <40%). LV cavity size was categorized by LV end-diastolic diameter (LVEDD) and volume index (LVEDVi) as normal, moderately increased and severe dilatation. Results The study included 135 patients with ATTR-CM (mean age, 78 years; 89% male; 89% wild-type ATTR-CM). Most patients were screened for ATTR-CM because of unexplained HF and increased LV wall thickness (57%). Echocardiography showed LVEF <50% in 60% of the patients, with a significant portion presenting with HFrEF. Patients with LVEF <50% had higher NYHA class and elevated N-terminal pro-B-type natriuretic peptide levels than HFpEF patients. LV dilatation was observed in 43% of the patients, with 10% presenting with both LVEF <50% and severe LV dilatation. Conclusion This study revealed significant variability in HF phenotypes among patients with ATTR-CM, from HFpEF without LV dilatation to HFrEF with severe LV dilatation. Relying solely on HFpEF for screening may lead to under-diagnosis. These findings suggest the need for more comprehensive diagnostic criteria beyond echocardiographic measures to improve ATTR-CM detection and management.

Weight status change during four years and left ventricular hypertrophy in Chinese children

ObjectiveIt is well-established that overweight/obesity is a major risk factor for left ventricular hypertrophy (LVH) in childhood. However, it is still unclear if reversing from overweight/obesity to normal weight is associated with decreased LVH in children. This study aimed to examine the association between weight status change during four years and LVH among Chinese children based on a prospective cohort study.MethodsData were obtained from the Huantai Childhood Cardiovascular Health Cohort Study in China. A total of 1,178 children without LVH at baseline (mean age: 8.3 years) were included in this study. According to weight status [normal weight or overweight (including obesity)] at baseline (2017) and follow-up (2021), children were divided, based on sex- and age-adjusted body mass index (BMI), into four groups: persistent normal weight (normal weight at both baseline and follow-up), incident overweight (normal weight at baseline but overweight at follow-up), reversal to normal weight (overweight at baseline but normal weight at follow-up), persistent overweight (overweight at both baseline and follow-up).ResultsAfter adjustment for potential confounding factors, children with incident overweight (n = 114, 30.63 ± 4.74 g/m2.7) and those with persistent overweight (n = 363, 31.56 ± 6.24 g/m2.7) had higher left ventricular mass index (LVMI) at the end of the follow-up period than those with persistent normal weight (n = 632, 28.46 ± 7.64 g/m2.7), while those who reversed from overweight to normal weight had a non-significantly lower LVMI (n = 69, 28.51 ± 4.28 g/m2.7). Compared to children with persistent normal weight, those with persistent overweight [odds ratio (OR) = 5.14, 95% confidence interval (CI) = 3.33–7.95] and those with incident overweight (OR = 3.34, 95% CI = 1.77–6.30) had an increased risk of LVH. The risk of LVH tended to decrease, although not significantly, in those who reversed from overweight to normal weight (OR = 0.76, 95% CI = 0.22–2.55).ConclusionOur findings demonstrate a positive association between overweight and left ventricular mass in children and suggest that LVH in childhood could be attenuated by weight loss.

Fine Tuning ECG Interpretation for Young Athletes: ECG Screening Using Z-score-based Analysis

BackgroundElectrocardiograms (ECGs) in athletes commonly reveal findings related to physiologic adaptations to exercise, that may be difficult to discern from true underlying cardiovascular abnormalities. North American and European societies have published consensus statements for normal, borderline, and abnormal ECG findings for athletes, but these criteria are not based on established correlation with disease states. Additionally, data comparing ECG findings in athletes to non-athlete control subjects are lacking. Our objective was to compare the ECGs of collegiate athletes and non-athlete controls using Z-scores for digital ECG variables to better identify significant differences between the groups and to evaluate the ECG variables in athletes falling outside the normal range.MethodsValues for 102 digital ECG variables on 7206 subjects aged 17–22 years, including 672 athletes, from Hawaii Pacific Health, University of Hawaii, and Rady Children’s Hospital San Diego were obtained through retrospective review. Age and sex-specific Z-scores for ECG variables were derived from normal subjects and used to assess the range of values for specific ECG variables in young athletes. Athletes with abnormal ECGs were referred to cardiology consultation and/or echocardiogram.ResultsAthletes had slower heart rate, longer PR interval, more rightward QRS axis, longer QRS duration but shorter QTc duration, larger amplitude and area of T waves, prevalent R’ waves in V1, and higher values of variables traditionally associated with left ventricular hypertrophy (LVH): amplitudes of S waves (leads V1-V2), Q waves (V6, III) and R waves (II, V5, V6). Z-scores of these ECG variables in 558 (83%) of the athletes fell within − 2.5 and 2.5 range derived from the normal population dataset, and 60 (8.9%) athletes had a Z-score outside the − 3 to 3 range. While 191 (28.4%) athletes met traditional voltage criteria for diagnosis of LVH on ECG, only 53 athletes (7.9%) had Z-scores outside the range of -2.5 to 2.5 for both S amplitude in leads V1-V2 and R amplitude in leads V5-6. Only one athlete was diagnosed with hypertrophic cardiomyopathy with a Z-score of R wave in V6 of 2.34 and T wave in V6 of -5.94.ConclusionThe use of Z-scores derived from a normal population may provide more precise screening to define cardiac abnormalities in young athletes and reduce unnecessary secondary testing, restrictions and concern.

Hydrogel encapsulating gold nanoparticles for targeted delivery of nitroglycerin to reduce post-cardiac dysfunction inflammation by inhibiting the Wnt/β-catenin signaling pathway.

The discovery of nitric oxide's role in biological processes like platelet function, vasodilation, cell permeability, and inflammation has advanced our understanding of organic nitrate therapy's hemodynamic and nonhemodynamic effects. Short-term use of organic nitrates prevents left ventricular enlargement and infarct expansion. However, information on their long-term impact on LV remodeling in post-acute cardiac dysfunction patients is limited. In this study, we utilized an innovative active hydrogel with gelatin (Gel)/polyethylene glycol (PEG)/polylactic acid (PLA) encapsulating gold nanoparticles (AuNPs)-based drug delivery system for the sustained release of nitroglycerin (NTG). Gel/PEG/PLA/NTG/AuNPs hydrogel-based system is a non-transplant surgical method that can adhere to the surface of the heart and deliver the drug directly to the epicardium. Cardiac dysfunction was induced by ligating the left anterior descending coronary artery. Echocardiograms were used to study the pre- and post-operative hemodynamics. Hematoxylin and eosin (H&E) and Masson's trichrome stain (MTS) stainingrevealed that the acute myocardial infarction (AMI) rats' group had irregularly shaped fibers and a lack of transverse striations, whereas Gel/PEG/PLA/NTG/AuNPs hydrogel group showed significant improvement. Rats in the Gel/PEG/PLA hydrogel group demonstrated marked vasodilation, compared to the AMI group. Mechanistically, we determined that hydrogel disrupts the initiation of post-cardiac dysfunction via inhibiting Wnt/β-catenin transcriptional activation. Hence, the Gel/PEG/PLA/NTG/AuNPs hydrogel group effectively protected against ischemic injury and inflammation in AMI, demonstrating a novel method for treating acute cardiac dysfunction.

Effect of ertugliflozin on left ventricular function in type 2 diabetes and pre-heart failure: the Ertu-GLS randomized clinical trial

BackgroundThe therapeutic effects of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcome are not fully understood. This study aimed to evaluate the efficacy and safety of ertugliflozin on cardiac function in people with type 2 diabetes and pre-heart failure.MethodsWe conducted a 24-week randomized, double-blind, placebo-controlled trial involving individuals with type 2 diabetes inadequately controlled with antidiabetic medications. Participants with left ventricular hypertrophy, E/e’ >15, or impaired left ventricular global longitudinal strain (LVGLS) were randomized 1:1 to receive either ertugliflozin (5 mg once daily) or a placebo. The primary outcome was the change in LVGLS. Secondary outcomes included changes in left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Prespecified exploratory outcomes, including angiotensin-converting enzyme 2 (ACE2) and angiotensin (1–7) levels, were also assessed.ResultsA total of 102 individuals (mean age, 63.9 ± 9.2 years; 38% women) were included. The ertugliflozin group showed a significant improvement in LVGLS (− 15.5 ± 3.1% to − 16.6 ± 2.8%, P = 0.004) compared to the placebo group (− 16.7 ± 2.7% to − 16.4 ± 2.6%, P = 0.509), with a significant between-group difference (P = 0.013). Improvements in LVMI and LVEF were also observed. Additionally, significant reductions in HbA1c, systolic blood pressure, whole-body and visceral fat, uric acid, proteinuria, N-terminal pro–B-type natriuretic peptide, and lipoprotein(a) were noted. ACE2 and angiotensin (1–7) levels significantly increased in the ertugliflozin group compared to the placebo group and correlated with changes in LVGLS [r = 0.456, P < 0.001 for ACE2; r = 0.541, P < 0.001 for angiotensin (1–7)]. Adverse events were similar between the two groups.ConclusionsThis study demonstrated that ertugliflozin has beneficial effects on left ventricular function in individuals with type 2 diabetes and pre-heart failure, and it provided insights into potential underlying mechanisms.Clinical trial registration ClinicalTrials.gov Identifier: NCT03717194.

Echocardiographic Phenotype in Severe Aortic Stenosis With and Without Transthyretin Cardiac Amyloidosis: The AMY-TAVI Study.

The relative apical sparing pattern of left ventricular (LV) longitudinal strain (RELAPS]>1) has been described as a typical sign of cardiac amyloidosis (CA). The objective was to validate this pattern in concomitant CA and aortic stenosis (AS) and to identify new echocardiographic variables suggestive of CA in the presence of AS. 324 consecutive patients (age 81.5±5.8 years, 51% women) with AS who underwent transcatheter aortic valve implantation (TAVI) were prospectively included. 2D-Speckle-tracking echocardiography was performed. Following TAVI, 99mTc-DPD-scintigraphy and protein electrophoresis were performed to screen for CA. 38 patients (11.7%) showed cardiac uptake in scintigraphy: 14 patients (4.3%) with grade 1, 13 (4%) with grade 2, and 11 (3.4%) with grade 3. Patients with grades 2 and 3 (AS-CA group) had more LV hypertrophy (LV mass index: 188 vs.172 g/m2, p=0.032), lower transvalvular aortic pressure gradient (p<0.003), and higher prevalence of low-gradient AS (50% vs.19%, p=0.001), as well as greater diastolic and systolic dysfunction. Strain analysis was limited to 243 patients due to poor acoustic window and COVID-19 restrictions (81 lost: 79 in AS alone, 1 each in AS-DPD1 and AS-CA groups). RELAPS>1 was more prevalent in AS-CA group (74% vs.44%, p=0.006). An echocardiographic prediction model (GRAM score) for CA in the presence of AS, that is more sensitive and specific than RELAPS>1 alone, is proposed using the LV mass, maximum aortic gradient, and RELAPS>1, in addition to age (AUC:0.85, 95%CI: 0.77-0.93). RELAPS>1 is more prevalent in AS-CA but can occur in almost half of AS patients without CA, which reduces its value as a screening tool. A more sensitive and specific prediction score for CA in patients with severe AS is proposed.

Phenotypic expression, genotypic profiling and clinical outcomes of infantile hypertrophic cardiomyopathy: a retrospective study

BackgroundInfantile hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder. Apart from registries in high-income nations, there is a shortage of data on the aetiological basis of infantile HCM in low- and...

Distinguishing hypertensive cardiomyopathy from cardiac amyloidosis in hypertensive patients with heart failure: a CMR study with histological confirmation.

Differentiation of the cause of left ventricular hypertrophy (LVH) is challenging in cases with co-existing hypertension. CMR offers assessment of diffuse myocardial abnormalities via T1 mapping with extracellular volume fraction (ECV) and macroscopic fibrosis via late gadolinium enhancement imaging (LGE). The goal of the study was to understand if CMR parameters can differentiate hypertensive cardiomyopathy (HC) from cardiac amyloidosis (CA) in patients with hypertension and heart failure, using endomyocardial biopsy (EMB) as the gold standard. We retrospectively analyzed patients with hypertension, LVH, and heart failure undergoing EMB due to uncertain diagnosis. CMR parameters including cine, LGE characteristics, T1 mapping, and ECV were analyzed. A total of 34 patients were included (mean age 66.5 ± 10.7 years, 79.4% male). The final EMB-based diagnosis was HC (10, 29%), light chain (AL) CA (7, 21%), and transthyretin (ATTR) CA (17, 50%). There was a significant difference in subendocardial LGE (p = 0.03) and number of AHA segments with subendocardial LGE (p = 0.005). The subendocardial LGE pattern was most common in AL-CA (85.7%) and African American with HC (80%). ECV elevation (≥ 29%) was present in all patients with CA (AL-CA: 57.6 ± 5.2%, ATTR-CA: 59.1 ± 15.3%) and HC (37.3 ± 4.5%). Extensive subendocardial LGE pattern is not pathognomonic for CA but might also be present in African American patients with longstanding or poorly controlled HTN. The ECV elevation in HC with HF might be more significant than previously reported with an overlap of ECV values in HC and CA, particularly in younger African American patients.

Evaluation of global and regional myocardial work by echocardiography in patients with Fabry disease

BackgroundThis study aimed to quantitatively evaluate the left ventricular global and regional myocardial work of patients in Fabry disease (FD) by echocardiographic pressure–strain loop (PSL) analysis.ResultsThe study included 48 patients with FD and 48 healthy controls matched for age and sex. According to the presence/absence of left ventricular hypertrophy (LVH), the patients with FD were divided into an LVH + group and an LVH– group. Left ventricular blood pressure was estimated noninvasively according to echocardiographic valvular events and systolic pressure in the brachial artery. Left ventricular myocardial work parameters were acquired by echocardiographic pressure–strain loop analysis.The FD groups had a significantly lower global longitudinal strain (GLS), global work index, global work efficiency (GWE), global constructive work and higher global waste work than the control group (P < .05). Regional analysis showed that all segmental myocardial waste work increased and myocardial work efficiency decreased in the LVH + group than in the LVH– group (P < .05). Segmental longitudinal strain, myocardial work index, and myocardial constructive work were markedly lower in the basal and middle segments (P < .05) and preserved in the apical segments. Multivariate analysis revealed that GWE and GLS were significant related to LVH.ConclusionsMyocardial work analysis can be used to assess global and regional myocardial work in patients with FD. In this study, GLS and GWE were reduced in patients with FD and associated with the presence of LVH. Basal and middle myocardial work decreased in relation to the LVH, while apical myocardial work remained, which added value to explore the distribution of myocardial impairment.

Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians.

Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.

Apical Sparing of Longitudinal Strain as a Specific Pattern of Myocardial Fibrosis in Patients with Severe Left Ventricular Hypertrophy: A Comparison between Deformation Imaging and Histological Findings.

Objectives: This study aimed to investigate the correlation between apical sparing of longitudinal strain (LS), as measured by speckle-tracking echocardiography (STE), and the histological presence of myocardial fibrosis (MF), in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods: Twenty-seven HOCM patients who underwent elective Morrow procedures +/- aortic valve replacement (AVR) were included. All patients had standard echocardiography, with STE pre- and post-operatively. Intraoperative probes of the interventricular septum were sent for histological analysis. Correlation of different regional LS patterns with the histological findings of MF and with clinical outcome were analyzed. In addition, a logistic regression and ROC analysis were performed. Results: All patients underwent the Morrow procedure for HOCM, with 33.3% also undergoing AVR. A total of 74.1% showed evidence of MF in the histological analysis. Patients with MF had significantly lower GLS than patients without MF (-12.7 ± 2.7% vs. -23.0 ± 5.7%, p < 0.001). The LS in patients with MF was significantly lower at the basal regions of the LV segments and increased significantly towards the apex as compared to the patients without MF (mean basal-strain %: -10.6 ± 2.6 vs. -17.3 ± 4.6, p < 0.001; mean apical strain %: -21.8 ± 4.8 vs. -16.7 ± 5.6, p = 0.032). In the logistic regression, only the GLS remained as an independent predictor of MF with an Odds ratio of 1.07 (95%-CI: 1.05-1.09, p < 0.001). Conclusions: Our study highlights the significant correlation between GLS and MF in HOCM patients. These findings contribute to the growing understanding of MF in HOCM and may inform future approaches to patient management and risk stratification.