Pressure-overload Left Ventricular Hypertrophy Research Articles

Renal Denervation Reduces Blood Pressure and Improves Cardiac Function: Results from a 12-Month Study.

Background Previous studies showed that a decline in BP can reverse pressure-overloaded left ventricular hypertrophy in the long term. Whether this structural remodeling and improved cardiac function were due to reduced BP levels or sympathetic tone is unclear. The aim of this study was to evaluate the efficacy of renal denervation (RDN) on cardiac function and left ventricular hypertrophy in patients diagnosed with resistant hypertension with systolic and diastolic dysfunction. Methods Thirteen patients diagnosed with resistant hypertension underwent bilateral RDN (RDN group), and 13 patients were selected as the control group (drug group) who received regular antihypertensive drugs for the first time. Demographic analysis and hematologic tests were performed to determine renal function as well as BNP levels. Echocardiogram was performed at baseline and 12 months after RDN. Results All the baseline characteristics are comparable in two groups. Both RDN and drug regiments resulted in significant reduction from baseline in SBP/DBP at 12-month follow-up (all P values < 0.01), and the decline due to two interventions showed no statistically significant difference (F = 1.64, P = 0.213 and F = 0.124, P = 0.853 for SBP and DBP, respectively). RDN significantly reduced mean LV mass index (LVMI) from 151.43 ± 46.91 g/m2 to 136.02 ± 37.76 g/m2 (P = 0.038) and ejection fraction (LVEF) increased from 57.15 ± 5.49% at baseline to 59.54 ± 4.18% at 12 months (P = 0.039). No similar changes were detected in the drug group (P values, 0.90 for EF and 0.38 for LVMI). Renal parameters including BUN, Cr, UA, and eGFR at baseline, 3 months, and 12 months showed no marked difference (P = 0.497, 0.223, 0.862, 0.075, respectively). Conclusions Our findings show that in addition to hypertension and its progression, elevated sympathetic hyperactivity is related to left ventricular hypertrophy and cardiac function.

The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy.

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.

Regional variations in ex-vivo diffusion tensor anisotropy are associated with cardiomyocyte remodeling in rats after left ventricular pressure overload

BackgroundPressure overload left ventricular (LV) hypertrophy is characterized by increased cardiomyocyte width and ventricle wall thickness, however the regional variation of this remodeling is unclear. Cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI) may provide a non-invasive, comprehensive, and geometrically accurate method to detect regional differences in structural remodeling in hypertrophy. We hypothesized that DTI parameters, such as fractional and planar anisotropy, would reflect myocyte remodeling due to pressure overload in a regionally-dependent manner.MethodsWe investigated the regional distributions of myocyte remodeling in rats with or without transverse aortic constriction (TAC) via direct measurement of myocyte dimensions with confocal imaging of thick tissue sections, and correlated myocyte cross-sectional area and other geometric features with parameters of diffusivity from ex-vivo DTI in the same regions of the same hearts.ResultsWe observed regional differences in several parameters from DTI between TAC hearts and SHAM controls. Consistent with previous studies, helix angles from DTI correlated strongly with those measured directly from histological sections (p < 0.001, R2 = 0.71). There was a transmural gradient in myocyte cross-sectional area in SHAM hearts that was diminished in the TAC group. We also found several regions of significantly altered DTI parameters in TAC LV compared to SHAM, especially in myocyte sheet angle dispersion and planar anisotropy. Among others, these parameters correlated significantly with directly measured myocyte aspect ratios.ConclusionsThese results show that structural remodeling in pressure overload LV hypertrophy is regionally heterogeneous, especially transmurally, with a greater degree of remodeling in the sub-endocardium compared to the sub-epicardium. Additionally, several parameters derived from DTI correlated significantly with measurements of myocyte geometry from direct measurement in histological sections. We suggest that DTI may provide a non-invasive, comprehensive method to detect regional structural myocyte LV remodeling during disease.

Abstract 753: Exercise Capacity, Cardiac fibrosis and Left Ventricular Remodeling in a Rat Model of Chronic Pressure Overload: Serial Echocardiography, Pressure-Volume Analysis and Gene Expression Profiling

Background: Pressure overload (PO) left ventricular (LV) hypertrophy is a known precursor of heart failure with preserved ejection fraction (EF). The aims of this study were to establish a reliable model of chronic PO in rats and verify the pathophysiological features of this model by evaluating cardiac function using serial echocardiography and a pressure-volume analysis. Methods: Constriction of the abdominal aorta was used to induce PO LV hypertrophy (n = 40) in rats. Twenty sham rats were compared with PO rats. Serial echo studies and exercise were performed at 2-week intervals, and invasive hemodynamic examination by a pressure-volume catheter system was performed 12 weeks after the procedure. The gene expression profiles of the left ventricle (LV) 12 weeks after the procedure were analyzed by DNA chip technology. Results: Serial echo revealed that the LV wall thickness began to increase after the PO and showed progressive increasing until the 8th week (LV septal wall thickness at 8 weeks 1.4mm±0.1mm for PO vs 0.6mm ±0.05mm for Sham, p &lt;0.01). LV dimension was comparable increased until 14 th week (LV end-systolic dimension at 14 weeks, 4.91±0.50 mm 4.71±0.25 mm for PO vs Sham; LV end-diastolic dimension, 9.02±0.42 mm vs. 8.71±0.47 mm for PO vs Sham, p&gt;0.05). The LV ejection fraction showed similar between groups until the 14th week (70.0±2.2% vs. 69.1±3.1% for PO vs. Sham). In hemodynamic analyses, the LV end-diastolic pressure and the end-diastolic pressure-volume relationship slope were greater in the PO group than sham group. When we compared LV remodeling and exercise capacity, cardiac fibrosis and exercise intolerance developed in the PO group but not in the sham group (exercise duration, 234.0 ± 80.3 vs. 597.8 ± 49.0 seconds, p &lt; 0.05, respectively). Transcriptional profiling of cardiac apical tissues revealed that gene expression related to the cardiac fibrosis, cytoskeletal pathway and G-protein signaling genes were enriched in the PO group. Conclusions: We established a small animal model of chronic PO and verified its pathophysiological features. Cardiac fibrosis and cytoskeletal pathway were important pathways in the PO group and influenced exercise capacity. This model may provide a useful tool for future research on PO heart failure.

Dysregulation of proangiogeneic factors in pressure-overload left-ventricular hypertrophy results in inadequate capillary growth.

Background:Pressure-overload left-ventricular hypertrophy (LVH) is an increasingly prevalent pathological condition of the myocardial muscle and an independent risk factor for a variety of cardiac diseases. We investigated changes in expression levels of proangiogeneic genes in a small animal model of LVH.Methods:Myocardial hypertrophy was induced by transaortic constriction (TAC) in C57BL/6 mice and compared with sham-operated controls. The myocardial expression levels of vascular endothelial growth factor (VEGF), its receptors (KDR and FLT-1), stromal-cell-derived factor 1 (SDF1) and the transcription factors hypoxia-inducible factor-1 and 2 (HIF1 and HIF2) were analyzed by quantitative polymerase chain reaction over the course of 25 weeks. Histological sections were stained for caveolin-1 to visualize endothelial cells and determine the capillary density. The left-ventricular morphology and function were assessed weekly by electrocardiogram-gated magnetic resonance imaging.Results:The heart weight of TAC animals increased significantly from week 4 to 25 (p = 0.005) compared with sham-treated animals. At 1 day after TAC, the expression of VEGF and SDF1 also increased, but was downregulated again after 1 week. The expression of HIF2 was significantly downregulated after 1 week and remained at a lower level in the subsequent weeks. The expression level of FLT-1 was also significantly decreased 1 week after TAC. HIF-1 and KDR showed similar changes compared with sham-operated animals. However, the expression levels of HIF1 after 4 and 8 weeks were significantly decreased compared with day 1. KDR changes were significantly decreased after 1, 2, 4, 8 and 25 weeks compared with week 3. After 4 weeks post-TAC, the size of the capillary vessels increased (p = 0.005) while the capillary density itself decreased (TAC: 2143 ± 293 /mm2 versus sham: 2531 ± 321 /mm2; p = 0.021). Starting from week 4, the left-ventricular ejection fraction decreased compared with controls (p = 0.049).Conclusions:The decrease in capillary density in the hypertrophic myocardium appears to be linked to the dysregulation in the expression of proangiogeneic factors. The results suggest that overcoming this dysregulation may lead to reconstitution of capillary density in the hypertrophic heart, and thus be beneficial for cardiac function and survival.

Monitoring of Cardiac Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy with [18F]FDG MicroPET.

This study aims to analyze the left ventricular function parameters, scar load, and hypertrophy in a mouse model of pressure-overload left ventricular (LV) hypertrophy over the course of 8weeks using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) micro-positron emission tomography (microPET) imaging. LV hypertrophy was induced in C57BL/6 mice by transverse aortic constriction (TAC). Myocardial hypertrophy developed after 2-4weeks. ECG-gated microPET scans with [18F]FDG were performed 4 and 8weeks after surgery. The extent of fibrosis was measured by histopathologic analysis. LV function parameters and scar load were calculated using QGS®/QPS®. LV metabolic volume (LVMV) and percentage injected dose per gram were estimated by threshold-based analysis. The fibrotic tissue volume increased significantly from 4 to 8weeks after TAC (​1.67 vs. 3.91mm3; P=0.044). There was a significant increase of the EDV (4weeks: 54±15μl, 8weeks: 79±32μl, P<0.01) and LVMV (4weeks: 222±24μl, 8weeks: 276±52μl, P<0.01) as well as a significant decrease of the LVEF (4weeks: 56±17%, 8weeks: 44±20%, P<0.01). The increase of LVMV had a high predictive value regarding the amount of ex vivo measured fibrotic tissue (R=0.905, P<0.001). The myocardial metabolic defects increased within 4weeks (P=0.055) but only moderately correlated with the fibrosis volume (R=0.502, P=0.021). The increase in end-diastolic volume showed a positive correlation with the fibrosis at 8weeks (R=0.763, P=0.017). [18F]FDG-PET is applicable for serial in vivo monitoring of the TAC mouse model. Myocardial hypertrophy, the dilation of the left ventricle, and the decrease in LVEF could be reliably quantified over time, as well as the developing localized scar. The increase in volume over time is predictive of a high fibrosis load.

P1444Comparison of global myocardial function with 2 types of pressure-overload left ventricular hypertrophy using 2-dimentional speckle-tracking echocardiography

P1444Comparison of global myocardial function with 2 types of pressure-overload left ventricular hypertrophy using 2-dimentional speckle-tracking echocardiography

Abstract 12513: Comparison of Global Myocardial Function With 2 Types of Pressure-Overload Left Ventricular Hypertrophy Using Two-Dimentional Speckle-Tracking Echocardiography

Introduction: Left ventricular hypertrophy (LVH) secondary to hypertension and aortic stenosis (AS) are often considered together to be pressure overload hypertrophy. Comparisons of myocardial function by the 2 most common causes of LVH are limited. The global LV afterload that may be assessed by valvuloarterial impedance plays a detrimental effect on LV systolic function. Hypothesis: We hypothesized that important differences may exist in the myocardial function with these 2 origins of pressure-overload LVH. Methods: Global LV longitudinal strain (GLS) were measured using speckle-tracking echocardiography in 38 hypertensive LVH (H-LVH) patients and 36 patients with severe AS and preserved LV ejection fraction. To estimate the global LV afterload, we calculated the valvuloarterial impedance (Z va ) as the sum of the systolic arterial pressure and the mean transvalvular pressure gradient divided by the stroke volume index. Results: The patients were divided into two groups according to the level of Z va : low Z va (Z va &lt;3mmHg ml/m 2 , n=25) and high Z va (Z va ≥3mmHg ml/m 2 , n=49). GLS was reduced in the high Z va group (p&lt;0.05). The patients in the high Z va group were divided into two subgroups: AS group (n=28) and H-LVH group (n=21). Systolic blood pressure was higher in the H-LVH group than in the AS group (p&lt;0.0001). However, LV mass index and LV ejection fraction were not significantly differences. GLS was significantly reduced in the AS group (p&lt;0.0001). In the AS group, GLS was significantly correlated with Zva (r=0.44). However, there was no correlation between GLS and mean transaortic pressure gradient. Conclusions: Despite of similar global LV afterload and LV hypertrophy, myocardial LV longitudinal systolic function is impaired in patients with severe AS compared with H-LVH patients. However, there is no correlation between AS severity and LV longitudinal deformation. The magnitude of the global LV afterload as reflected by Z va is a powerful determinant of altered LV longitudinal deformation in severe AS patinets with preserved LV ejection fraction.

Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy.

The Dysregulation of Pro-angiogeneic Factors in Pressure-overload Left Ventricular Hypertrophy Results in Inadequate Myocardial Capillarization

Objective: Pressure-overload left ventricular hypertrophy (LVH) as observed in patients with aortic stenosis or arterial hypertension is the most common secondary diagnosis in cardiovascular patients. Untreated LVH is associated to increased myocardial susceptibility to an ischemia-reperfusion injury and results in progressive heart failure due to a vascular insufficiency. We investigated changes in the gene expression of factors related to angiogenesis in a mouse model.

Central Sympathoinhibition by Moxonidine Improves Prognosis in Rats with Hypertensive Heart Failure

Aim: Excessive sympathetic activity is associated with pathologies such as hypertension and heart failure (HF) [1]. Central sympathetic nervous system activity is an indicator of the prognosis of HF [2]. Although the central sympatholytic drug, moxonidine, is an established therapeutic strategy for hypertension [3], its benefits for hypertensive HF are poorly understood. The present study investigated the effects of central sympathoinhibition by moxonidine on hypertensive HF. Methods: As the model of hypertension-induced HF, we fed Dahl salt-sensitive (DS) rats with 8% NaCl diet from the age of 7 weeks [4]. Intracerebroventricular (ICV) infusion of moxonidine (Mox-ICV) or vehicle (Veh-ICV) was performed from 14 to 20 week-old, during the increased HF phase. We examined survival first of all, measured systolic blood pressure and heart rate with tail-cuff system and left ventricular (LV) function and remodeling by echocardiography every 2 weeks. And we measured 24-hour urinary norepinephrine excretion (uNE) as an index of sympathetic activity before and after the treatment. We also investigated LV performance by Millar catheter and pathological changes in LV at the end of the treatment. Results: Hypertension and pressure-overload LV hypertrophy were established by 13 week-old. At about 20 weeks of age, DS rats-treated with Veh-ICV experienced overt heart failure associated with sympathetic hyperactivity (Fig. 1). Mox-ICV treatment decreased uNE, suppressed LV dysfunction, remodeling and pathological changes compared with Veh-ICV treatment. Survival at 21weeks of age was significantly improved in DS rats-treated with Mox-ICV compared to Veh-ICV (76 vs. 23 %; p<0.05, n=17 and 28, respectively) (Fig. 2). Conclusion: Moxonidine-induced central sympathoinhibition prevented cardiac dysfunction and remodelling, and improved the prognosis in rats with hypertensive HF. Central sympathoinhibition can be effective for the treatment of hypertensive HF.

Quantitative PET Imaging Detects Early Metabolic Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy In Vivo

We proposed that metabolic remodeling in the form of increased uptake of the myocardial glucose analog (18)F-FDG precedes and triggers the onset of severe contractile dysfunction in pressure-overload left ventricular hypertrophy in vivo. To test this hypothesis, we used a mouse model of transverse aortic constriction (TAC) together with PET and assessed serial changes in cardiac metabolism and function over 7 d. Scans of 16 C57BL/6 male mice were obtained using a small-animal PET device under sevoflurane anesthesia. A 10-min transmission scan was followed by a 60-min dynamic (18)F-FDG PET scan with cardiac and respiratory gating. Blood glucose levels were measured before and after the emission scan. TAC and sham surgeries were performed after baseline imaging. Osmotic mini pumps containing either propranolol (5 mg/kg/d) or vehicle alone were implanted subcutaneously at the end of surgery. Subsequent scans were taken at days 1 and 7 after surgery. A compartment model, in which the blood input function with spillover and partial-volume corrections and the metabolic rate constants in a 3-compartment model are simultaneously estimated, was used to determine the net myocardial (18)F-FDG influx constant, Ki. The rate of myocardial glucose utilization, rMGU, was also computed. Estimations of the ejection fractions were based on the high-resolution gated PET images. Mice undergoing TAC surgery exhibited an increase in the Ki (580%) and glucose utilization the day after surgery, indicating early adaptive response. On day 7, the ejection fraction had decreased by 24%, indicating a maladaptive response. Average Ki increases were not linearly associated with increases in rMGU. Ki exceeded rMGU by 29% in the TAC mice. TAC mice treated with propranolol attenuated the rate of (18)F-FDG uptake, diminished mismatch between Ki and rMGU (9%), and rescued cardiac function. Metabolic maladaptation precedes the onset of severe contractile dysfunction. Both are prevented by treatment with propranolol. The early detection of metabolic remodeling may offer a metabolic target for modulation of hypertrophy.

A Designed Zinc-finger Transcriptional Repressor of Phospholamban Improves Function of the Failing Heart

Selective inhibition of disease-related proteins underpins the majority of successful drug–target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repressor as therapy for heart failure, and provide evidence that delivery of engineered ZFP TFs to native organs can drive therapeutically relevant levels of gene repression in vivo. Given the adaptability of designed ZFPs for binding diverse DNA sequences and the ubiquity of potential targets (promoter proximal DNA), our findings suggest that engineered ZFP repressors represent a powerful tool for the therapeutic inhibition of disease-related genes, therefore, offering the potential for therapeutic intervention in heart failure and other poorly treated human diseases.

Spatial variability in T-tubule and electrical remodeling of left ventricular epicardium in mouse hearts with transgenic Gαq overexpression-induced pathological hypertrophy

Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic Gαq overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in Gαq hearts were unchanged compared to wild-type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic Gαq overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium.

Increased angiogenesis as a mechanism for the preserved cardiac function in rats with chronic pressure overload

Reduced coronary reserve and left ventricular (LV) function are hallmarks of chronic pressure overload. In rats with 4–8 wks of transverse aortic constriction (TAC), the LV/aortic pressure gradient (145±7mmHg), was greater than that observed in most other models of TAC, but LV systolic wall stress was not significantly increased and LV ejection fraction, measured by echocardiography, was not decreased, but actually was enhanced, p&lt;0.05, compared with sham rats at 8 wks (79±3% vs. 73±1%). Coronary reserve, the increase in coronary flow velocity with adenosine measured echocardiographically, which is depressed in almost all models of LV hypertrophy, was preserved in TAC rats vs. sham. There was a significant increase, p&lt;0.05, in vascular endothelial growth factor (VEGF), measured by western blotting (11.9 vs. sham 3.3) and there were increased, p&lt;0.05, Ki67 positive endothelial cells in TAC rats (22±3 Ki67 positive/mm2) vs. sham (12±2 Ki67 positive/mm2), indicative of angiogenesis. Capillary density, quantified microscopically with isolectin staining, was also increased in TAC (480 units/mm2) vs. sham (397 units/mm2). Thus, this unusual model of chronic pressure overload LV hypertrophy in the rat demonstrated enhanced LV function and preserved coronary reserve, which in turn could be attributed to the increased angiogenesis.

Non-invasive assessment of interstitial myocardial fibrosis in pressure-overload left ventricular hypertrophy

Non-invasive assessment of interstitial myocardial fibrosis in pressure-overload left ventricular hypertrophy Andrew Jabbour, Tevfik F Ismail, Sofia V De Noronha, Carl Shakespeare, Sameer Zaman, Oluwatosin Sotubo, Saman S Zaman, Callum Ettles, Benjamin Hewins, Rick Wage, Ankur Gulati, Pedro F Ferreira, Pierre Croisille, Yanqiu Feng, Katsuya Norita, Raad H Mohiaddin, Taigang He, John Pepper, David N Firmin, Mary Sheppard, Dudley J Pennell, Mario Petrou, Sanjay K Prasad

Whole-exome sequencing and an iPSC-derived cardiomyocyte model provides a powerful platform for gene discovery in left ventricular hypertrophy.

Rationale: Left ventricular hypertrophy (LVH) is a heritable predictor of cardiovascular disease, particularly in blacks. Objective: Determine the feasibility of combining evidence from two distinct but complementary experimental approaches to identify novel genetic predictors of increased LV mass. Methods: Whole-exome sequencing (WES) was conducted in seven African-American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT) using Illumina HiSeq technology. Identified missense or nonsense (MS/NS) mutations were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and familial relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (induced pluripotent stem cell-CM) were stimulated to induce hypertrophy; mRNA sequencing (RNA-seq) was used to determine gene expression differences associated with hypertrophy onset. Statistically significant findings under both experimental approaches identified LVH candidate genes. Candidate genes were further prioritized by seven supportive criteria that included additional association tests (two criteria), regional linkage evidence in the larger HyperGEN cohort (one criterion), and publically available gene and variant based annotations (four criteria). Results: WES reads covered 91% of the target capture region (of size 37.2 MB) with an average coverage of 65×. WES identified 31,426 MS/NS mutations among the 21 individuals. A total of 295 MS/NS variants in 265 genes were associated with LVMHT with q-value <0.25. Of the 265 WES genes, 44 were differentially expressed (P < 0.05) in hypertrophied cells. Among the 44 candidate genes identified, 5, including HLA-B, HTT, MTSS1, SLC5A12, and THBS1, met 3 of 7 supporting criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH. THBS1 gene expression was 34% higher in hypertrophied cells (P = 0.0003) and a predicted conserved and damaging NS variant in exon 13 (A2099G) was significantly associated with LVHMT (P = 4 × 10−6). Conclusion: Combining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci.

The effect of telmisartan on the metabolism of cardial type I collagen of rat with pressure-overloaded left ventricular hypertrophy

Objective: This study is aimed to explore metabolic characteristics of type I collagen of rats with pressure-overloaded left ventricular hypertrophy and the effect of telmisartan intervention. Methods: 24 male Sprague–Dawley rats were randomly divided into three groups: sham-operation group (n=8), left ventricular hypertrophy group (n=8) and telmisartan group (n=8). Abdominal aorta constriction operation was performed to construct rat model of hypertensive left ventricular hypertrophy. Rats in each group were killed after 4weeks of treatment to weigh their body and their left ventricular, and then left ventricular mass index (LVMI) was calculated.

38 Does interaction between peroxisome proliferator-activated receptor-α and NADPH oxidases play an important role in regulating pressure-overload cardiac hypertrophy?

Activation of NADPH oxidases and deactivation of peroxisome proliferator-activated receptor-α (PPAR-α) are known individually to play key roles in the development of left ventricular hypertrophy (LVH). Interestingly, it appears that...

Beneficial effect of eNOS overexpression on pressure overload induced cardiac hypertrophy and dysfunction unmasked by ROS scavenging

Although initiated as a compensatory mechanism, left ventricular hypertrophy (LVH) resulting from pressure overload increases the risk for heart failure. Nitric Oxide (NO) constitutes an important protective molecule against LVH possibly in part by its ability to scavenge reactive oxygen species (ROS). We previously showed NO to be protective after myocardial infarction. However, whether additional NO attenuates pressure overload LVH and the role therein of reducing ROS levels, is currently unknown. Consequently, we studied the effect of endothelial NO synthase (eNOS) overexpression on LVH and left ventricular (LV) function after transverse aortic constriction (TAC) in mice in the absence and the presence of the ROS scavenger N-acetyl cysteine. In wildtype mice, TAC induced marked LVH, LV dysfunction and pulmonary congestion. eNOS overexpression had no effect on LV geometry and function in sham-operated animals and surprisingly failed to protect against overload induced LVH while even aggravating LV dysfunction. Scavenging of ROS, which had no beneficial effects in wildtype TAC mice, reduced LVH and pulmonary congestion and improved LV function in eNOS transgenic TAC mice. In conclusion, eNOS overexpression increases rather than reduces ROS levels after TAC, possibly as a result of eNOS uncoupling. Consequently, ROS scavenging unmasked the beneficial effects of eNOS. Supported by NHF grant 2007B024