Development Of Left Ventricular Hypertrophy Research Articles

Fabry disease: development and progression of left ventricular hypertrophy despite long-term enzyme replacement therapy

BackgroundEnzyme replacement therapy (ERT) may halt or attenuate disease progression in patients with Anderson-Fabry disease (AFD). However, whether left ventricular hypertrophy (LVH) can be prevented by early therapy or may...

Aerobic Exercise Training Attenuates Differences between Black and White Adults in Left Ventricular-Vascular Coupling and Wasted Pressure Effort

Background: Black adults have a higher risk for left-ventricular hypertrophy and heart failure, when compared to white adults. This stems, in part, from their frequent potential alterations in ventricular-vascular coupling indexed by the arterial (Ea) to ventricular elastance (Ev) ratio and heightened wasted pressure effort (Ew). Exercise training preserves ventricular-vascular coupling and attenuates Ew, but whether this applies to black adults is unknown. Purpose: We hypothesized that aerobic training would attenuate reported racial differences in both left ventricular-vascular coupling and Ew. Methods: Fifty-four young adults [blacks= 24 (14 females); whites= 30 (15 females), aged: 19-35 years] completed an 8-week aerobic training intervention (3 times/wk, 65-85% peak oxygen uptake). Pre-and post-training systolic function and ventricular-vascular coupling were assessed via echocardiography. The Ew was estimated from pulse contour analysis. Pre-and-post-training changes were examined with linear mixed models. Results: Pre-training, blacks had higher Ev (difference (d) = 0.49, 95% CI: 0.14 to 0.84 mmHg/ml, p=0.007) and Ew (d= 1130, 95% CI: 477 to 1784 dyne cm−2 s, p<0.001). After training, both groups exhibited similar reductions in Ea (d= -0.22, 95% CI: -0.32 to -0.13 mmHg/ml, p<0.001). In white, but not black adults, Ev increased (dwhite= 0.30, 95% CI: 0.04 to 0.56 mmHg/ml , p=0.027) and Ea/Ev was reduced (dwhite= -0.21, 95% CI: -0.29 to -0.12 mmHg/ml, p<0.001). Conversely, black but not white adults exhibited reductions in Ew after training (dblack= -699, 95% CI: -1209 to -189 dyne cm−2 s, p=0.008). Systolic function markers (i.e., race-independent increases in ejection fraction) supported ventricular-vascular coupling results. Controlling for cardiorespiratory fitness, and body mass index attenuated training-induced changes in Ev and Ew, while controlling for sex did no change results. Conclusions: In black adults, Ew was reduced following 8 weeks of aerobic training, while Ea was reduced in both black and white adults. Although ventricular-vascular coupling was only altered in white adults, there was no difference between white and black adults in coupling or its components following training. Despite not controlling for social determinants of health shown to partly explain biological racial disparities, our data suggests a positive effect of aerobic training on risk factors associated with the development of left ventricular hypertrophy and heart failure in black adults. This study was funded by the National Instituteof Health (NHLBI 1R01HL093249-01A1 awarded to Bo Fernhall). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Incidence and risk factors for development of left ventricular hypertrophy in Fabry disease

BackgroundLeft ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of...

Novel Leptin-Cardiac TRH pathway responsible for the cardiac alterations in the Hyperleptinemic obesity.

The association between hypertension andobesity-induced cardiac damage is usually accepted.However, no studies have been focused on cardiac alterations in obesity, independently of blood pressure increase. It iswell known that Cardiac TRH induces Left Ventricular Hypertrophy (LVH) and fibrosis, and its inhibition prevents the development ofhypertrophy. Also, it has been described that the adiponectin leptin induces TRH expression. Thus, we hypothesized that in obesity, the increase in TRH induced by hyperleptinemia is responsible for LVH, until now mostly attributed to pressure load. We studied obese Agouti mice suffering from hypertension with hyperleptinemia and found a significant LVH development with increased TRH gene expression. Consequently, we found higher fibrotic (collagens and TGF-β) and hypertrophic markers (BNP and β-MHC) expressionvs lean black controls. As pressure could explain these results, we treated obese mice with diuretic (hydrochlorothiazide 20mg/kg/day) since weaning. Diuretic treatment was successful as the diuretic group was normotensive in contrast to control obese mice. Nevertheless, both groups showed LVH development, higher cardiac precursor TRH gene and peptide expressions and elevated fibrotic and hypertrophic markers expression,pointing out that obesity-induced LVH is not due to hypertension. In addition, we performed Cardiac TRH inhibition by specific siRNA injection compared to control siRNA treatment and evaluated cardiac damage. As expected, expressions and protein increase in hypertrophic and fibrotic markers observed in the AG mouse with the native cTRH system were not seen in the AG mouse with the cTRH silencing. Indeed, the AG + TRH-siRNA group showed hypertrophicmarkers expression and fibrosis measurements similar to the lean BL mice. On the whole, these results point out that the novel Leptin-Cardiac TRH pathway is responsible for the cardiac alterations present in hyperleptinemic obesity, independent of blood pressure, and cTRH long-term silencing since early stages totally preventLVH development and cardiac fibrosis.

Sacubitril/Valsartan Alleviates Cardiac Remodeling and Dysfunction in L-NAME-Induced Hypertension and Hypertensive Heart Disease.

There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male Wistar rats were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease.

Abstract P493: A Multivariate Analysis of Genetic Risk Scores for Heart Failure and Left Ventricular Mass Derived From Multi-Ancestry Populations and Left Ventricular Mass Amongst African Americans: The Jackson Heart Study

Background: Increased left ventricular (LV) mass is an outcome of LV remodeling that can result in development of left ventricular hypertrophy (LVH), a maladaptive disorder that increases the risk of heart failure. Elevated LV mass is a sensitive predictor of adverse cardiovascular events. African Americans experience a disproportionate burden of heart failure risk and development of LVH. The influence of genetics on this health disparity is unclear and a topic of interest. Genome-wide association studies (GWAS) have uncovered many variants associated with numerous adverse cardiovascular outcomes, such as heart failure and LV phenotypes. However, the relevance of these studies for African Americans may be limited as these analyses have been conducted in multi-ancestry populations with limited representation of African heritage. The question of whether these genetic risk variants can be used to predict LV phenotypes in an independent African American population remains unanswered. Hypothesis: Variant loci that have been associated with heart failure and LV mass in multi-ancestry populations will be associated with LV mass amongst African Americans in the Jackson Heart Study (JHS). Methods: Thirty-nine (39) SNPs associated with heart failure and ten (10) SNPs associated with LV mass were identified from two published studies in which participants of African ancestry or Black individuals comprised less than 15% and 2%, respectively. Using the published effect size estimates, genetic risk scores (GRSs) for heart failure and LV mass were computed for 2,175 African American participants (mean age 55, 63% female) in the JHS with complete data and consent for genetic research. We assessed the linear association of heart failure and LV mass GRSs with LV mass indexed to height (LVM h ) and indexed to body surface area (LVM bsa ). A multivariate general linear model was fit to both LVM h and LVM bsa containing both GRS predictors and accounting for age, sex, BMI (mean 31.5), diabetes (22%), and hypertension (52%). No multicollinearity was noted among these explanatory variables using variance inflation factors. Due to non-constant error variance, a log transformation was conducted on both LV mass response variables. Type III MANOVA Pillai tests were run to assess the effects of the GRSs on the log LVM bsa and log LVM h values. Conclusion: When accounting for age, BMI, sex, diabetes, and hypertension, we found that neither the heart failure GRS (p-val = 0.4012) nor the LV mass GRS (p-val = 0.8332) had an effect on both log LVM bsa and log LVM h . There is insufficient evidence to suggest that heart failure and LV mass variants derived from predominantly European multi-ancestry populations are linearly associated with log LV mass amongst African Americans in the Jackson Heart Study. Our work highlights the need for greater recruitment and targeted studies of populations with African ancestry for GWAS of LV phenotypes.

INFLUENCE OF LGALS-3 GENE POLYMORPHISM (rs2274273) ON THE PLASMA LEVELS OF GALECTIN-3 IN WOMEN WITH ESSENTIAL HYPERTENSION AND CHRONIC HEART FAILURE IN RESIDENTS OF THE PODILLYA REGION OF UKRAINE

Background. Individual genetic features can influence to formation of structural and functional changes in organs during EH and encourage the search for biological markers of the state of the myocardium and conclusions about their diagnostic effectiveness.
 Aim: to improve the early diagnosis of changes in the structure and function of the myocardium and the formation of prerequisites for chronic heart failure (CHF) in women with EH carriers of various polymorphic variants of the LGALS-3 gene (rs2274273), based on galectin-3 plasma level.
 Materials and methods. 180 postmenopausal women, average age 57,34±0,45, residents of the Podillya region of Ukraine were examined. The main group included 113 women with EH, of which 62 people had EH II, 51 people - EH with CHF C stage according to the ESH 2023 classification. The control group included 67 women without signs of cardiovascular pathology. In addition to the general clinical examination, the research used the enzyme immunoassay method to determine the level of galectin-3 in blood plasma, genotyping of the LGALS3 gene (rs2274273) by means of polymerase chain reaction, and ultrasound of the heart. The statistical processing of the obtained results was carried out using the package of statistical programs SPSS, STATISTICA v. 10.0. Using the MedCalc Software Ltd. Odds ratio calculator (https://www.medcalc.org/calc/odds_ratio.php) the conformity of the frequency distribution of genotypes in the studied population to the Hardy-Weinberg equilibrium was checked and calculated the odds ratio (OR) of the development of left ventricular myocardial hypertrophy (LVH) and CHF on the background of EH. The threshold levels of galectin-3 in blood plasma for the diagnosis of LVH and CHF were calculated using the ROC analysis method.
 Results. During study the frequency distribution of genotype variants of the galectin-3 gene (rs2274273) among women residents of the Podillya region of Ukraine, it was found that both in people without cardiovascular pathology and in patients with EH II and EH III, the GA genotype predominates, although there is a significant difference between the frequency of occurrence genotypes GA and GG are not noted (p>0.05). The AA genotype variant is significantly less frequent than both the GA and GG genotypes (p<0.01). The frequency distribution of genotype variants corresponds to the Hardy-Weinberg equilibrium. Moreover, the ratio between genotypes in patients of different stages of EH does not reliably differ from that in the control group. However, in EH complicated by CHF among patients with LVEF < 50% A allele carriers significantly predominate compared to GG homozygotes (79.31%, n=23 vs. 20.69%, n=6). In patients with EH, it was found that the concentration of galectin-3 in blood plasma in carriers of the A allele is significantly higher than in carriers of the GG genotype: EH without CHF - 16.82±0.54 ng/ml vs. 12.82±0.54 ng/ml (p<0.01); EH with CHF – 35.70±1.53 ng/ml vs. 25.39±1.38 ng/ml (p<0.001). The threshold levels of galectin-3 plasma concentrations, which indicate the presence of LVH and CHF, are significantly higher in carriers of the A allele than in carriers of the GG genotype.
 Conclusion. The carriers of the A allele of the LGALS3 gene (rs2274273) have a greater chance of developing CHF with a LVEF < 50% (OR 4.60; 95% CI 1.35 - 15.73 z statistic 2.43 p<0.01 χ2=6 .28; p=0.0122) and correspondingly higher levels of galectin-3 in blood plasma compared to carriers of the GG genotype.

ARTERIAL HYPOTENSION IN HEART FAILURE PATIENTS INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS

HighlightsArterial hypotension is a factor aggravating the course of heart failure in HIV-infected people in 18.3% of cases, more often accompanied by the development of left ventricular hypertrophy. The risk factor for the development of arterial hypotension in persons infected with the human immunodeficiency virus (HIV) and having HF is the concentration of caspase-6 in the blood serum, which probably indicates the intensification of apoptosis processes in cardiomyocytes. The value of the glomerular filtration rate, calculated by the CKD-EPI formula with the inclusion of the level of cystatin C in the blood serum, is associated with the development of arterial hypotension. AbstractAim. To study the features of arterial hypotension in HIV-infected patients with HF in comparison with patients with normal blood pressure.Methods. The study included 44 patients with arterial hypotension (AHT) and 76 patients with normal blood pressure (BP) with heart failure (HF) and HIV admitted to a multidisciplinary hospital. All patients underwent the same number of examinations conducted personally by the author: echocardiography, noninvasive arteriography, assessment of the severity of HF using the Clinical Status Assessment Scale by V. Yu. Mareeva, six-minute walk test. Additionally, studies such as the determination of the N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), cystatin C, caspase-6 and lipocaine 2 (NGAl) were conducted in a laboratory.Results. HIV-infected patients with HF are prone to developing AHT in 18.3% of cases. The results of the study indicate the predominance of males with low body mass index and high alcohol consumption in the group of patients with AHT. Moreover, patients with AHT are more likely to have pericardial effusion in front of the anterior wall of the right ventricle greater than 5 mm, anemia, unsuppressed viral load, left ventricular diastolic dysfunction and hypertrophy. At the same time, the level of cystatin C in their blood serum is lower, and the glomerular filtration rate is higher than in patients without AHT. The level of caspase-6 in the blood serum was significantly higher in the group of patients with AHT.Conclusion. HIV-infected patients with HF are prone to developing AHT in 18.3% of cases. The results of the study indicate a significant predominance of patients with LVH in the group of patients with AHT. The concentration of caspase-6 in blood serum equal to 148.35 pg/mL and higher turned out to be a risk factor for the development of AHT in HIV-infected patients with HF, probably indicating an intensification of apoptosis processes in cardiomyocytes. A glomerular filtration rate (GFR) equal to 47.5 mL/min/1.73 m2 and higher, calculated using the CKD-EPI formula with the inclusion of the level of cystatin C in the blood serum, is associated with a high probability of developing AHT. The pattern obtained may indicate both the activation of apoptosis processes against the background of AHT in the cells of the heart muscle, and the preservation of GFR against this background in patients with HF and HIV infection.

The significance of catestatin and relaxin-2 in the diagnosis of myocardial remodeling in patients with essential hypertension and type 2 diabetes mellitus

Objective — to evaluate the peculiarities of electrocardiographic (ECG) and echocardiographic (EchoCG) parameters in patients with essential hypertension (EH) in combination with type 2 diabetes mellitus (T2DM) and their relationships with plasma catestatin (CTS) and relaxin­‑2 (RLN­­2) levels.
 Materials and methods. Examinations involved 106 patients with EH, from whom 55 subjects had concomitant T2DM, and 30 practically healthy volunteers. The mean age of the participants was (64.06±8.44) years, and women prevailed in the patients’ group (55.9%). All study participants underwent anthropometric data measurement, laboratory and instrumental investigations. The levels of biomarkers CTS and RLN­­2 were determined with the enzyme‑linked immunosorbent assay. Instrumental investigations included electrocardiography and transthoracic echocardiography.
 Results. CTS levels were reduced in patients with concentric (5.04±1.14 ng/mL) and eccentric left ventricular hypertrophy (LVH) (5.08±0.89 ng/mL) compared with the normal geometry (6.63±0.73 ng/mL, p <0.001). The significant correlation has been established between CTS levels and ECG parameters of LVH (Cornell voltage criterion (r=–0.222; p=0.009) and Sokolow‑Lyon index (r=–0.226; p=0.008)), and EchoCG parameters, including LV end‑diastolic dimension (EDD (r=–0.388; p <0.001), LV end‑systolic dimension (ESD (r=–0.453; p <0.001), LV end‑diastolic volume index (EDVi (r=–0.329; p <0.001), LV end‑systolic volume index ESVi (r=–0.415; p <0.001), LV ejection fraction (EF (r=0.469; p <0.001), septal sickness (SS) (r=–0.593; p <0.001), posterior wall thickness (PWS) (r=–0.647; p <0.001), relative wall thickness (RWS) (r=–0.568; p <0.001), and LV myocardial mass index (LVMi) (r=–0.576; p <0.001). Patients with RLN­­2 ≥ 4.69 pg/mL had higher EchoCG parameters, including LV EDD, LV ESD, LV EDVi, LV ESVi, SV, SS, PWS, RWS, LVMi (p <0.05). In addition, a significant positive relationship between CTS and RLN­­2 levels has been revealed (r=0.191; p=0.026), which was also confirmed in the subgroup of patients with RLN­­2 levels above 4.69 pg/mL (r=0.585; p <0.001).
 Conclusions. The decrease in CTS levels at LVH and established correlations with the ECG signs of LVH and EchoCG parameters allow us to consider CTS as a predictor of the development of LVH, especially in patients with EH combined with T2DM.

Myocardial Interstitial Fibrosis in Hypertensive Heart Disease: From Mechanisms to Clinical Management.

Hypertensive heart disease (HHD) can no longer be considered as the beneficial adaptive result of the hypertrophy of cardiomyocytes in response to pressure overload leading to the development of left ventricular hypertrophy. The current evidence indicates that in patients with HHD, pathological lesions in the myocardium lead to maladaptive structural remodeling and subsequent alterations in cardiac function, electrical activity, and perfusion, all contributing to poor outcomes. Diffuse myocardial interstitial fibrosis is probably the most critically involved lesion in these disorders. Therefore, in this review, we will focus on the histological characteristics, the mechanisms, and the clinical consequences of myocardial interstitial fibrosis in patients with HHD. In addition, we will consider the most useful tools for the noninvasive diagnosis of myocardial interstitial fibrosis in patients with HHD, as well as the most effective available therapeutic strategies to prevent its development or facilitate its regression in this patient population. Finally, we will issue a call to action for the need for more fundamental and clinical research on myocardial interstitial fibrosis in HHD.

Epigenetic study of the differential phenotypic expression of a hypertrophic cardiomyopathy-related pathological variant at MYBPC3 in a cohort of monozygotic twins

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a inherited cardiac disease with a variable penetrance and expressivity. Epigenetics orchestrates the interplay between the environment and the molecular changes that lead to the development of the pathological phenotype. It is of great interest to identify the changes that determine the magnitude of left ventricular hypertrophy (LVH) in patients carrying a given pathogenic variant. Methods In this work, we used peripheral blood samples from a cohort of three homozygous twin pairs carrying the p.Gly263Ter pathogenic variant at MYBPC3 gene to suppress the underlying genetic effect and isolate the role of DNA methylation in its divergent phenotypic expressivity. Results We found a poorer life-style and a more anxious personality among the more severely affected patients. Using a pair-matched model corrected by cell type proportions, a total of 2486 differentially methylated positions (DMP) were extracted with moderate but proportional methylation changes to the LVH of the patients. DMP were enriched in functional regions controlled by repressor histone marks (H3K27me3, H3K9me3) and tended to colocalise forming differentially methylated regions (DMR) across genes mainly related to homophilic surface adhesion molecules and Ca2+ transport. Strikingly, many affected genes were found to be involved in LVH development, such as PLSCR2, ELMO3, TRIM68, HOXA5, UCN3, PCDHGA3, PAX8-AS1, suggesting that the analysis of blood samples could be able to recapitulate alterations at cardiac tissue level. Furthermore, the relationship of the observed changes with the development of the pathology was successfully validated with an external cohort of peripheral blood samples from healthy patients. Further studies are needed to validate the observed changes at cardiac tissue and to verify their causal role. Conclusions In this cohort of monozygotic twins we were able to identify promising epigenetic peripheral blood changes that relate to the expressivity of the HCM. Anxious personalities and lifestyle divergences could lie behind our findings. DNA methylation changes tend to locate at key positions related to cell-to-cell communication and Ca2+ metabolism, as well as at other loci already described to regulate LVH and stress.

Left atrial mechanics evaluated by two-dimensional strain analysis: alterations in essential hypertension.

Hypertension is a cardiovascular risk factor that predisposes to cardiac structural alterations namely increased left ventricular (LV) wall thickness, reduced LV compliance and diastolic dysfunction, with consequent left atrial (LA) dilation and functional impairment. In this article, we evaluated differences in left atrial structure and function using two-dimensional speckle tracking echocardiography in patients with hypertension compared with controls. This was a retrospective cross-sectional study of 208 hypertensive patients and 157 controls who underwent a comprehensive transthoracic echocardiogram. Patients with hypertension were stratified by the presence of left ventricular hypertrophy (LVH). Non-LVH hypertension patients had lower left atrial reservoir strain (LAS RES ) (34.78 ± 29.78 vs. 29.78 ± 6.08; P = 0.022) and conduit strain (LAS CD ) (19.66 ± 7.29 vs. 14.23 ± 4.59; P = 0.014) vs. controls despite similar left atrial volumes (LAV) . Left atrial contractile strain (LAS CT ) was not significantly different between non-LVH hypertension patients and controls (15.12 ± 3.77 vs. 15.56 ± 3.79; P = 0.601). Left atrial mechanical dispersion was significantly higher in the LVH group compared with the non-LVH hypertension group (42.26 ± 13.01 vs. 50.06 ± 14.95; P = 0.009). In multivariate regression analysis, LVH correlated with left atrial mechanical dispersion ( P = 0.016). An age-hypertension interaction independently correlated with LAS CT ( P < 0.001). Hypertension results in functional left atrial changes even before development of LV hypertrophy and structural left atrial changes with increased left atrial volume. We demonstrate both a likely hypertension-associated left atrial myopathy that prevents age-related compensatory increase in left atrial contractile function, and impact of LVH in hypertension on left atrial dyssynchrony.

Abstract 18294: The Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients With Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: The effect of intensive blood pressure (BP) lowering on cardiac remodeling remains uncertain, with emerging evidence suggesting that it can prevent the development of left ventricular hypertrophy (LVH) in patients with hypertension (HTN). We aim to investigate the effect of intensive BP lowering on LVH and cardiovascular disease (CVD) incidence in HTN patients. Methods: A systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through June 8 th , 2023. We used the random-effect model to pool dichotomous data using risk ratio (RR) and hazard ratio (HR), with a 95% confidence interval (CI). Trial sequential analysis (TSA) was performed to weigh type I and II errors, estimating if the effect is large enough to be unaffected by further studies. Results: We included four RCTs with a total of 20,747 patients. Two RCTs investigated an intensive target of &lt; 120 mmHg, and another two investigated &lt;130 mmHg. Intensive BP lowering was associated with a decreased risk of LVH incidence (RR: 0.66, with 95% CI [0.56 - 0.77]). Our TSA revealed that the cumulative Z-curve consistently crossed the TSA boundary, indicating a statistically significant effect, signifying that the available evidence has reached a predefined threshold for statistical significance, providing robust evidence. Also, intensive BP lowering was associated with a decreased risk of CVD (HR: 0.71, with 95% CI [0.60 - 0.85]). Conclusion: Intensive BP lowering protects against LVH in HTN patients. TSA suggests that additional RCTs may not be necessary to establish the efficacy of intensive BP lowering on LVH. Also, intensive BP lowering was associated with decreased CVD incidence; however, LVH did not explain this effect in the included RCTs. Therefore, further research is warranted to explore possible mechanisms of decreasing CVD with intensive BP lowering in HTN patients.

Abstract 14403: Echocardiographic Predictors of Phenotype Development in Hypertrophic Cardiomyopathy Mutation-Carriers

Introduction: Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by unexplained left ventricular (LV) hypertrophy (LVH). Genetic family screening of probands identifies mutation carriers (Gen+) without phenotype (Phen-), who require clinical follow-up. Hypothesis: Identification of early phenotype signs may facilitate clinical management of Gen+/Phen-. We assessed if echocardiography LV global longitudinal strain (GLS) and strain rate (SR) may predict LVH development in Gen+/Phen- HCM. Methods: We identified 16 Gen+/Phen- (25% women; age 20±11 years). Echocardiogram was performed at baseline, when no phenotype was evident, and repeated yearly. The end of follow up was the HCM diagnosis date in subjects who developed HCM (FU-Phen+) and the last visit date in those who didn’t develop HCM (FU-Phen-). Mitral inflow peak E and A velocities and Tissue Doppler E’ and A’ peak velocities were measured. LV GLS and SR-peak during isovolumic relaxation (SRIVR) were calculated offline independently by two investigators blind to the clinical data. Results: GLS and SRIVR were not age-dependent (p=0.08 and 0.55, respectively), whereas E/E’ ratio was directly related to age (p=0.011). During follow-up (8±5 years, interquartile range 5-10 years) 5 subjects became FU-Phen+. At baseline, FU-Phen+ compared to FU-Phen- were older and had higher maximal wall thickness, higher EF, less negative GLS and lower SRIVR (Table). Abnormal baseline GLS, despite a normal EF, and reduced SRIVR indicate reduced systolic deformation and covert diastolic dysfunction which may be caused by disarray preceding LVH and fibrosis. Conclusions: This is the first HCM preclinical study to compare at baseline HCM Gen+/Phen- subjects who will develop to those who will not develop LVH. We identified sensitive, easily obtainable, age- and load-independent echocardiographic predictors of phenotype development in HCM gene carriers who may undergo early preventive treatment.

Polymorphism of the coding gene LGALS-3 rs2274273 as an endogenous factor of the predictive effectiveness of the plasma concentration of galectin-3 in relation to the risk of development of chf on the background of eh in women

Objective. The purpose of the study is to improve the early diagnosis of the development of left ventricular myocardial hypertrophy (LVH) and the formation of prerequisites for chronic heart failure (CHF) in women with essential hypertension, residents of the Podillya region of Ukraine by determining the plasma concentration of galectin-3 in carriers of different polymorphic variants of the LGALS-3 (rs2274273) gene. Material and methods. 180 women of postmenopausal age, average age of 57.34±0.45, residents of the Podillya region of Ukraine, who lived in this territory in the third generation, were examined. The control group consisted of 67 women, average age of 56.43±0.64 years, without signs of cardiovascular pathology and signs of left ventricular hypertrophy (LVH) for other reasons were detected. The main group included 113 women with essential hypertension, of which 62 had essential hypertension with LVH without heart failure (EH II), 51 had essential hypertension with chronic heart failure stage C according to the ESH/ESC 2023 classification. General clinical examination, enzyme immunoassay method for determining the level of galectin-3 in blood plasma, genotyping of the LGALS3 (rs2274273) gene using polymerase chain reaction, and ultrasound of the heart were performed. The statistical processing of the obtained results was carried out using the package of statistical programs SPSS, STATISTICA v. 10.0. Mathematical methods were used: multiple regression stepwise analysis of proportional risks with 95% CI confidence interval, Fisher's linear discriminant analysis with the creation of a mathematical prognostic model, and cluster analysis. Compliance of the frequency distribution of genotypes in the studied populations to the Hardy-Weinberg equilibrium was checked using the MedCalc Software Ltd. Odds ratio calculator. https://www.medcalc.org/calc/odds_ratio.php and calculated the odds ratio (OR) of developing left ventricular myocardial hypertrophy (LVH) and chronic heart failure (CHF).Results. In patients with EH and CHF, carrying the A allele of the LGALS-3 (rs2274273) gene was associated with a more severe degree of diastolic dysfunction and reduced LVEF compared with carriers of the GG genotype, and higher plasma levels of galectin-3 were also recorded, which were associated with a more significant deterioration structural and functional indicators of the myocardium. With the help of cluster analysis, it was found that carriers of the A allele of the LGALS-3 (rs2274273) gene are more likely to be included in unfavorable cluster 1. In contrast, in cluster 2, with a more favorable course of the disease, carriers of the GG genotype and carriers of the A allele occur with almost the same frequency. Conclusions. In postmenopausal women, residents of the Podillya region of Ukraine, carrying the A allele of the LGALS-3 (rs2274273) gene is associated with a more severe course of EH with the development of LVH, a higher concentration of galectin-3 in the blood plasma, and the formation of CHF with reduced LVEF when compared with carriers of the genotype GG.

Exploring the Interactive Role of Parathyroid Hormone and Sodium Intake in Inducing Cardiac Hypertrophy in Rats: A Novel Study.

Background and objectives Previous research has suggested that hyperparathyroidism and excessive salt intake may contribute to the development of cardiac hypertrophy. This study aimed to investigate the relationship and underlying mechanisms between parathyroid hormone (PTH) and salt intake in the development of left ventricular hypertrophy (LVH). Additionally, the study sought to determine whether captopril intervention could reduce the impact of sustained PTH stimulation and excessive salt intake on LVH. Methodology We employed 40 eight-week-old male Sprague-Dawley rats, which were randomly assigned to eight groups: a sham group, a PTH group, a low-salt group (0.6% NaCl), a high-salt group (8% NaCl), a PTH + low-salt group, a PTH + high-salt group, a PTH + low salt + captopril group, and a PTH + high salt + captopril group. The rats were continuously infused with recombinant PTH (1-34) (2 pmol/kg per hour) via an osmotic pump for two weeks and were administered varying concentrations of saline for gavage over two weeks, according to their group. We monitored changes in blood pressure, measured heart weight, left ventricular wall thickness, and myocardial histological morphology, and assessed the relative expression of type III collagen. Results The PTH + high-salt group displayed a significant increase in blood pressure, heart weight, and left ventricular posterior wall thickness (P＜0.05), in addition to myocardial cell hypertrophy and increased Col III expression (P＜0.05), compared to other groups. Captopril intervention significantly reduced blood pressure (P＜0.05), ameliorated myocardial tissue morphology changes, and significantly decreased Col III expression (P＜0.05) but did not entirely reverse the increase in heart weight and left ventricular posterior wall thickness (P＞0.05). Conclusions Our findings suggest that the co-intervention of PTH and high salt can lead to an increase in blood pressure, heart weight, myocardial cell hypertrophy, LVH, and myocardial fibrosis levels in Sprague-Dawley rats. Captopril intervention can lower blood pressure and alleviate pathological myocardial tissue changes and myocardial fibrosis but cannot completely reverse LVH.

A machine learning-based score for precise echocardiographic assessment of cardiac remodelling in hypertensive young adults.

Accurate staging of hypertension-related cardiac changes, before the development of significant left ventricular hypertrophy, could help guide early prevention advice. We evaluated whether a novel semi-supervised machine learning approach could generate a clinically meaningful summary score of cardiac remodelling in hypertension. A contrastive trajectories inference approach was applied to data collected from three UK studies of young adults. Low-dimensional variance was identified in 66 echocardiography variables from participants with hypertension (systolic ≥160 mmHg) relative to a normotensive group (systolic < 120 mmHg) using a contrasted principal component analysis. A minimum spanning tree was constructed to derive a normalized score for each individual reflecting extent of cardiac remodelling between zero (health) and one (disease). Model stability and clinical interpretability were evaluated as well as modifiability in response to a 16-week exercise intervention. A total of 411 young adults (29 ± 6 years) were included in the analysis, and, after contrastive dimensionality reduction, 21 variables characterized >80% of data variance. Repeated scores for an individual in cross-validation were stable (root mean squared deviation = 0.1 ± 0.002) with good differentiation of normotensive and hypertensive individuals (area under the receiver operating characteristics 0.98). The derived score followed expected hypertension-related patterns in individual cardiac parameters at baseline and reduced after exercise, proportional to intervention compliance (P = 0.04) and improvement in ventilatory threshold (P = 0.01). A quantitative score that summarizes hypertension-related cardiac remodelling in young adults can be generated from a computational model. This score might allow more personalized early prevention advice, but further evaluation of clinical applicability is required.

Evolving Concept of Aortic Valve Replacement in Asymptomatic Patients With Severe Aortic Stenosis

BackgroundSurgical treatment of asymptomatic severe aortic stenosis (AS) has been gaining attention ever since the results of the Early Surgery Versus Conventional Treatment in Very Severe Aortic Stenosis (RECOVERY) and Aortic Valve replacement versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR) trials showed survival benefits with early surgical aortic valve replacement (SAVR). This study analyzed the long-term clinical and echocardiographic outcomes of SAVR in asymptomatic severe AS. MethodsBetween 2002 and 2020, 272 patients with asymptomatic severe AS and a left ventricular ejection fraction ≥50% underwent SAVR with or without concomitant aortic surgery and met the study criteria. The median follow-up was 8.5 years (interquartile range, 6-12.8 years), for a total of 2584 patient-years. The time course of the left ventricular mass index (LVMI) and the average E/E′ (ratio of the Doppler-derived E wave to the tissue Doppler-derived E′ wave) were assessed using 594 postoperative echocardiograms. The association of preoperative LVMI and average E/E′ with survival was assessed using Cox proportional hazards. ResultsThere was no operative mortality. On longitudinal analyses, LVMI improved in patients who presented with moderate or severe preoperative left ventricular hypertrophy (LVH). However, after the early decline in average E/E′, there was a late increase to greater than upper limit normal, particularly in patients with a preoperative average E/E′≥14. Postoperative survival was 100%, 94%, 84%, and 76% at 1, 5, 10, and 15 years, respectively, comparable to age- and sex-matched expected survival on the basis of the US general population. On adjusted Cox survival analysis, only moderate to severe LVH was associated with a survival penalty (hazard ratio], 2.32; 95% CI, 1.02-5.27; P = .045). ConclusionsIn asymptomatic patients with AS, SAVR restores survival and improves LVH, but patients with diastolic dysfunction are left with persistent dysfunction. Presentation with moderate or severe LVH at the time of surgery translated to a survival penalty. This observational study supports early SAVR in this population before development of LVH, although further investigation is needed.

Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension

BackgroundA dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes.MethodsTwo-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway.ResultsThe TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway.ConclusionsWe demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.

Distinguishing left ventricular hypertrophy from hypertrophic cardiomyopathy in adolescents - a longitudinal observation study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): MF: The South-Eastern Norway Regional Health Authority [grant number 2017207]. KHH, MKS: Norwegian Research Council [grant number 309762 ProCardio]. Background Distinguishing athlete´s heart from hypertrophic cardiomyopathy (HCM) can be challenging. There is a lack of data describing physiological and pathological remodelling in adolescents. Purpose The purpose of this study was to compare development of left ventricular (LV) hypertrophy in adolescent athletes to HCM genotype positive adolescents. Methods Athletes and age- and sex-matched HCM genotype positive adolescents underwent echocardiography at baseline and at follow-up, minimum two years later. Echocardiographic parameters were evaluated by pediatric reference values (Z-scores). LV hypertrophy was defined as Z-score &amp;gt;2 for intraventricular septum diameter (IVSd) or posterior wall thickness (LVPWd). Results Seventy-six athletes were compared to 63 (1 proband, 62 family members) HCM genotype positive adolescents (37% vs 44% female, p = 0.36, mean age baseline 12.1±0.2 vs 12.4±1.4 years, p = 0.10). Mean follow-up-time was alike by protocol (3.1±0.2 vs 3.2±1.3 years, p = 0.59). LV hypertrophy was found in a similar proportion of athletes and HCM genotype positive adolescents (28% vs 30% at baseline, p = 0.75, 30% vs 32% at follow-up, p = 0.80). Compared with athletes, interventricular septum was thicker in HCM genotype positive adolescents at baseline (Z IVSd 1.4±0.9 vs 2.7±5.2, p = 0.03). Left ventricular volumes were greater in athletes (Z LVEDV 1.0±0.6 vs −0.1±0.9, p&amp;lt;0.001). Septum thickness increased only in HCM genotype positive adolescents (Z IVSd progression rate −0.17(SE0.05), p = 0.001 vs 0.54(SE0.16), p = 0.001, p for interaction &amp;lt;0.001). There was no difference in LVPWd (0.6±1.3 vs 0.8±0.8, p = 0.13). Conclusions LV hypertrophy was observed in nearly 1/3 of both athletes and HCM genotype positive adolescents in the first longitudinal study comparing these populations. We found a significant difference in progression of LV hypertrophy, with increasing septum thickness only in the HCM genotype positive adolescents. These findings highlight the importance of repeated examinations to distinguish physiological from pathological remodelling.