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Cardiovascular Research Feb 2020In patients with pulmonary hypertension, right ventricular hypertrophy (RVH) is a detrimental condition that ultimately results in right heart failure and death. The...
AIMS
In patients with pulmonary hypertension, right ventricular hypertrophy (RVH) is a detrimental condition that ultimately results in right heart failure and death. The ubiquitin proteasome system has been identified as a major protein degradation system to regulate cardiac remodelling in the left heart. Its role in right heart hypertrophy, however, is still ambiguous.
METHODS AND RESULTS
RVH was induced in mice by pulmonary artery banding (PAB). Both, expression and activity of the proteasome was found to be up-regulated in the hypertrophied right ventricle (RV) compared to healthy controls. Catalytic inhibition of the proteasome by the two proteasome inhibitors Bortezomib (BTZ) and ONX-0912 partially improved RVH both in preventive and therapeutic applications. Native gel analysis revealed that specifically the 26S proteasome complexes were activated in experimental RVH. Increased assembly of 26S proteasomes was accompanied by elevated expression of Rpn6, a rate-limiting subunit of 26S proteasome assembly, in hypertrophied cardiomyocytes of the right heart. Intriguingly, patients with RVH also showed increased expression of Rpn6 in hypertrophied cardiomyocytes of the RV as identified by immunohistochemical staining.
CONCLUSION
Our data demonstrate that alterations in expression and activity of proteasomal subunits play a critical role in the development of RVH. Moreover, this study provides an improved understanding on the selective activation of the 26S proteasome in RVH that might be driven by the rate-limiting subunit Rpn6. In RVH, Rpn6 therefore represents a more specific target to interfere with proteasome function than the commonly used catalytic proteasome inhibitors.
Topics: Animals; Disease Models, Animal; Heart Ventricles; Humans; Hypertrophy, Right Ventricular; Inflammation Mediators; Mice; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Signal Transduction; Ubiquitination; Ventricular Function, Right; Ventricular Remodeling
PubMed: 31020333
DOI: 10.1093/cvr/cvz103 -
Clinical Journal of the American... Nov 2016Prior studies suggested that women with CKD have higher risk for cardiovascular disease (CVD) and mortality than men, although putative mechanisms for this higher risk... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Prior studies suggested that women with CKD have higher risk for cardiovascular disease (CVD) and mortality than men, although putative mechanisms for this higher risk have not been identified. We assessed sex differences in (1) CVD risk factors and left ventricular hypertrophy (LVH), and (2) the relationship of left ventricular mass (LVM) with different measures of body size in children with CKD.
DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS
The study population comprised 681 children with CKD from the Chronic Kidney Disease in Children cohort, contributing 1330 visits. CVD risk factors were compared cross-sectionally by sex. LVH was defined as LVM/height >95th percentile and LVM relative to estimated lean body mass (eLBM) >95th percentile for age and sex. Differences in LVM by sex were assessed by adjusting for age, weight, height, and eLBM using bivariate and multivariate regression models.
RESULTS
Girls were less likely to have uncontrolled hypertension (26% versus 38%, P=0.001), had lower diastolic BP z-scores (+0.3 versus +0.6, P=0.001), and had lower prevalence of high triglycerides (38% versus 47%, P=0.03) compared with boys. When LVH was defined by LVM indexed to height, girls had higher prevalence of LVH (16% versus 9%, P=0.01); when LVH was defined by LVM relative to eLBM, prevalence of LVH was similar between girls and boys (18% versus 17%, P=0.92). In regression models adjusting for eLBM, no sex differences in LVM were observed.
CONCLUSIONS
Despite lack of increased prevalence of CVD risk factors, indexing LVM to height showed a higher proportion of LVH among girls, while estimates of LVH based on eLBM showed no sex differences. Indexing LVM to eLBM may be an alternative to height indexing in children with CKD.
Topics: Adolescent; Body Composition; Body Height; Body Weight; Child; Child, Preschool; Cohort Studies; Cross-Sectional Studies; Echocardiography; Female; Heart Ventricles; Humans; Hypertension; Hypertriglyceridemia; Hypertrophy, Left Ventricular; Male; Organ Size; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Sex Factors; United States; Young Adult
PubMed: 27630183
DOI: 10.2215/CJN.01270216 -
Journal of Molecular and Cellular... May 2018Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary...
BACKGROUND
Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary vascular resistance induces RV hypertrophy (RVH) and at term RV failure (RVF). However, the molecular mechanisms of RVH and RVF remain understudied. In this study, we gained insights into cytosolic Ca signaling remodeling in ventricular cardiomyocytes during the pathogenesis of severe pulmonary hypertension (PH) induced in rats by monocrotaline (MCT) exposure, and we further identified molecular candidates responsible for this Ca remodeling.
METHODS AND RESULTS
After PH induction, hypertrophied RV myocytes presented longer action potential duration, higher and faster [Ca] transients and increased sarcoplasmic reticulum (SR) Ca content, whereas no changes in these parameters were detected in left ventricular (LV) myocytes. These modifications were associated with increased P-Ser-phospholamban pentamer expression without altering SERCA2a (Sarco/Endoplasmic Reticulum Ca-ATPase) pump abundance. Moreover, after PH induction, Ca sparks frequency were higher in hypertrophied RV cells, while total RyR2 (Ryanodine Receptor) expression and phosphorylation were unaffected. Together with cellular hypertrophy, the T-tubules network was disorganized. Hypertrophied RV cardiomyocytes from MCT-exposed rats showed decreased expression of classical STIM1 (Stromal Interaction molecule) associated with increased expression of muscle-specific STIM1 Long isoform, glycosylated-Orai1 channel form, and TRPC1 and TRPC4 channels, which was correlated with an enhanced Ca-release-activated Ca (CRAC)-like current. Pharmacological inhibition of TRPCs/Orai1 channels in hypertrophied RV cardiomyocytes normalized [Ca] transients amplitude, the SR Ca content and cell contractility to control levels. Finally, we showed that most of these changes did not appear in LV cardiomyocytes.
CONCLUSIONS
These new findings demonstrate RV-specific cellular Ca cycling remodeling in PH rats with maladaptive RVH and that the STIM1L/Orai1/TRPC1/C4-dependent Ca current participates in this Ca remodeling in RVH secondary to PH.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Capillaries; Fibrosis; Glycosylation; Heart Ventricles; Hypertrophy, Right Ventricular; Inflammation; Monocrotaline; Myocytes, Cardiac; ORAI1 Protein; Protein Isoforms; Rats, Wistar; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Stromal Interaction Molecule 1; TRPC Cation Channels; Up-Regulation
PubMed: 29634917
DOI: 10.1016/j.yjmcc.2018.04.003 -
The American Journal of Forensic... Dec 2023Hypertrophy of the heart is assessed by heart weight (and dimensions) and myocyte hypertrophy. Establishing an association between the two may be useful in assessing...
Hypertrophy of the heart is assessed by heart weight (and dimensions) and myocyte hypertrophy. Establishing an association between the two may be useful in assessing hypertrophy in cases where there are limitations in assessing the heart weight. This preliminary study explored the association between the number of binucleated myocytes (a feature of myocyte hypertrophy) in a randomly chosen single high-power field of the left ventricular free wall and heart weight in an adult White population. It also compared the number of binucleated myocytes between cases with increased heart weight (>400 g in female and >500 g in male) and cases with normal heart weight. Heart weight and number of binucleated myocytes correlated significantly in male only. Increased heart weight had a significantly higher number of binucleated myocytes, with 8.5 binucleated myocytes being able to segregate cases with increased heart weight (74% sensitivity and 79% specificity). The results of this study showed the number of binucleated myocytes may have a complementary role in assessing hypertrophy of the heart.
Topics: Adult; Male; Female; Humans; Myocardium; Heart; Cardiomegaly; Heart Ventricles; Hypertrophy; Muscle Cells; Myocytes, Cardiac
PubMed: 37527350
DOI: 10.1097/PAF.0000000000000869 -
Clinical and Experimental Pharmacology... Nov 2014Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the...
Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the present study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity, and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 Wistar-Kyoto pregnant rats in late gestation giving rise to F1 restricted and control offspring, respectively. F1 control and restricted females were mated with normal males, resulting in F2 control and restricted offspring, respectively. F1 restricted male offspring were significantly lighter at birth (P < 0.05), but there were no differences in birthweight of F2 offspring. Left ventricular weights and volumes were significantly increased (P < 0.05) in F1 and F2 restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 restricted offspring. At 6 months-of-age, F1 and F2 restricted offspring had elevated blood pressure (8-15 mmHg, P < 0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 restricted male offspring, and this was transmitted to the F2 offspring. The findings support transgenerational programming effects.
Topics: Aging; Animals; Animals, Newborn; Birth Weight; Disease Models, Animal; Female; Fetal Growth Retardation; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Male; Organ Size; Placental Circulation; Placental Insufficiency; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Inbred WKY; Sex Characteristics
PubMed: 25199478
DOI: 10.1111/1440-1681.12303 -
Circulation. Arrhythmia and... Apr 2016
Review
Topics: Animals; Disease Management; Electrocardiography; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging, Cine; Prognosis
PubMed: 27009417
DOI: 10.1161/CIRCEP.115.003629 -
Journal of the American Heart... Sep 2015
Think Small and Examine the Constituents of Left Ventricular Hypertrophy and Heart Failure: Cardiomyocytes Versus Fibroblasts, Collagen, and Capillaries in the Interstitium.
Topics: Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Ventricular Remodeling
PubMed: 26374296
DOI: 10.1161/JAHA.115.002491 -
Echocardiography (Mount Kisco, N.Y.) Apr 2022Pregnancy is a process that can cause several physiologic changes to the cardiovascular system such as ventricular hypertrophy and dilation of cardiac chambers. Although...
INTRODUCTION
Pregnancy is a process that can cause several physiologic changes to the cardiovascular system such as ventricular hypertrophy and dilation of cardiac chambers. Although there are studies about pregnancy-related changes in echocardiographic examination; there is no data about the long-term effects of parity on these alterations. Therefore, we evaluated the long-term effect of pregnancy on right ventricular (RV) dilation and RV hypertrophy and their relation to the parity number.
METHODS
This prospective study included a total of 600 women (200 consecutive women who had no parity, 200 women who had a parity number of 1 to 4 and 200 women who had a parity number of more than 4). Right chambers' measurements were compared between the groups.
RESULTS
In echocardiographic analysis, RV and right atrial dimensions and areas and RV wall thickness were higher in parous women. On the other hand, RV systolic function parameters were significantly lower in parous women. These significant changes showed a gradual increase or decrease by increasing parity number. By multivariate hierarchical logistic regression analysis, the four independent factors that increased the risk of RV dilation were age (OR: 1.16 CI: 1.10-1.20), body mass index (OR: 1.05, CI: 1.02-1.08), smoking (OR: 1.87, CI: 1.28-4.02), and giving a birth (OR: 3.94 CI: 1.82-8.81). There was also independent relationship between the number of parity and RV hypertrophy even after adjustment for several confounders.
CONCLUSION
Pregnancy-related physiological changes mostly resolve after delivery. This study about long-term effects of pregnancy on RV has demonstrated that there is a significant relation between the number of parity and either RV dilation or RV hypertrophy. Each parity had also additive effect on these changes.
Topics: Female; Heart; Heart Ventricles; Humans; Hypertrophy, Right Ventricular; Parity; Pregnancy; Prospective Studies; Ventricular Dysfunction, Right; Ventricular Function, Right
PubMed: 35253268
DOI: 10.1111/echo.15333 -
Turk Kardiyoloji Dernegi Arsivi : Turk... Apr 2023Down syndrome is a genetic syndrome characterized with various dysmorphisms and congenital malformations such as congenital heart diseases. We aimed to evaluate the...
OBJECTIVE
Down syndrome is a genetic syndrome characterized with various dysmorphisms and congenital malformations such as congenital heart diseases. We aimed to evaluate the relationship between Down syndrome, hypothyroidism, and cardiac ���ndings.
METHODS
Thyroid hormone pro���les and echocardiographic ���ndings were evaluated. Patients with hypothyroidism and Down syndrome were named group 1; patients with hypothyroidism without Down syndrome group 2 and group 3 was control. The echocardiographic parameters (interventricular septum and left ventricular systolic, diastolic posterior wall thickness, left ventricular end-diastolic diameter, ejection fraction) were indexed to body surface area. Left ventricular mass index and relative wall thickness were calculated. Patients with relative wall thickness equal to or below 0.42 were classi���ed as eccentric hypertrophy or normal geometry, while those over 0.42 as concentric remodeling or concentric hypertrophy.
RESULTS
Thyroid stimulating hormone values of groups 1 and 2 were signi���cantly higher than those of group 3. There were no signi���cant di���erences for fT4 between the groups. Interventricular septum and left ventricular posterior wall end-diastolic and end-systolic thickness were signi���cantly higher in group 1 than groups 2 and 3. There was no statistically signi���cant di���erence in left ventricular mass index between groups 1 and 2. In terms of relative wall thickness, 16 out of 29 patients in group 1 were revealed as concentric remodeling, 12 as normal geometry, 1 patient as eccentric hypertrophy. In group 2, 6 patients were revealed as concentric remodeling, 14 as normal geometry. There was no statistically signi���cant di���erence of left ventricular end-diastolic thickness between 3 groups.
CONCLUSION
Cardiac morphology and functions were signi���cantly a���ected by hypothyroidism in patients with Down syndrome. Hypertrophy in Down syndrome may be caused by the cellular changes in myocardium.
Topics: Humans; Child; Down Syndrome; Heart; Echocardiography; Heart Ventricles; Hypertrophy; Hypothyroidism; Hypertrophy, Left Ventricular; Hypertension
PubMed: 36999332
DOI: 10.5543/tkda.2023.70337 -
The Journal of Physiology Jun 2017Heart size increases with age (called hypertrophy), and its ability to contract declines. However, these reflect average changes that may not be present, or present to...
KEY POINTS
Heart size increases with age (called hypertrophy), and its ability to contract declines. However, these reflect average changes that may not be present, or present to the same extent, in all older individuals. That aging happens at different rates is well accepted clinically. People who are aging rapidly are frail and frailty is measured with a 'frailty index'. We quantified frailty with a validated mouse frailty index tool and evaluated the impacts of age and frailty on cardiac hypertrophy and contractile dysfunction. Hypertrophy increased with age, while contractions, calcium currents and calcium transients declined; these changes were graded by frailty scores. Overall health status, quantified as frailty, may promote maladaptive changes associated with cardiac aging and facilitate the development of diseases such as heart failure. To understand age-related changes in heart structure and function, it is essential to know both chronological age and the health status of the animal.
ABSTRACT
On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodelling. Frailty was quantified as deficit accumulation in adult (≈7 months) and aged (≈27 months) C57BL/6J mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r = 0.67-0.55, P < 0.0003). Myocyte area also correlated positively with FI (r = 0.34, P = 0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (-dP/dt) declined with age and this was graded by frailty (r = -0.51, P = 0.0007; r = -0.48, P = 0.002; r = -0.56, P = 0.0002 for LVDP, +dP/dt and -dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca currents (r = -0.40, P = 0.008), lower gain (r = -0.37, P = 0.02) and reduced expression of Cav1.2 protein (r = -0.68, P = 0.003). These results show that cardiac hypertrophy and contractile dysfunction in naturally aging mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac aging.
Topics: Aging; Animals; Calcium; Cardiomegaly; Frailty; Heart Failure; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Sarcoplasmic Reticulum; Ventricular Function, Left; Ventricular Remodeling
PubMed: 28502095
DOI: 10.1113/JP274134