Ventricular Hypertrophy In Response Research Articles

The inflammatory role of dysregulated IRS2 in pulmonary vascular remodeling under hypoxic conditions.

Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown previously that insulin receptor substrate 2 (IRS2), a molecule highly critical to insulin resistance and metabolism, has an anti-inflammatory role in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the hypothesis that IRS2 has an immunomodulatory role in human and experimental PH. Expression analysis showed that IRS2 was significantly decreased in the pulmonary vasculature of patients with pulmonary arterial hypertension and in rat models of PH. In mice, genetic ablation of IRS2 enhanced the hypoxia-induced signaling pathway of Akt and Forkhead box O1 (FOXO1) in the lung tissue and increased pulmonary vascular muscularization, proliferation, and perivascular macrophage recruitment. Furthermore, mice with homozygous IRS2 gene deletion showed a significant gene dosage-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy in response to hypoxia. Functional studies with bone marrow-derived macrophages isolated from homozygous IRS2 gene-deleted mice showed that hypoxia exposure led to enhancement of the Akt and ERK signaling pathway followed by increases in the pro-PH macrophage activation markers, vascular endothelial growth factor-A and arginase 1. Our data suggest that IRS2 contributes to anti-inflammatory effects by regulating macrophage activation and recruitment, which may limit the vascular inflammation, remodeling, and right ventricular hypertrophy that are seen in PH pathology. Restoring the IRS2 pathway may be an effective therapeutic approach for the treatment of PH and right heart failure.

Lumican deficiency promotes pulmonary arterial remodeling

Pulmonary arterial hypertension (PAH) is caused by progressive extracellular matrix disorganization and increased pulmonary vascular cell proliferation. Lumican is a member of the small leucine-rich proteoglycan family that controls cell proliferation, and is a potential endogenous modulator of TGF-β signaling pathway. We show that the decreased lumican protein levels in pulmonary arterial smooth muscle cells (PASMCs) is related to the vascular remodeling and stiffening observed in PAH. The role of lumican in PASMC accumulation and activation in response to pulmonary vascular remodeling remains unclear and we hypothesized that the loss of lumican in PASMCs promotes the development of PAH. Our aim was to establish that lumican plays a pivotal role in modulating pathological vascular remodeling in humans using a rat model of monocrotaline-induced PAH and chronically hypoxic mice. We found that mice with a homozygous deletion of lumican (Lum-/-) showed severe pulmonary arterial remodeling and right ventricular hypertrophy in response to hypoxia, and these effects in mice with chronic hypoxia-induced pulmonary hypertension were successfully treated by the administration of a lumican C-terminal peptide (LumC13C-A, lumikine). We identified a mechanistic link by which lumican signaling prevents the activation of phosphorylated AKT, resulting in the suppression of PASMC proliferation. Lumican deficiency promotes pulmonary arterial remodeling. Administration of lumikine reverses the PAH pathogenesis caused by hypoxia-induced experimental PAH. Lumican is an antiproliferative target that functions to suppress pAKT activation during pathogenesis.

Chronic Angiotensin 1-7 Infusion Prevents Angiotensin-II-Induced Cognitive Dysfunction and Skeletal Muscle Injury in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is increasingly viewed as a neurological disease accompanied by a systemic disorder. Accumulating evidence supports that angiotensin II and angiotensin 1-7 exert opposite effects on various organs including the brain. However, the interaction between angiotensin II and angiotensin 1-7 in AD remains to be defined. The present study was undertaken to examine the interaction between these peptides in AD. 5XFAD mice, a useful model of AD, were separated into three groups: 1) saline-infused, 2) angiotensin II-infused, and 3) angiotensin II-infused and angiotensin 1-7-co-infused. These peptides were systemically given to 5XFAD mice via osmotic minipump for 4 weeks. Systemic angiotensin II infusion for 4 weeks induced significant hypertension in both wild-type and 5XFAD mice. Angiotensin II induced cognitive abnormality in 5XFAD mice as estimated by the Morris water maze test and the nest building test, and this effect was associated with cerebral blood flow reduction, cortical arterial amyloid-β deposition, hippocampal inflammation, and neuron loss in 5XFAD mice. In addition, angiotensin II infusion led to gastrocnemius muscle atrophy in 5XFAD mice. Co-infusion of angiotensin 1-7 prevented the above mentioned detrimental effects of angiotensin II in the brain and gastrocnemius muscle in 5XFAD mice, without significant influence on blood pressure. The left ventricular hypertrophic response to angiotensin II was attenuated in 5XFAD mice compared with wild-type mice, which was not significantly altered by co-administration of angiotensin 1-7. Our results show that angiotensin 1-7 counteracts angiotensin II-induced cognitive impairment, brain injury, and skeletal muscle injury in AD mice.

Interleukin 6 modulates PPARα and PGC-1α and is involved in high-fat diet induced cardiac lipotoxicity in mouse

BackgroundInterleukin 6 (IL-6) may be involved in regulation of cardiac lipid metabolism and mitochondrial function through its influence on peroxisome proliferator-activated receptors (PPARs). In this study we evaluated the impact of the physiological level of IL-6 on the expression of PPARα and PGC-1α in the heart and the effect of lack of this cytokine on high-fat diet (HFD) induced lipotoxicity. MethodsMale C57BL6/J wild type (WT) and IL-6 knock-out (IL-6KO) mice were used. 20 animals of each genotype were fed with HFD for 15–18weeks. Cardiac function was assessed using echocardiography and cardiomyocyte ultrastructure was examined using electron microscopy. QT-PCR and Western blotting were applied to estimate the expression of PPARα and PGC-1α at the transcriptional and protein levels. ResultsAt baseline WT and IL-6KO mice had similar size and function of the left ventricle. HFD induced similar left ventricular hypertrophic response in both groups without causing heart failure, but only WT animals had increased resting ejection fraction of the LV. Ultrastructure of HFD groups showed markers of lipotoxicity, that were more pronounced in IL-6KO group. In basal conditions IL-6KO animals had lower PPARα and similar PGC-1α expression as compared to WT. HFD induced downregulation of both PPARα and PGC-1α in WT animals, while in IL-6KO mice this effect was constrained. ConclusionIL-6 is involved in basal regulation of PPARα and PGC-1α expression in cardiomyocytes. The lack of this cytokine promotes high-fat diet induced lipotoxicity but without overt manifestations of cardiac failure.

PM303 Gender Differences In Left Ventricular Hypertrophy In Response To Increased Body Weight

PM303 Gender Differences In Left Ventricular Hypertrophy In Response To Increased Body Weight

Response to Letter About Article, “Left Ventricular Wall Thickness and the Presence of Asymmetric Hypertrophy in Healthy Young Army Recruits: Data From the LARGE Heart Study”

HomeCirculation: Cardiovascular ImagingVol. 6, No. 5Response to Letter About Article, “Left Ventricular Wall Thickness and the Presence of Asymmetric Hypertrophy in Healthy Young Army Recruits: Data From the LARGE Heart Study” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter About Article, “Left Ventricular Wall Thickness and the Presence of Asymmetric Hypertrophy in Healthy Young Army Recruits: Data From the LARGE Heart Study” Marc R. Dweck, MD, PhD and Phong Teck Lee, MD Sparsh Prasher, MD Anoop S. Shah, MD Steve E. Humphries, MD Dudley J. Pennell, MD Hugh Montgomery, MD John Payne, MD Marc R. DweckMarc R. Dweck Centre for Cardiovascular Science, University of Edinburgh, UK Search for more papers by this author and Phong Teck LeePhong Teck Lee Centre for Cardiovascular Science, University of Edinburgh, UK Search for more papers by this author Sparsh PrasherSparsh Prasher Scottish National Advanced Heart Failure Service, Golden Jubilee Hospital, Glasgow, UK Search for more papers by this author Anoop S. ShahAnoop S. Shah Centre for Cardiovascular Science, University of Edinburgh, UK Search for more papers by this author Steve E. HumphriesSteve E. Humphries Cardiovascular Genetics, University College London, UK Search for more papers by this author Dudley J. PennellDudley J. Pennell Royal Brompton Hospital and Imperial College, London, UK Search for more papers by this author Hugh MontgomeryHugh Montgomery Institute for Human Health and Performance, UCL Archway Campus, London, UK Search for more papers by this author John PayneJohn Payne Scottish National Advanced Heart Failure Service, Golden Jubilee Hospital, Glasgow, UK Search for more papers by this author Originally published1 Sep 2013https://doi.org/10.1161/CIRCIMAGING.113.000773Circulation: Cardiovascular Imaging. 2013;6:e29That left ventricular growth occurs in response to exercise is, of course, well known. This relates to the increase in cardiac work, in turn a function of increased volume and pressure loading. As such, variation in the left ventricular hypertrophic response to exercise will result from differences in the external work undertaken, the cardiac work performed to deliver this work (the environmental stimulus to growth), and the genetic background of each individual.1 As such, we do not doubt that differences in the pressor response to exercise may have contributed to the differences in hypertrophy noted. With regret, we do not have data with respect to our recruits’ blood pressure response to exercise, much of which was done in the field, making this difficult to acquire. However, this was not the intention of our article, whose key point was that such hypertrophy may commonly be asymmetrical in nature.2 Whether differences in pressure loading contributed to such differences in hypertrophic pattern cannot be ascertained from our study nor from those reported by Dr Yalçin et al.Concerning whether some forme fruste of hypertension existed in our subjects, we would note that all of the subjects studied were either in their teens or early twenties. This contrasts sharply with the patient populations in the studies referenced by Dr Yalçin, where participants were on average in their midforties.3,4 We believe that subclinical hypertension is, therefore, much less likely to be a factor in our cohort than in those studies. Moreover, we did not observe an increase in our subjects’ blood pressure readings after the training regime (indeed among those who developed asymmetrical wall thickening, diastolic blood pressure reduced: pre 120/84 versus post 115/61), confirming that the development of hypertension before the end of the follow-up period is unlikely to be of relevance.Marc R. Dweck, MD, PhDPhong Teck Lee, MDCentre for Cardiovascular ScienceUniversity of EdinburghUKSparsh Prasher, MDScottish National Advanced Heart Failure ServiceGolden Jubilee HospitalGlasgow, UKAnoop S. Shah, MDCentre for Cardiovascular ScienceUniversity of EdinburghUKSteve E. Humphries, MDCardiovascular GeneticsUniversity College LondonUKDudley J. Pennell, MDRoyal Brompton Hospital and Imperial CollegeLondon, UKHugh Montgomery, MDInstitute for Human Health and PerformanceUCL Archway CampusLondon, UKJohn Payne, MDScottish National Advanced Heart Failure ServiceGolden Jubilee HospitalGlasgow, UKDisclosuresNone.

SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart.

A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We postulated that SRC-2 suppression plays a mechanistic role in the stress response and that SRC-2 activity is an important regulator of the adult heart gene expression profile. Genome-wide microarray analysis, confirmed with targeted gene expression analyses revealed that genetic ablation of SRC-2 activates the “fetal gene program” in adult mice as manifested by shifts in expression of a) metabolic and b) sarcomeric genes, as well as associated modulating transcription factors. While these gene expression changes were not accompanied by changes in left ventricular weight or cardiac function, imposition of transverse aortic constriction (TAC) predisposed SRC-2 knockout (KO) mice to stress-induced cardiac dysfunction. In addition, SRC-2 KO mice lacked the normal ventricular hypertrophic response as indicated through heart weight, left ventricular wall thickness, and blunted molecular signaling known to activate hypertrophy. Our results indicate that SRC-2 is involved in maintenance of the steady-state adult heart transcriptional profile, with its ablation inducing transcriptional changes that mimic a stressed heart. These results further suggest that SRC-2 deletion interferes with the timing and integration needed to respond efficiently to stress through disruption of metabolic and sarcomeric gene expression and hypertrophic signaling, the three key stress responsive pathways.

Can losartan and blood pressure control peri arteriovenous fistula creation ameliorate the early associated left ventricular hypertrophic response a randomised placebo controlled trial

BackgroundHaemodialysis results in a left ventricular hypertrophic response. It is unclear whether tight blood pressure control or particular medications might attenuate this response. We sought to determine, in a pre-dialysis cohort on atenolol, whether Losartan might attenuate left ventricular hypertrophy post arteriovenous fistula creation in end stage kidney disease.Materials and methodsPlacebo controlled double blind randomisation of 26 patients to fixed dose atenolol plus fixed dose losartan or placebo occurred 1 day prior to fistula creation. Pre-randomisation echocardiography was repeated at 1 week and 1-month. Measurement was undertaken of blood pressure, heart rate, brain natriuretic peptide, serum creatinine and estimated glomerular filtration rate. The primary pre-specified endpoint was the change in left ventricular mass at 1 month. Non-parametric statistical comparison was performed within and between groups.ResultsThere was no difference in left ventricular mass between our groups 1-month post fistula creation. In the entire cohort, change in left ventricular mass was driven by changes in blood pressure and volume loading. Blood pressure changes correlated with left ventricular mass changes seen shortly post arteriovenous fistula creation, suggesting blood pressure control during this time period may be an important part of the management of end stage kidney disease.ConclusionsWe did not see an advantage with the use of losartan with respect to diminution of the LVM response. However, our demonstrated change in LVM was relatively small compared to previous literature and suggests a possible role for beta blockade as a neurohormonal modulator around the time of arteriovenous fistula creation.Trial registrationClinical trials.gov (NCT00602004).

Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy

Ornithine decarboxylase (ODC), the first enzyme of polyamine metabolism, is rapidly upregulated in response to agents that induce a pathological cardiac hypertrophy. Transgenic mice overexpressing ODC in the heart (MHC-ODC mice) experience a much more dramatic left ventricular hypertrophy in response to β-adrenergic stimulation with isoproterenol (ISO) compared to wild-type (WT) controls. ISO also induced arginase activity in transgenic hearts but not in controls. The current work studies the cooperation between the cardiac polyamines and L-arginine (L-Arg) availability in MHC-ODC mice. Although ISO-induced hypertrophy is well-compensated, MHC-ODC mice administered L-Arg along with ISO showed a rapid onset of systolic dysfunction and died within 48 h. Myocytes isolated from MHC-ODC mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca(2+)] homeostasis, and abbreviated action potential duration, which may contribute to arrhythmogenesis. The already elevated levels of spermidine and spermine were not further altered in MHC-ODC hearts by L-Arg/ISO treatment, suggesting alternative L-Arg utilization pathways lead to dysregulation of intracellular calcium. MHC-ODC mice administered an arginase inhibitor (Nor-NOHA) along with ISO died almost as rapidly as L-Arg/ISO-treated mice, while the iNOS inhibitor S-methyl-isothiourea (SMT) was strongly protective against L-Arg/ISO. These results point to the induction of arginase as a protective response to β-adrenergic stimulation in the setting of high polyamines. Further, NO generated by exogenously supplied L-Arg may contribute to the lethal consequences of L-Arg/ISO treatment. Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility.

Is the ‘Athleteʼs Heart’ Arrhythmogenic?

Whether the ventricular hypertrophic response to athletic training can predispose to fatal ventricular dysrhythmias via mechanisms similar to that of pathological hypertrophy is controversial. This review examines current information regarding the metabolic and electrophysiological differences between the myocardial hypertrophy of heart disease and that associated with athletic training. In animal studies, the biochemical and metabolic profile of physiological hypertrophy from exercise training can largely be differentiated from that of pathological hypertrophy, but it is not clear if the former might represent an early stage in the spectrum of the latter. Information as to whether the electrical remodelling of the athlete's heart mimics that of patients with heart disease, and therefore serves as a substrate for ventricular dysrhythmias, is conflicting. If ventricular remodelling associated with athletic training can trigger fatal dysrhythmias, such cases are extraordinarily rare and thereby impossible to investigate by any standard experimental approach. Greater insight into this issue may come from a better understanding of the electrical responses to both acute bouts of exercise and chronic training in young athletes.

Towards the molecular diagnosis of hypertensive heart disease?

Towards the molecular diagnosis of hypertensive heart disease?

Determinants of left ventricular mass in obesity; a cardiovascular magnetic resonance study.

BackgroundObesity is linked to increased left ventricular mass, an independent predictor of mortality. As a result of this, understanding the determinants of left ventricular mass in the setting of obesity has both therapeutic and prognostic implications. Using cardiovascular magnetic resonance our goal was to elucidate the main predictors of left ventricular mass in severely obese subjects free of additional cardiovascular risk factors.Methods38 obese (BMI 37.8 ± 6.9 kg/m2) and 16 normal weight controls subjects, (BMI 21.7 ± 1.8 kg/m2), all without cardiovascular risk factors, underwent cardiovascular magnetic resonance imaging to assess left ventricular mass, left ventricular volumes and visceral fat mass. Left ventricular mass was then compared to serum and anthropometric markers of obesity linked to left ventricular mass, i.e. height, age, blood pressure, total fat mass, visceral fat mass, lean mass, serum leptin and fasting insulin level.ResultsAs expected, obesity was associated with significantly increased left ventricular mass (126 ± 27 vs 90 ± 20 g; p < 0.001). Stepwise multiple regression analysis showed that over 75% of the cross sectional variation in left ventricular mass can be explained by lean body mass (β = 0.51, p < 0.001), LV stroke volume (β = 0.31 p = 0.001) and abdominal visceral fat mass (β = 0.20, p = 0.02), all of which showed highly significant independent associations with left ventricular mass (overall R2 = 0.77).ConclusionThe left ventricular hypertrophic response to obesity in the absence of additional cardiovascular risk factors is mainly attributable to increases in lean body mass, LV stroke volume and visceral fat mass. In view of the well documented link between obesity, left ventricular hypertrophy and mortality, these findings have potentially important prognostic and therapeutic implications for primary and secondary prevention.

Proteasome inhibition in hypertrophied myocardium

Proteasome inhibition in hypertrophied myocardium

Cardiac Remodeling After Enzyme Replacement Therapy with Acid α-Glucosidase for Infants with Pompe Disease

Infantile Pompe disease (glycogen storage disease type 2) is a fatal disorder caused by deficiency of acid alpha-glucosidase. This deficiency results in glycogen accumulation in the lysosomes of many tissues including cardiac muscle. The disease is characterized by profound hypotonia, poor growth, organomegaly, and cardiomegaly. Severe hypertrophic cardiomyopathy often is present in early infancy, and most patients die of cardiac or respiratory failure in the first year of life. This report describes the cardiac response of infants with Pompe disease to a phase 2 trial of enzyme replacement therapy (ERT). Eight patients with classical infantile Pompe disease were given intravenous recombinant human GAA (rhGAA) for 1 year. Cardiac monitoring included echocardiography, electrocardiograms (ECGs), chest radiographs, and clinical cardiac evaluation at 4, 8, 12, 24, 36, and 52 weeks. At 52 weeks, 6 patients were alive. Most of the treated patients had rapid regression of ventricular hypertrophy in response to ERT, with near normalization of posterior wall thickness, ventricular mass, and ventricular size. Systolic ventricular function was preserved despite rapid changes in ventricular mass and size. Concomitantly, ECGs documented lengthening of the PR interval and decreased ventricular voltages, whereas chest radiographs documented a decreased cardiothoracic ratio. Symptoms of pulmonary congestion were diminished, and survival was improved. The cardiovascular system responds quickly and strikingly to ERT with rhGAA, suggesting rapid reversal of excessive glycogen storage in cardiac muscle cells. Changes in ventricular mass and function are maintained throughout 1 year of follow-up evaluation and associated with decreased morbidity and prolonged survival.

Haplotype of growth hormone and angiotensin I-converting enzyme genes, serum angiotensin I-converting enzyme and ventricular growth: pathway inference in pharmacogenetics

An insertion/deletion (I/D) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with variations in circulating and tissue angiotensin I-converting enzyme activity, and differences in exercise-induced left ventricular hypertrophic response. A genetic marker (CSH1.01) in the syntenic GH-CSH gene cluster correlates with metabolic syndrome in adult life in males. Approximately 24% linkage disequilibrium between CSH1.01T and D alleles of ACE I/D has also been reported. The objective was to examine the hypothesis that effects ascribed to ACE genotype may reflect causality in the GH-CSH cluster. The ACE I/D polymorphism and GH-CSH BglII-B single nucleotide polymorphism (in strong linkage disequilibrium with CSH1.01) were determined in 847 British Army recruits. Serum angiotensin I-converting enzyme activity and left ventricular mass were measured before and after a 12-week physical training program. Genotype and haplotype analyses of both markers were performed in relation to these phenotypes. The ACE I/D polymorphism was in linkage disequilibrium with BglII-B (D'=0.3). Strong association was seen between ACE I/D genotypes and serum angiotensin I-converting enzyme activity (P<0.0001), but not left ventricular mass change. BglII-B genotypes also associated significantly with serum angiotensin I-converting enzyme level (P<0.0001). Haplotype analysis, however, showed that most of this association resulted from linkage disequilibrium between BglII-B and ACE I/D. BglII-B did not associate with left ventricular mass change. GH-CSH BglII-B genotype associates significantly with angiotensin I-converting enzyme levels, but only through linkage disequilibrium with ACE I/D. Every phenotype with which ACE I/D has been associated merits investigation of potential causal effects originating in the GH-CSH cluster (and vice versa), otherwise the chain of causality could be misinterpreted.

Tumor Necrosis Factor-α Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload State

Pressure overload is accompanied by cardiac myocyte apoptosis, hypertrophy, and inflammatory/fibrogenic responses that lead to ventricular remodeling and heart failure. Despite incomplete understanding of how this process is regulated, the upregulation of tumor necrosis factor (TNF)-alpha after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF-alpha regulates the cardiac inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in response to mechanical overload and contributes to ventricular dysfunction. C57/BL wild-type mice and TNF-knockout (TNF-/-) mice underwent descending aortic banding or sham operation. Compared with sham-operated mice, wild-type mice with aortic banding showed a significant increase in cardiac TNF-alpha levels, which coincided with myocyte apoptosis, inflammatory response, and cardiac hypertrophy in week 2 and a significant elevation in matrix metalloproteinase-9 activity and impaired cardiac function in weeks 2 and 6. Compared with wild-type mice with aortic banding, TNF-/- mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis. These mice also showed reduced cardiac matrix metalloproteinase-9 activity and improved cardiac function. Findings from the present study have suggested that TNF-alpha contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.

Left and right ventricular hypertrophy in response to high salt intake is blood pressure independent

Objective: To evaluate the mechanisms of myocardial hypertrophy induced by salt overload. Methods: Eighteen-week-old Wistar rats were fed a normal (NS: 1.3% NaCl), a high 1 (HS1 4%) or a high 2 (HS2 8%) salt diet since weaning. HS2 group was divided into HS2 and HS2+hydralazine (HZ: 15mg/kg/day - since 7 weeks of age). Body weight (BW), tail cuff blood pressure (BP), left (LVM) and right (RVM) ventricular mass, echocardiography and urinary sodium (US) were evaluated. Results [mean±SEM – p<0.05, (n=4–8/group)]: The BW from weaning to adulthood did not differ among the four groups. At 18 weeks of age, the BP (mmHg) was higher on HS1 (150±2) and HS2 (154±3) than on NS (123±2). BP on HS2+HZ (126±2) did not differ from NS. US (mEq/24h) was higher on HS1 (9±0.5), HS2 (13±1.0) and HS2+HZ (13±1.5) than on NS (2±0.3). LVM (mg/g) was higher on HS1 (2.26±0.06), HS2 (2.46±0.05) and HS2+HZ (2.50±0.09) when compared to NS (2.03±0.06). RVM (mg/g) was higher on HS2 (0.69±0.01) and HS2+HZ (0.85±0.09) compared to NS (0.69±0.02) group. Interventricular septal thickness, left ventricular end-diastolic dimension - and left ventricular posterior wall thickness - LVPW (mm) were higher on HS1, HS2 and HS2+HZ compared to NS (LVPW: HS1 0.16±0.002, HS2 0.19±0.005, HS2+HZ 0.16±0.003, and NS 0.13±0.002). Conclusions: Left and right ventricular hypertrophy in response to high salt intake is not dependent on BP. Supported by FAPESP

Novel estrogen receptor alpha promoter polymorphism increases ventricular hypertrophic response to hypertension

Given the strong genetic contribution to blood pressure and left ventricular hypertrophy (LVH), and the influence of estrogen on these parameters, we hypothesized that polymorphisms in the estrogen receptor alpha (ERα) promoter may influence LVH. Three novel polymorphisms were identified upstream of the ERα alternatively spliced exon 1E, within sequence which demonstrated significant promoter activity in vitro. Demonstration of ERα E isoform expression in human ventricle by RT-PCR supported a possible functional role for the 1E novel polymorphisms in estrogen signaling in the heart. Indeed, G > A (−721 E) was significantly associated with LVH after controlling for systolic blood pressure and sex in a healthy population ( n = 74), contributing to 23% of interventricular septum (IVS) width variance ( p < 0.001) and 9.4% of left ventricular mass index (LVMI) variance ( p = 0.035). In a separate hypertensive cohort, male carriers of the A allele ( n = 8) had a 17% increase in IVS (95% CI: 6–28%) and a 19% increase in LVMI (3–34%) compared to GG homozygotes ( n = 84). We conclude that a novel polymorphism in the promoter of a cardiac mRNA splice isoform of ERα is associated with LVH.

Blockade of NF-κB ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II

Nuclear factor (NF)-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we assessed the hypothesis that blockade of NF-kappaB may ameliorate ventricular hypertrophy in response to chronic infusion of angiotensin II. Mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. Male KO and age-matched wild-type (WT) mice were chronically infused with angiotensin II at the rate of 0.2 (low dose) or 2 microg/kg/min (high dose) for 4 weeks. High- but not low-dose angiotensin II significantly increased systemic blood pressure and left ventricular weight in WT mice. In contrast, although the pressor response was slightly but significantly augmented, the hypertrophic effect of angiotensin II was significantly attenuated in KO mice. The attenuated hypertrophic responsiveness was confirmed histologically (cross-sectional area) and transcriptionally (atrial natriuretic peptide). Echocardiography revealed no evidence of cardiac dysfunction in angiotensin II-treated KO mice. Although phosphorylation of MAPKs, including ERK, JNK, or p38-MAPK, was not affected after 4 weeks of angiotensin II treatment in WT mice, phosphorylation of JNK was specifically abrogated in KO mice. Angiotensin II increased myocardial expression of proinflammatory cytokines and chemokines in WT mice, while expression of TNF-alpha and RANTES was paradoxically augmented in KO mice. Blockade of NF-kappaB activation attenuated myocardial hypertrophy without deteriorating cardiac function. NF-kappaB may play an important role in cardiac hypertrophy and remodeling besides promoting inflammation.

The Many Possible Benefits of Natriuretic Peptides After Myocardial Infarction

Natriuretic peptides (NPs) are well-known markers of the ventricular hypertrophic response, as documented in many studies performed either in animals or with cultured cardiomyocytes. In recent years, evidence has been mounting that NPs are in fact negative regulators of the hypertrophic response, as reviewed recently.1 In this light, NPs appear as endogenous cardioprotective agents of which expression increases in reaction to myocardial pathological conditions, but it is still unclear to which extent these agents may actually decrease mortality. In this issue of Hypertension , Nakanashi et al2 show that when myocardial infarction (MI) is induced by permanent occlusion of the coronary artery, mortality by heart failure is increased in knockout mice with inactivation of the gene coding for the NP receptor guanylyl cyclase-A (GC-A). Beyond these short-term effects, inactivation of GC-A also worsens post-MI chronic ventricular remodeling. Although the present study does not show whether these chronic remodeling processes also increase mortality at a later stage, the remodeling is accompanied by ventricular enlargement and decreased fractional shortening, both of which usually associate with poor prognosis. The importance of these data is enhanced by the fact that increasing numbers of studies are investigating the utility of recombinant NPs in humans.3 However, several questions remain concerning the particular modes of action of NPs. One issue concerns the question of whether NPs work via peripheral mechanisms or via a direct action on the myocardium. Importantly, congestive heart failure is accompanied by volume expansion, and the present article shows that the natriuresis and diuresis are decreased in GC-A knockout animals during the 4 days that follow MI, thus possibly contributing to increased heart failure during …