Left Ventricular Hypertrophy Research Articles

Correlation between indole-3-acetic acid and left ventricular hypertrophy in hemodialysis patients.

Among hemodialysis patients, left ventricular hypertrophy (LVH) is a prevalent cardiac abnormality. The uremic toxin indole-3-acetic acid (IAA) is elevated in uremia patients, but the connection between IAA and LVH in individuals undergoing hemodialysis remains uncertain. Hence, the objective of this research was to examine the correlation between blood IAA levels and LVH in individuals undergoing hemodialysis. In total, 205 individuals undergoing hemodialysis were chosen and categorized into two groups, with (143 patients) and without LVH (62 patients). Patient clinical data were collected, and serum creatinine, calcium, phosphorus, hemoglobin, and IAA levels were measured. Compared to the non-LVH group, the LVH group had higher IAA and serum phosphorus but lower hemoglobin. The serum IAA concentration was positively correlated with both left ventricular mass (LVM) and left ventricular mass index (LVMI) but negatively correlated with both left ventricular ejection fraction (LVEF) and the ratio of left ventricular transmitral early peak flow velocity to left ventricular transmitral late peak flow velocity (E/A). Logistic regression analysis indicated that increased IAA levels are a risk factor for LVH and are not influenced by other factors. In addition, we exposed primary neonatal cultured mouse cardiomyocytes to varying concentrations of IAA in a controlled environment. Cardiomyocyte hypertrophy was induced by IAA in a concentration-dependent manner. Serum IAA is correlated with alterations in both the function and structure of the left ventricle. The serum IAA concentration is an independent risk factor for LVH. IAA may be a novel biomarker of LVH in hemodialysis patients.

Characterization of a novel ovine model of hypertensive heart failure with preserved ejection fraction.

The lack of animal models which accurately represent heart failure with preserved ejection fraction (HFpEF) has been a major barrier to the mechanistic understanding and development of effective therapies for this prevalent and debilitating syndrome characterized by multisystem impairments. Herein, we describe the development and characterization of a novel large animal model of HFpEF in older, female sheep with chronic 2-kidney, 1-clip hypertension. At six weeks post-unilateral renal artery clipping, hypertensive HFpEF sheep had higher mean arterial pressure compared to similarly aged ewes without unilateral renal artery clipping (mean arterial pressure = 112.7±15.9 vs 76.0±10.1 mmHg, P < 0.0001). The hypertensive HFpEF sheep were characterized by (i) echocardiographic evidence of diastolic dysfunction (lateral e' = 0.11±0.02 vs 0.14±0.04 m/s, P = 0.011; lateral E/e' = 4.25±0.77 vs 3.63±0.54, P = 0.028) and concentric left ventricular hypertrophy without overt systolic impairment, (ii) elevated directly measured left ventricular end-diastolic pressure (13±5 vs 0.5±1 mmHg, P = 2.1x10-6), and (iii) normal directly measured cardiac output. Crucially, these hypertensive HFpEF sheep had impaired exercise capacity as demonstrated by their (i) attenuated cardiac output (P = 0.001), (ii) augmented pulmonary capillary wedge pressure (P = 0.026), and (iii) attenuated hindlimb blood flow (P = 3.4x10-4) responses, during graded treadmill exercise testing. In addition, exercise renal blood flow responses were also altered. Collectively, our data indicates that this novel ovine model of HFpEF may be a useful translational research tool since it exhibits similar and clinically relevant impairments as that of HFpEF patients.

Left Ventricular Hypertrophy in Women With a History of Preeclampsia.

As a hypertensive disorder of pregnancy, preeclampsia is associated with increased cardiovascular morbidity and mortality later in life. Since early signs of myocardial affection could indicate a higher risk of future cardiovascular disease manifestations, we investigated whether women with prior preeclampsia have a higher prevalence of left ventricular hypertrophy compared with women from the general population and to what extent chronic hypertension affects any potential difference. In a cohort study, women aged 40 to 55 years with prior preeclampsia were compared with age- and parity-matched women from the general population. They underwent a research cardiac computed tomography, and the primary outcome was left ventricular hypertrophy, defined as a left ventricular mass index >30 g/m2.7. In 679 women with prior preeclampsia and 672 controls (median age, 47 years), we found a higher prevalence of left ventricular hypertrophy (14.0% versus 6.4%) in the preeclampsia group with an odds ratio of 1.62, 95% CI (1.07-2.46), P=0.024, median of 15 years (range, 0-28) after pregnancy, after adjustment for cardiovascular risk factors, including chronic hypertension. Left ventricular hypertrophy was more frequent among women with preeclampsia with (26.2% versus 15.6%) and without (5.5% versus 2.4%) chronic hypertension, and a mediation analysis showed that chronic hypertension explained 22% of the association between preeclampsia and left ventricular hypertrophy. Women with prior preeclampsia had a 2-fold higher prevalence of left ventricular hypertrophy compared with women from the general population, and preeclampsia was independently associated with left ventricular hypertrophy, regardless of the presence of cardiovascular risk factors, including chronic hypertension. URL: https://www.clinicalTrials.gov; Unique identifier: NCT03949829.

Electrocardiographic strain and relationship with LV remodelling and clinical outcomes in patients with aortic stenosis undergoing transcatheter aortic valve implantation.

Left ventricular (LV) remodelling and fibrosis is known to occur in patients with aortic stenosis (AS) and is linked to post-intervention outcomes. These myocardial changes may be detected upon the routine 12-lead electrocardiogram by the presence of a LV strain pattern (LVS-ECG). Although LVS-ECG has been related to excessive cardiovascular morbidity and mortality in multiple patient populations, there is currently a dearth of data upon its impact in patients undergoing transcatheter aortic valve implantation (TAVI). The aim of the current study was to investigate the prevalence, predictors and prognostic value of LVS-ECG. Between 2012 and 2019, 640 consecutive patients underwent TAVI at Haukeland University Hospital, Bergen. Of these, 600 patients with severe AS were included in the TAVI-NOR study. Patients with known bundle branch block (n=85) or permanent pacing (n=25) were excluded, leaving 490 patients (mean age 81±6years, 52% females) eligible for the analyses. LVS-ECG was defined as down-sloping, convex ST-segment depression with asymmetric T-wave inversion in V5 or V6. LVS-ECG was present in 25.7% patients. Higher levels of NT-proBNP (OR 1.96; 95% CI:1.08-3.55, p=0.028), LVEF<50% (OR 3.14; 95% CI:1.61-6.13, p=0.001), increase in LV mass index per SD (32g/m2) (OR 1.37; 95 CI:1.06-1.76, p=0.014), and the presence of LV hypertrophy on ECG (OR 3.23; 95% CI:1.97-5.32, p<0.001) were independent predictors of LVS-ECG in the multivariable-adjusted analysis. Although all-cause mortality was significantly higher in patients with LVS-ECG compared to those without (54.8% vs 44.2%, p=0.041), the presence of LVS-ECG did not predict all-cause mortality during a median follow-up of 64±24 months (HR 1.05; 95% CI:0.79-1.39, p=0.742). Patients with LVEF <50% and concomitant LVS-ECG had a worse prognosis than those with LVEF >50% and no LVS-ECG (p<0.001). LVS-ECG may represent a simple marker of structural and functional LV remodelling that signals a propensity to excess mortality during long-term follow-up after TAVI, as it is strongly associated with other prognosticators such as reduced LVEF and increased levels of NT-proBNP.

Left ventricular myocardial deformation in patients on maintenance haemodialysis

Background Patients with chronic kidney disease (CKD) undergoing maintenance haemodialysis (MHD) develop several abnormalities of left ventricular (LV) structure and function. Speckle-tracking echocardiography permits compressive assessment of LV myocardial deformation. Previous studies involving CKD patients have shown a significant reduction in LV global longitudinal strain (GLS) with strong prognostic implications. However, the other components of LV deformation have not been fully elucidated. Methods A total of 90 CKD patients undergoing MHD (mean age 41.3 ± 12.5 years, 80% men) were compared with 45 apparently healthy age- and gender-matched controls. Results The CKD patients had a high prevalence (77.8% patients) of LV hypertrophy. They also had a significantly elevated ratio of early diastolic mitral inflow velocity to annular velocity (12.1 ± 4.6 vs. 7.1 ± 1.5, p < .001) indicating a high prevalence of LV diastolic dysfunction. LV ejection fraction (LVEF) was the same between the two groups, but the CKD patients had significantly impaired LVGLS (−17.8 ± 3.9 vs. −20.8 ± 2.6, p < .001), global circumferential strain (−14.0 ± 3.5 vs. −16.1 ± 3.4, p = .001), LV apical rotation (6.6 ± 4.7° vs. 8.8 ± 4.0°, p = .008) and LV twist (12.8 ± 6.1° vs. 15.0 ± 6.0°, p = .037). There was no difference in the global radial strain between the two groups. Conclusions The present study shows that CKD patients on MHD have significantly impaired LV longitudinal and circumferential mechanics despite preserved LVEF. The prognostic implications of reduced LVGLS have already been demonstrated previously. Future studies are needed to assess the prognostic implications of abnormal LV circumferential mechanics as well as their reversibility following renal transplant.

Abstract 4138292: Smoking cessation is linked to regression of electrocardiographic left ventricular hypertrophy

Introduction/Background: Electrocardiographic left ventricular hypertrophy is a strong predictor of cardiovascular morbidity and mortality. Further, smoking cessation provides a range of health benefits; however, its association with left ventricular hypertrophy is unclear. Research Questions/Hypothesis: What impact does smoking cessation have on left ventricular hypertrophy regression? Goals/Aims: We investigated the association between smoking cessation and regression of left ventricular hypertrophy. Methods/Approach: We compared electrocardiographic left ventricular hypertrophy between baseline and 6 years after smoking cessation follow-up visits in 752 non-hypertensive subjects (695 males, 47.8±9.2 years), from available datasets of 234 596 health check-ups. Left ventricular hypertrophy on ECG was assessed using the Sokolow-Lyon voltage criteria: SV1+RV5 (mV), with left ventricular hypertrophy defined as &gt;3.5 mV. Results/Data: After 6 years of smoking cessation, body weight was found to increase (from 65.7±10.5 to 68.1±10.8 kg, p &lt;0.0001) and systolic blood pressure also increased (from 112.9±12.7 to 122.0±14.2 mmHg, p &lt;0.0001). Nevertheless, left ventricular hypertrophy on ECG regressed significantly (from 2.47 to 2.41 mV, p &lt;0.0001), and the proportion fulfilling the criteria for left ventricular hypertrophy also decreased from 8.4 to 6.5%. In addition, the antihypertensive drug prescription rate due to elevated blood pressure after 6 years was 13.7% (103/752). Therefore, the regression of left ventricular hypertrophy with or without antihypertensive drug use was assessed. The results showed that left ventricular hypertrophy regressed significantly both [2.68→2.45 mV ( p &lt;0.0001)] and [2.44→2.40 mV ( p =0.01)] in the groups administered (n=103) and not administered (n=649) antihypertensive drugs, respectively. Conclusions: Smoking cessation was found to be associated with regression of electrocardiographic left ventricular hypertrophy, despite being potentially associated with future weight gain, increased blood pressure, and with or without antihypertensive drugs. The results indicated that the health benefits of left ventricular hypertrophy regression from smoking cessation may outweigh the negative effects of weight gain and increased blood pressure from smoking cessation.

Abstract 4137204: Classifying Left Ventricular Hypertrophy from ECG in Overall Population and Bundle Branch Blocks: Machine Learning Models are Superior to Published ECG Criteria

Background: Published ECG criteria for left ventricular hypertrophy (LVH) have low diagnostic yield, esp. with right/left bundle branch block (RBBB/LBBB). Machine learning (ML) may improve LVH classification. Hypothesis: ML performs better than published LVH criteria to classify LVH from ECG in overall population, and subgroups of RBBB/LBBB. Methods: In addition to standard ECG features like rates, intervals, axis etc., R, S and overall QRS amplitudes, and voltage-time-integrals were extracted from standard 12 leads and reconstructed vectorcardiographic X, Y, Z lead representative beats. Further, a variational autoencoder was used to extract latent encodings from the representative beats. ML algorithms (logistic regression, random forest, light gradient boosted machine, multilayered perceptron, residual network, and convolutional neural network) were trained to predict LVH (LV mass index women &gt;95, men &gt;115 g/m 2 ) from ECG features on a training set of adult ECGs and echocardiogram within 45 days of each other (general population N=240,476, RBBB n=22,110, LBBB n=12,563). We obtained ROC AUCs in a separate validation set for LVH classification by (a) individual ECG variables, (b) published LVH criteria and (c) ML models. Results: As shown in Tables 1-2 and Figure 1 , for LVH classification among the validation sets, AUCs were highest for ML models, intermediate for univariable models and least for published criteria (best ML model vs. best criteria: general population women 0.77 vs. 0.63, men 0.78 vs. 0.63; RBBB women 0.70 vs. 0.57, men 0.77 vs. 0.57; LBBB women 0.71 vs. 0.55, men 0.72 vs. 0.54). Conclusions: ML models perform better than published LVH criteria at classifying LVH from ECG in overall population, RBBB and LBBB.

Abstract 4131736: Myocardial Work in Patients with Systemic Arterial Hypertension: Correlation with Left Ventricular Mass and Aortic Strain Lidia Capotosto 1,2 , Enrico Mangieri 2 , Gaetano Tanzilli 2 , Giuseppe Placanica 2 , Attilio Placanica 2 , Fabio Miraldi 2 , Antonio Vitarelli 1,21 Department of Echocardiography, Cardiodiagnostica CS, Rome, Italy, 2 Department of Cardiology and Cardiac Surgery, Sapienza

Background: Myocardial work (MW) is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops and has been validated against invasively derived pressure-volume measurements. The purpose of the present study was to analyze whether systemic arterial hypertension is associated with abnormal left ventricular (LV) function assessed by myocardial work and how these changes are related to left ventricular hypertrophy (LVH) and aortic strain. Methods: We examined 86 hypertensive (mean age, 66±14 years, 51% male) and 86 sex- and age-matched healthy controls (mean age, 64±15 years, 53% male). Hypertensive patients were divided into two groups: patients without LVH (group-A) and patients with LVH (group-B, LVMI&gt;115g/m2 men, LVMI&gt;95g/m2 women). All of them had preserved LV ejection fraction. Global LV longitudinal strain (GLS) was calculated by speckle tracking echocardiography. The following indices of MW were assessed: global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). Corrected circumferential aortic strain (Ao-S) was calculated in the ascending aorta by two-dimensional speckle tracking echocardiography as global aortic strain /pulse pressure. Data analysis was performed offline (GE EchoPAC). Results: GWI and GCW were increased in group-A compared to controls (p&lt;0.05) and decreased in group-B (p=0.04). GWW was increased in group-A(p=0.02) and group-B(p&lt;0.001). GWE was decreased in group-A(p&lt;0.01) and group-B(p&lt;0.005). There was a positive correlation between GWE and Ao-S(r=0.51,p=0.03). GWE was independently associated with GLS(β=0.26,p=0.034), LV mass(β=0.31,p=0.02) and Ao-S(β=0.37,p=0.01) in the whole hypertensive population. At the receiver operating characteristic (ROC) analysis, optimal cutoff values of GWI, GLS, Ao-S, GWE and (GWE+Ao-S) discriminating LV hypertrophy were 0.7329, 0.7613, 0.8011, 0.8442 and 0.8986, respectively. Conclusions: Decreased GWE in systemic hypertension was related to aortic strain and occurred even in the absence of LV hypertrophy. Additional assessment of aortic strain improved the ability of myocardial work variables to differentiate patients with LVH, patients without LVH, and control subjects.

Abstract 4121733: Comprehensive Plasma Proteomics Profiling Identifies Circulating Biomarkers to Distinguish Hypertrophic Cardiomyopathy from Other Cardiomyopathies with Left Ventricular Hypertrophy

Introduction: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. It is sometimes challenging to distinguish HCM from other cardiomyopathies that cause left ventricular hypertrophy (LVH) such as hypertensive LVH, transthyretin cardiac amyloidosis (ATTR-CA), and aortic stenosis (AS). We aimed to identify a set of plasma protein biomarkers that distinguishes HCM from the other cardiomyopathies with LVH. Methods: In this multi-center case-control study, we conducted plasma proteomics profiling of 4,979 proteins in cases with HCM (n=879) and controls with hypertensive LVH (n=331), ATTR-CA (n=169), and AS (n=36). We identified clinical parameters that were significantly (univariable P&lt;0.05) different between HCM and hypertensive LVH. We then specified proteins that were significantly (multivariable P&lt;0.001) upregulated or downregulated in HCM compared to hypertensive LVH by performing multivariable logistic regression analysis on each protein adjusting for the identified clinical parameters (comparison #1). We performed the same analysis between HCM and ATTR-CA (comparison #2) as well as between HCM and AS (comparison #3). We identified proteins that were upregulated in HCM in all 3 comparisons. We also specified proteins downregulated in HCM throughout all 3 comparisons. Finally, using these proteins, we constructed a logistic regression model to distinguish HCM from all 3 control groups combined, and calculated an area under the receiver-operating-characteristics curve (AUROC). Results: Eight clinical parameters listed in Image 1 were significantly different between HCM and the controls and adjusted for in the multivariable logistic regression analyses. In the comparison between HCM and hypertensive LVH, 444 proteins were upregulated and 267 downregulated with multivariable P&lt;0.001 ( Image 1 ). There were 226 upregulated and 170 downregulated proteins comparing HCM with ATTR-CA, and 57 upregulated and 74 downregulated proteins when comparing HCM with AS ( Image 1 ). Among these proteins, 4 were upregulated in all 3 comparisons with multivariable P&lt;0.001 and 5 were downregulated ( Image 2 ). The logistic regression model with these 9 proteins had AUROC of 0.86 (95% confidence interval 0.84-0.88, Image 3 ). Conclusions: This study serves as the first to apply comprehensive proteomics profiling to identify circulating biomarkers that distinguish HCM from other cardiomyopathies with LVH independently from potential confounders.

Abstract 4147616: Targeting Skeletal Muscle Growth Improves Diastolic Dysfunction and Left Ventricular Hypertrophy in Obesity-Related Diabetic Cardiomyopathy

Background and Significance: Mice fed a high-fat, high-sucrose (HFHS) “Western” diet develop a cardiac phenotype similar to patients with type 2 diabetes mellitus-related heart failure with preserved ejection fraction (HFpEF). This includes obesity, insulin resistance, left ventricular hypertrophy (LVH), and diastolic dysfunction. Skeletal muscle is responsible for up to 80% of whole-body glucose disposal, making the relationship between muscle mass and insulin resistance crucial for identifying new therapeutic targets in HFpEF. Myostatin is an evolutionally conserved skeletal muscle growth-limiting signaling molecule. Although whole-body deletion of myostatin/activin signaling (MAS) promotes skeletal muscle hypertrophy (SH) and provides metabolic benefits, overall benefits are complicated by direct inhibition in the myocardium. Hypothesis: Sedentary mice with skeletal muscle-specific deletion of MAS will be protected from the adverse cardiac effects of HFHS diet. Methods and Results: BL6 mice with floxed alleles for myostatin Acvr2 and Acvr2b receptors were crossbred with mice expressing Cre recombinase from a myosin light chain promoter, rendering the MAS downregulation skeletal muscle specific. Four months of HFHS feeding resulted in similar increase in body weight between Cre+ and Cre- (34% and 37%, respectively). SH was present in Cre+ mice as the muscle weight/tibia length ratio of m. pectoralis, triceps and quadriceps was elevated by 44, 22 and 25%, respectively. Oral glucose tolerance was improved in Cre+ vs Cre-. Echocardiography showed improved LV hypertrophy and diastolic function (increased E/A ratio and Em by 27 and 21%) in the Cre+ group. Moreover, exercise capacity was improved in Cre+ mice by 59%. Conclusion: Our novel study demonstrates that targeting skeletal muscle growth through the inhibition of MAS, without direct cardiac effects, can ameliorate the cardiac dysfunction associated with obesity-related diabetic cardiomyopathy. Increased muscle mass improves glucose tolerance, LVH, and diastolic function, demonstrating skeletal muscle-to-myocardium cross-talk. This highlights the potential for muscle-targeted therapies in managing HFpEF, particularly in insulin-resistant conditions.

Abstract 4120929: Silent Myocardial Infarctions in Women with Ischemic Sudden Cardiac Death

Background: Sudden cardiac death (SCD) is a significant mode of death in both sexes, with most cases attributed to coronary artery disease (CAD). In women, ischemic SCD seems to occur more often without previously diagnosed CAD, but the prevalence and characteristics of silent myocardial infarctions (SMI) in women are not known. Aim: This study aimed to investigate the prevalence and characteristics of women with silent myocardial infarction (SMI) and ischemic SCD. Methods: The Fingesture study consists of 5,869 autopsy-verified SCD cases (21.1% women) in Northern Finland 1998-2017. In this study, we investigated women with ischemic SCD without previous CAD diagnosis (N=660). SMI was defined as a myocardial infarction (MI) scar at autopsy in the absence of CAD history in medical records. As a control group, we used women with ischemic SCD without MI scar and previous CAD diagnosis. Coronary artery stenosis, myocardial fibrosis, and MI scars were evaluated through macroscopic assessment during autopsy, with further histological verification for myocardial fibrosis and MI scars. Results: Among 660 ischemic SCD subjects without prior CAD diagnosis, 220 (33.3%) had SMI. Women with SMI were older compared to those without SMI (73.4 vs. 71.4 years in subjects without SMI, p=0.03), and SMIs became more prevalent with advancing age (+4.4% per decade, p&lt;0.01). Women with SMI had higher heart weight (411 vs. 386 g in subjects without SMI, p&lt;0.01) and a higher prevalence of left ventricular hypertrophy (LVH) (73.6% vs. 64.5% in subjects without SMI, p=0.02). The average body mass index was 27.1 kg/m 2 in subjects with SMI and 27.6 kg/m 2 in subjects without SMI (p=0.34). Subjects with SMI were more likely to have severe coronary artery stenosis with &gt;90% occlusion (37.3% vs. 22.5% in subjects without SMI, p&lt;0.01). Severe (15.0% vs. 3.0% in subjects without SMI, p&lt;0.01) and moderate (69.1% vs. 39.4% in subjects without SMI, p&lt;0.01) degrees of myocardial fibrosis were more prominent among subjects with SMI. Conclusions: One-third of ischemic SCD cases without prior CAD diagnosis in women had findings of SMI at autopsy. Women with SMI were slightly older and exhibited more severe coronary disease, LVH and myocardial fibrosis at autopsy. These findings underscore the importance of earlier diagnosis and treatment of CAD in SCD prevention in women.

Abstract 4137975: 9-Year Longitudinal Assessment of the 12-lead Electrocardiogram of Volunteer Firefighters

Introduction: In the US, the most common cause of death among active-duty firefighters is sudden cardiac death (SCD). Underlying heart diseases are important propagator of ventricular tachyarrhythmias that cause SCD. The objective of this abstract is to assess the incidence of underlying heart disease, identified on 12-lead electrocardiograph (ECG), that may place firefighters at greater risk of SCD. Methods: We digitalized 12-lead ECGs recorded among firefighters who visited a firefighter health screening program at least 4 times from 2011-2019. We extracted the interval measurements (Heart Rate, T-axis, QRS-axis, QRS duration, QTc duration) and interpretation statements from each of the 12-lead ECGs and grouped potential propagators of ventricular tachyarrhythmias including left ventricular hypertrophy (LVH), coronary artery disease (CAD), and cardiac conduction disease. We used simple mean imputation to handle missing data. Descriptive statistics including means and frequencies were used to analyze the sample. Results: Among 465 firefighters (90.1% male) with a mean age of 47.1 (±13.6) whom 1,296 12-lead ECGs were analyzed, 21.5% (n=278) of Heart Rate, 0.39% (n=5) T-axis, 26.4% (n=342) QRS-axis, 40.0% (n=518) QRS duration, 5.40% (n=70) QTc duration were abnormal. In addition to intervals, the 12-lead ECGs generated 1,970 interpretation statements of which 28.2% (n=555) were deemed possible pathoanatomical substrates including 3.1% (n=34) LVH, 24.7% (n=137) CAD, and 69.2% (n=384) cardiac conduction diseases. Among cardiac conduction diseases, intraventricular conduction disease was the most prevalent (n=204, 36.8%), followed by vertical axis (n=70, 12.6%), right bundle branch block (n=59, 10.6%), left anterior fascicular block (n=34, 6.1%), and left bundle branch block (n=17, 3.1%). Interestingly, we did not observe a temporal relationship regarding the number of pathoanatomical substrates over the screening period. Conclusions: Nearly 30% of the interpretation statements generated from 12-lead ECGs were indicative of possible pathoanatomical substrates that cause SCD, which reflects the apparently negative effect of fire suppression activity on one’s cardiopulmonary health. Our result justifies the imperative need of effective prevention method for cardiac conduction diseases among firefighters. Further research is needed to collect 12-lead ECG systematically amongst other measures such as diet and BMI which reflect work culture and lifestyle of firefighters.

Abstract 4139187: Electrophysiological and Mechanical Characterization of Human Ventricular Myocardium from Patients with Primary or Secondary Cardiac Hypertrophy

Left-ventricular hypertrophy (LVH) is an adaptive condition to hemodynamic stress often involving the left ventricle (LV). This pathological condition is associated with clinical complications such as ventricular arrhythmias and diastolic dysfunction, the molecular and cellular mechanisms of which have been poorly investigated in the human heart. We collected myocardial samples from the upper interventricular septum of 132 patients with hypertrophic cardiomyopathy (HCM), 42 patients with aortic stenosis and severe LVH (AoS-LVH) and 12 non-failing non-hypertrophic patients with valve disease (NF-NH), who underwent myectomy operations at our cardiac surgery center. Samples were used to isolate single viable cardiomyocytes from the left ventricle to perform patch-clamp electrophysiological studies and intracellular calcium measurements with fluorescent dyes. Intact trabeculae were also dissected to perform isometric force measurements of electrically-stimulated twitches. Single-cell patch-clamp studies revealed a marked prolongation of action potential duration (APD) in HCM (N=82, mean APD at 90% repolarization=763±252ms at 0.5Hz) and AoS-LVH (N=22, APD90%=579±147ms) samples with respect to NF-NH (N=12, APD90%=447±88ms). In both HCM and AoS-LVH cardiomyocytes, APD prolongation was associated with increased late-Na + current with respect to NF-NH, while L-type Ca 2+ current was enlarged only in HCM samples. Ca 2+ -fluorescence studies revealed markedly slower Ca-transient (CaT) kinetics in myocardial samples from HCM (N=38, mean CaT 50% decay time at 0.5 Hz = 658±179ms) and AoS-LVH patients (N=9, CaT50%= 568±187ms), when compared with NF-NH samples (N=8, CaT50%=283±59ms), paralleled by elevated diastolic [Ca 2+ ]. Twitch force measurements in intact trabeculae revealed prolonged isometric contractions in HCM (N=78, overall twitch duration at 0.5Hz= 730±147ms) and in AoS-LVH patient-samples (N=24, TwD=669±116ms), as compared with NF-NH (N=7, TwD=511±73ms). Force-frequency relationship was flat in pathological samples, while NF-NH trabeculae showed a clear increase in twitch amplitude while increasing pacing rate to 2Hz. Our results suggest that the main features of functional cardiomyocyte remodeling (that is, changes in the expression and/or function of ion-channel and EC-coupling proteins) are qualitatively similar in primary vs. secondary LVH, albeit abnormalities are quantitatively more extensive in HCM samples.

Abstract 4119472: Predictors of Sudden Cardiac Death in Patients with Atrial Fibrillation and No Apparent Risk Factor of Sudden Cardiac Death

Background: Atrial fibrillation (AF) is associated with sudden cardiac death (SCD). It is known that AF is associated with multiple traditional risk factors of SCD, such as coronary artery disease (CAD), history of myocardial infarction (MI), left ventricular hypertrophy (LVH) and low left ventricular ejection fraction (LVEF). However, AF per se could predispose SCD not mediated by these cardiovascular risk factors, and predictors of SCD in AF patients without these apparent SCD risk factors are unknown. Methods: Using the NTUH iMED database, AF patients without apparent SCD risk factors were longitudinal followed up from Jan. 2010 to Dec. 2021. The primary outcome was implantation of implantable cardioverter defibrillator (ICD) due to SCD. Cox regression was used to identify the predictors of SCD. Results: A total of 11250 AF patients without cardiovascular SCD risk factors and LVEF ≥55 % were longitudinally followed up. We first found CHA2DS2-VASc score did not predict SCD event. We found male gender (hazard ratio [HR ] 1.71 [1.05-2.78 ], p =0.032), hyperthyroidism (HR 3.50 [1.40-8.77 ], p=0.007）and paroxysmal AF (PAF)(HR 2.86 [1.63-5.04 ], p&lt;0.001）were associated with higher SCD risks. We created a AFSCD score using these parameters. We found SCD risk incrementally increased with increasing AFSCD score (p &lt;0.001 for trend). Patients with highest score (5 points) had more than 3-fold SCD risk compared with those with 0-point score (1.18 % person-year vs 0.36 %, p&lt;0.001). The C statistic of AFSCD score was significantly higher than CHA2DS2-VASc score (0.64 [0.57-0.70] vs 0.40 [0.33-0.48], p &lt;0.01). Conclusions: Male gender, hyperthyroid AF and PAF were predictors of incident SCD in AF patients and AFSCD scoring scheme based on these risk factors could possibly be implemented in clinical practice.

Abstract 4135531: The Ubiquitin-Specific Protease 30 Inhibitor, MTX652, Attenuates Cardiac Dysfunction And Remodelling In a Murine Model Of Transverse Aortic Constriction

Introduction: Mitochondrial abnormalities are a characteristic of heart failure leading to energy deprivation and disease worsening. The mitochondrial deubiquitinating enzyme USP30, removes ubiquitin and represses PINK1/PARKIN-mediated mitophagy leading to accumulation of dysfunctional mitochondria. In this study we investigated the role of MTX652, a clinical stage USP30 inhibitor, in a mouse model of cardiac hypertrophy using transverse aortic constriction (TAC). Hypothesis: Inhibition of USP30 will promote mitophagy resulting in clearance of dysfunctional mitochondria and improved cellular health leading to cardioprotective effects. Aims: To determine if MTX652 can protect from TAC induced cardiac hypertrophy and remodelling. Methods: Male C57BL/6 mice, 8 weeks old, were subjected to sham surgeries or TAC using a 26G needle to induce cardiac pressure overload. MTX652 (1.5 or 5 mg/kg, n =12-13) or vehicle ( n =11) was administered orally, twice daily, starting 2 days post-surgery. Captopril (30 mg/kg/d, n =13) was also included as a positive control. After 4 weeks, echocardiography assessed left ventricle (LV) function and morphology. Cell based assays assessed MTX652 target engagement and TOM20 ubiquitination in vitro. Results: LV hypertrophy and wall thickening was observed in TAC animals. Treatment with MTX652 decreased systolic LV volume (1.5 mg/kg p&lt;0.05 and 5 mg/kg p&lt;0.01) and diameter (1.5 mg/kg p&lt;0.01 and 5 mg/kg p&lt;0.05,) demonstrating comparable effects to Captopril. A reduction in anterior wall thickness in diastole was also observed with MTX652 (5 mg/kg, p&lt;0.01). Cardiac dysfunction was also evident in TAC animals with MTX652 showing improvements in both ejection fraction (1.5 mg/kg and 5 mg/kg, p&lt;0.0001) and fractional shortening (1.5 mg/kg and 5 mg/kg, p&lt;0.0001). Cellular target engagement for MTX652 was confirmed in HeLa-YFP-Parkin cells with an EC 50 of 2.7 nM ( n =2). Furthermore, the USP30 substrate TOM20 was ubiquitinated following MTX652 treatment in vitro (EC 50 =6.1 nM, n =4) providing evidence of mitophagy activation, a finding also confirmed in mouse heart tissue (MTX652, 5mg/kg). Conclusions: The USP30 inhibitor, MTX652 significantly protected mice from TAC induced cardiac hypertrophy and LV dysfunction. Furthermore, MTX652 potentiates ubiquitylation of TOM20 as a mechanism to promote mitophagy. These data suggest our clinical stage molecule could provide a novel therapeutic approach for the treatment of cardiac hypertrophy and heart failure.

Abstract 4138417: A Novel Echocardiography Risk Score Predicted Mortality In Patients With Heart Failure With Preserved Ejection Fraction.

Introduction: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit several echocardiographic abnormalities, including diastolic dysfunction, left ventricular (LV) hypertrophy, left atrial enlargement or pulmonary hypertrophy. It is not fully understood how these abnormalities are related with prognosis in HFpEF patients. Hypothesis: A combination of echocardiography parameters can predict clinical outcome in patients with HFpEF. Aims: This study aimed to develop a model to predict all-cause mortality in patients with HFpEF using echocardiography parameters. Methods: We analyzed data from 952 patients (81±9 years, 43% male) registered in the PURSUIT-HFpEF (Prospective, Multicenter, Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) study, a multicenter registry of patients hospitalized for acute decompensated HFpEF. Comprehensive echocardiography was performed before discharge. Patients were randomly assigned to the derivation and validation cohorts (2:1 ratio). Stepwise model selection was performed on age, sex and 26 echocardiography parameters to identify independent predictors of mortality. These predictors were used to construct a risk model for mortality. The accuracy of the risk score was validated using time-dependent ROC curves in both the derivation cohort (n=629) and in the validation cohort (n=323). Results: During the follow-up period (720 days, IQR: 376, 1100 days), all-cause death was observed in 248 patients (26.1%). Age, sex, diastolic (DWS), E/e’ ratio, LV mass index, LV posterior wall thickness (PWth), relative wall thickness (RWT), tricuspid regurgitant pressure gradient (TRPG) were selected as independent predictors of all-cause death. The score shown in the Table was applied to each factor, and the sum of the scores was calculated as the risk score. The AUC of the risk score for predicting 1-year mortality in the derivation cohort was 0.71 and the optimal cut-off value of 4.5 provided a sensitivity and specificity of 62.8% and 69.1%, respectively. The AUC for 1-year mortality in the validation cohort was 0.67. Conclusions: The novel echocardiography score effectively predicted mortality in HFpEF. This model could be a valuable tool for risk stratification.

Abstract 4129974: Increased Expression of Histone Deacetylases-2 and -6 in Left Ventricular Myocardium of Dogs with Chronic Heart Failure

Background: Histone deacetylases (HDACs) -2 and -6 are localized in the nucleus and cytoplasm of cells and have been implicated in the development of left ventricular (LV) hypertrophy, cardiac interstitial fibrosis, inflammation and worsening of LV systolic and diastolic function thus contributing to progressive worsening of heart failure (HF) with reduced ejection fraction (HFrEF) as well as HF with preserved ejection fraction (HFpEF). There is considerable interest in the application of small molecules that inhibit the activity of HDAC proteins in HF in the hope of fostering clinical benefit. Purpose: In the present study we examined the expression of HDAC-2 and -6 in LV tissue from normal (NL) dogs and dogs with chronic HF (LVEF &lt;35%) produced by multiple sequential intracoronary microembolizations. Methods: Studies were performed in LV tissue from 7 NL dogs and 7 HF dogs. HDAC-2 and -6 protein levels were determined by Western blotting in the lysate of homogenate and 9000g supernatant (cytosolic) fractions prepared from powder of approximately 200 mg frozen LV tissue. After determining the protein by Lowry method, approximately 30 μg homogenate and 15 μg supernatant for HDAC-2 and 8 μg protein for both homogenate and supernatant for HDAC-6 were separated on 4%-20% SDS-PAGE and transferred on PVDF membrane. Band intensities were quantified in densitometric units (du). All data were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Results: HDAC-2 proteins levels normalized to GAPDH were higher in the cytosol (0.59 ± 0.10 vs. 0.17 ± 0.04, p&lt;0.05 vs. NL) and homogenate (0.75 ± 0.12 vs. 0.55 ± 0.10, not statistically significant) of LV tissue of dogs with HF compared to NL dogs. HDAC-6 protein levels were higher in the homogenate (2.54 ± 0.36 vs. 0.57 ± 0.19, p&lt;0.05 vs. NL) and the cytosol (0.96 ± 0.15 vs. 0.78 ± 0.13, not statistically significant) of LV tissue of dogs with HF compared to NL dogs. Conclusions: These findings indicate upregulation of protein levels of HDAC-2 and -6 isoforms in LV myocardium of dogs with chronic HF. These abnormalities are likely to contribute to worsening HF. Selective inhibition of HDAC-2 and -6 represents a potential therapeutic approach for the treatment of both HFrEF and HFpEF.

Abstract 4139169: Treatment with methotrexate associated with LDL-like nanoparticles prevents the development of left ventricular fibrosis in a spontaneously hypertensive rat model

Introduction: Systemic arterial hypertension (SAH) can lead to left ventricle (LV) fibrosis and ventricular dysfunction. Methotrexate (MTX) associated with lipid nanoparticles (LDE) increases the cellular uptake of MTX by ninety-fold, which leads to therapeutic efficacy and reduces drug toxicity. Previously, treatment of rats with myocardial infarction with LDE-MTX decreased LV fibrosis and prevented ventricular dysfunction. The aim was to test LDE-MTX to preclude the development of cardiac damages caused by hypertension in spontaneously hypertensive rats (SHR). Methods: Twenty-four male rats with six-week-old were allocated in 3 groups: Control (CT): Wistar-Kyoto rats injected with saline; SHR: treated with LDE only and SHR-LDE-MTX: treated with LDE-MTX (1mg/Kg/week, I.P.). After 20 weeks of treatment, echocardiography, morphometry and protein expression were performed in the LV. The data were analyzed by ANOVA with Turkey’s post-test or Kruskal-Wallis test with Dunn's post-test. Linear regression was used to evaluate potential relationships. Results: Compared to CT, the two SHR groups showed dilation (increase in systolic and diastolic diameter); hypertrophy (increased thickness of the posterior wall) and systolic dysfunction (decreased ejection and shortening fractions). Furthermore, the SHR group showed increased LV fibrosis in both the interstitial region and the papillary muscle, possibly resulting from increased of type I collagen content. Treatment of SHR with LDE-MTX had no effect on LV dilation, hypertrophy or systolic dysfunction. However, LDE-MTX decreased LV fibrosis of the interstitial region and the papillary muscle. In addition, LDE-MTX increased the expression of MMP-2, and increased the bioavailability of intracellular adenosine, via increased expression of the adenosine A3 receptor. There was a negative correlation between the expression of the adenosine A3 receptor with interstitial fibrosis (r2=-0.31, p=0.03) and papillary muscle (r2=-0.47, p=0.03), indicating that the increased bioavailability of intracellular adenosine also contributed to the decrease in LV fibrosis in SHR. Conclusion: In SHR, treatment with LDE-MTX reduced LV fibrosis, possibly by modulating MMP-2 expression and increasing the bioavailability of intracellular adenosine, via the adenosine A3 receptor. These results suggest a therapeutic role for LDE-MTX in patients with LV fibrosis and heart failure caused by SAH, to be explored in future clinical studies.

Abstract 4112620: Cardiomyocyte-specific Increases in Forkhead Box M1 (FoxM1) Expression May Promote Cardiomyocyte Proliferation and Improve Recovery from Myocardial Injury in Mice and Pigs

Background: The cardiomyocytes (CMs) can not regenerate after myocardial infarction (MI) in adult mammals. FoxM1 is essential for cell proliferation. Targeted deletion of the Foxm1 in mice leads to serious cardiac proliferation defects and embryo death. The primary aim of this study was to demonstrate that the Specific Modified mRNA Translation System (SMRTs) can specifically overexpress FoxM1 in CMs and observe the benefits of overexpressing FoxM1 on myocardial repair in mice and pigs with myocardial injury. Methods: The FoxM1-CM SMRTs is composed of two modRNA constructs: one encoding L7Ae regulates the specific expression of FoxM1 on the other coding chain in CMs and inhibits its expression in non-cardiomyocytes through he CM-specific microRNAs miR-1 and miR-208 on L7Ae coding chain. Myocardial-specific expression of FoxM1-CM SMRTs and its proliferation-promoting effect were detected in hiPSC-CM (human-induced pluripotent stem cell-derived cardiomyocyte), mouse and pig models (days 3 after FoxM1-CM SMRTs treatment). In vivo experiments were conducted in both mouse and pigs with LAD (left anterior descending) ligation. The effects of FoxM1-CM SMRTs on cardiac function, MI size and hypertrophy in mice and pig models were detected after 4 weeks of FoxM1-CM SMRTs treatment. Results: FoxM1 was abundantly expressed in postmitotic CMs after transfection with the FoxM1-CM SMRTs, accompanied by activation of cell-cycle and proliferation markers (Ki67, PH3 and Aurora B kinase) and an increase in cell number. When the GFP-CM SMRTs was injected into mouse hearts with MI, GFP was only expressed in CMs, but not in non-CMs. Compared with the MI group, FoxM1-CM SMRTs significantly increased CM proliferation (days 3 after treatment administration in mice and pigs), improved left-ventricular ejection fractions (days 10 and 28 in both species) and hypertrophy, and reduced MI size (days 28 in both species). Conclusion: Intramyocardial injections of the FoxM1-CM SMRTs promoted CM proliferation, reduced MI size, and improved cardiac function in small and large mammals with acute myocardial infarction.

Abstract 4138491: Association of histologic findings with long-term outcomes in symptomatic obstructive hypertrophic cardiomyopathy patients undergoing surgical myectomy

Background: In hypertrophic cardiomyopathy (HCM), histologic findings like myocyte hypertrophy&amp;disarray, interstitial fibrosis (IF)&amp;small intramural coronary arteriole dysplasia (SICAD) account for the left ventricular hypertrophy, diastolic dysfunction, arrhythmogenicity&amp;microvascular ischemia. Objectives: To evaluate the association between histology&amp;outcomes in obstructive HCM (oHCM) patients undergoing surgical myectomy (SM). Methods: This was an observational study of 1722 symptomatic oHCM patients (mean age 56±14 years, 948 [55%] men) who underwent SM at a tertiary care center between 2005-18. Baseline clinical data was collected. The SM specimen was analyzed for presence&amp;severity of a) myocyte hypertrophy b) myocyte disarray c) IF&amp;d) SICAD. Histologic findings were graded as 0-3 (none, mild, moderate,&amp;severe)&amp;a score from 0-12 was calculated. Primary endpoint was a composite of death, appropriate defibrillator discharge or cardiac transplantation during follow-up. Results: 896 (52%) were in New York Heart Association (NYHA) class III/IV, 457 (21%) had exertional syncope, 727 (42%) had ≥1 sudden death risk factor&amp;409 (24%) had atrial fibrillation (AF). Moderate&amp;severe histologic findings were distributed as follows: myocyte hypertrophy (1341 [78%]), disarray (237 [14%]), IF (448 [26%])&amp;SICAD (258 [15%]). The mean total histologic score was 5.1±1.4. At 5.1±5.2 years, there were 352 (20%) primary events (317 [18%] deaths). On spline analysis (Figure 1A), a total histology score of ≥ 6 was associated with primary events. On Kaplan-Meier analysis (Figure 1B), patients with a histology score ≥ 6 had greater events vs. those with a score &lt;6 (147/598 [25%] vs. 205/1124 [18%], log-rank p-value 0.002). On multivariable Cox analysis, age (for 10-year increase, Hazard ratio or HR 1.49 [95% confidence interval or CI 1.35-1.65], p&lt;0.001), NYHA Class III/IV (HR 1.58 [95% CI -1.25-2.01], p&lt;0.001), AF (HR 1.65 [95% CI 1.30-2.10], p&lt;0.001)&amp;histology score ≥6 (HR 1.24 [95% CI 1.03-1.54], p=0.03) were independently associated with higher primary events. Conclusions: In symptomatic oHCM patients undergoing SM, a higher histologic score was independently associated with long-term outcomes.