Cardiac Left Ventricular Hypertrophy Research Articles

A novel variant in VMA21 causing adult-onset phenotype of X-linked myopathy with excessive autophagy with cardiac involvement in a Chinese patient

X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive hereditary disorder, characterized by childhood onset weakness of predominantly limb and trunk skeletal muscles due to progressive loss of muscle tissue. Cardiovascular system is clinically spared generally. Here, we report the clinical characteristics, muscle biopsy and genetic findings of one adult-onset individual suffering from XMEA, caused by a novel variant in a Chinese patient. Unusually, the patient developed unexplained hypertension with high left ventricular voltage and cardiac left ventricular hypertrophy at the age of 27. Muscle MRI revealed extensive fat infiltration in the lower extremities involving vastus medialis, vastus lateralis, vastus intermedius, and long head of the biceps femoris, while rectus femoris, gracilis, adductor magnus, semimembranosus, and sartorius muscle relatively preserved. A muscle biopsy indicated numerous cytoplasmic autophagic vacuoles and deposition of complement C5b-9 and also expression of MHC class I. Immunofluorescence staining showed increased immunoreactivity of lysosomal membrane protein LAMP2 and autophagosome protein LC3A/B both localized with cytoplasmic vacuoles, and autophagy carrier protein P62-positive vacuoles accumulated remarkably in the patient's muscle. VMA21 protein levels were lower than controls in skeletal muscle tissue, suggesting a possible pathogenicity related to an alteration of the splicing efficiency in intronic mutation. This is the first report of a Chinese patient with a novel hemizygous intronic c.163 + 3A > G variant in the VMA21 gene, expanding the mutational and phenotypic spectrum of this disease.

ACHIEVED SYSTOLIC BLOOD PRESSURE BELOW 130 MMHG PRESERVES KIDNEY FUNCTION IN DIABETIC AND NON-DIABETIC HYPERTENSIVE PATIENTS WITHOUT CARDIAC HYPERTROPHY

Objective: Kidney function is preserved by achieving systolic blood pressure (SBP) primarily <140mmHg and possibly <130mmHg in hypertensive patients. We aimed to investigate kidney function when achieving SBP 130-139 and <130mmHg in type-2 diabetic and non-diabetic hypertensive patients without cardiac hypertrophy who participated in a major prospective hypertension outcome trial. Design and method: Of the 15,245 study participants, 13,803 patients were without cardiovascular events during the first six months after randomization with roll-over from previous medications to blinded study drugs and had a minimum of 3 subsequent BP visits during 4-6 years. Of these, 2,458 patients with cardiac left ventricular hypertrophy (LVH) by ECG were not included in the present analysis because, as previously reported, they had increased cardiac and all-cause mortality at average achieved SBP <130mmHg. Of the remaining 11,345 patients, 3932 had diabetes. Cox analyzes adjusted for baseline covariates compared the pre-specified kidney endpoints 50% rise of se-creatinine (worsening kidney function, WKF) and end-stage renal disease (ESRD, dialysis and/or transplantation) for patients who achieved average SBP 130-139 and <130mmHg with those who remained with SBP >=140mmHg. Results: Patients with diabetes had less WKF at SBP 130-139mmHg (HR=0.50, 95% CIs 0.34-0.72, n=1605, p<0.001) and at SBP <130mmHg (HR=0.43, CIs 0.23-0.80, n=599, p=0.008). They also had less ESRD at SBP 130-139mmHg (HR=0.32, CIs 0.12-0.88, p=0.03) with similar trend at SBP <130mmHg (HR=0.21, CIs 0.03-1.65) which was significant for the 3rd quartile of SBP (135mmHg) (HR=0.09, CIs 0.01-0.71, p=0.02) and for the 4th quartile of SBP (126mmHg) (HR=0.12, CIs 0.02-0.92, p=0.04). Patients without diabetes (n=7413) also had less WKF at SBP 130-139mmHg (HR=0.58, CIs 0.40-0.83, n=3258, p=0.003) and at SBP <130mmHg (HR=0.38, CIs 0.21-0.68, n=1542, p<0.001). For ESRD the trend was similar as for diabetes at 3rd quartile of SBP (135mmHg) (HR=0.37, CIs 0.14-1.00, p=0.05) and at 4th quartile of SBP (126mmHg) (HR=0.23, CIs 0.07-0.75, p=0.02). Conclusions: In high-risk hypertensive patients above 50 years, with and without type-2 diabetes, but without cardiac hypertrophy, we found stepwise less worsening of kidney function and end-stage renal disease with lower average achieved systolic BP from >=140mmHg to 130-139mmHg to <130mmHg.

Large animal models of pressure overload-induced cardiac left ventricular hypertrophy to study remodelling of the human heart with aortic stenosis.

Pathologic cardiac hypertrophy is a common consequence of many cardiovascular diseases, including aortic stenosis (AS). AS is known to increase the pressure load of the left ventricle, causing a compensative response of the cardiac muscle, which progressively will lead to dilation and heart failure. At a cellular level, this corresponds to a considerable increase in the size of cardiomyocytes, known as cardiomyocyte hypertrophy, while their proliferation capacity is attenuated upon the first developmental stages. Cardiomyocytes, in order to cope with the increased workload (overload), suffer alterations in their morphology, nuclear content, energy metabolism, intracellular homeostatic mechanisms, contractile activity, and cell death mechanisms. Moreover, modifications in the cardiomyocyte niche, involving inflammation, immune infiltration, fibrosis, and angiogenesis, contribute to the subsequent events of a pathologic hypertrophic response. Considering the emerging need for a better understanding of the condition and treatment improvement, as the only available treatment option of AS consists of surgical interventions at a late stage of the disease, when the cardiac muscle state is irreversible, large animal models have been developed to mimic the human condition, to the greatest extend. Smaller animal models lack physiological, cellular and molecular mechanisms that sufficiently resemblance humans and in vitro techniques yet fail to provide adequate complexity. Animals, such as the ferret (Mustello purtorius furo), lapine (rabbit, Oryctolagus cunigulus), feline (cat, Felis catus), canine (dog, Canis lupus familiaris), ovine (sheep, Ovis aries), and porcine (pig, Sus scrofa), have contributed to research by elucidating implicated cellular and molecular mechanisms of the condition. Essential discoveries of each model are reported and discussed briefly in this review. Results of large animal experimentation could further be interpreted aiming at prevention of the disease progress or, alternatively, at regression of the implicated pathologic mechanisms to a physiologic state. This review summarizes the important aspects of the pathophysiology of LV hypertrophy and the applied surgical large animal models that currently better mimic the condition.

Clinical study of left ventricular structure and function in patients with Anderson-Fabry disease before and after enzyme replacement therapy.

Cardiac left ventricular hypertrophy (LVH) is the most common manifestation of heart involvement in Anderson-Fabry disease (AFD). Conventional cardiac imaging is not sensitive enough to detect early signs of LVH in AFD. It remains uncertain whether enzyme replacement therapy (ERT) can prevent LVH progression and improve myocardial function. This study aimed to assess the effectiveness of two-dimensional speckle tracking echocardiography (2D-STE) in early detection of cardiac involvement in AFD and monitoring the efficacy of agalsidase alfa and agalsidase beta therapy. Thirteen consecutive AFD patients and 12 healthy controls underwent standard transthoracic 2D, color Doppler, tissue Doppler echocardiography, and 2D strain analysis. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Diastolic strain rate (SR) was extracted. Compared to healthy subjects, AFD patients without LVH showed lower levels of GLS (p < 0.001) and SR (p = 0.01), while there was no difference in GCS (p = 0.82). Following treatment, apical circumferential strain (ACS) showed improvement (p = 0.01). In AFD patients without LVH, there was a decrease in global and segmental LS. Higher plasma Lyso-GL-3 concentrations were associated with elevated ACS values after ERT, indicating that ACS in AFD patients without LVH, albeit normal, is involved in early LV dysfunction.

Prognostic significance of unexplained left ventricular hypertrophy in patients undergoing carpal tunnel surgery.

AimsCarpal tunnel (CT) syndrome is a recognized red‐flag of cardiac amyloidosis (CA) and increased cardiovascular (CV) morbidity. We designed this study to characterize the CV profile of patients with CT syndrome at the time of first surgery and to identify high‐risk presentations.Methods and resultsWe retrospectively reviewed 643 patients who underwent CT surgery between 2007 and 2019. Of them, 130 patients (77 years, 45% male patients, left ventricular ejection fraction 62%) with available CV characterization within ±12 months from CT surgery were included. Abnormal loading conditions causing cardiac left ventricular hypertrophy (LVH) were investigated to distinguish explained LVH (Ex‐LVH) from unexplained LVH (Un‐LVH). LVH was found in 66 (51%) patients, 33% of them presented Un‐LVH. Compared with the others, Un‐LVH patients were older (77 and 75 vs. 70 years in Un‐LVH, Ex‐LVH, and non‐LVH, respectively; P = 0.002), had higher rates of electrocardiogram‐echo discrepancy (70%, 14.3%, and 1.6%, respectively; P < 0.001) and of echocardiographic findings of CA (24%, 7%, and 0%, P < 0.001). Among Un‐LVH patients, 9 (43%) experienced death and 7 (33%) developed heart failure (HF) at 3.8 and 2.4 years from CT surgery, respectively. Compared with the others, death and HF development rates were higher in Un‐LVH patients both at unadjusted (P = 0.01 and P = 0.02, respectively) and adjusted analysis for age, gender, and renal insufficiency (P = 0.00038 and P = 0.050, respectively).ConclusionsAt the time of CT surgery, Un‐LVH was found in more than 30% of patients with LVH, and 24% of them showed echocardiographic features suggesting an underdiagnosed CA. Un‐LVH was associated with higher all‐cause mortality and HF development.

SRAGE attenuates angiotensin II-induced cardiomyocyte hypertrophy by inhibiting RAGE-NFκB-NLRP3 activation.

The receptor for advanced glycation endproducts (RAGE) is an innate immunity receptor that has been implicated in the pathogenesis of atherosclerotic cardiovascular disease. However, the possibility that RAGE-mediated signaling is involved in angiotensin II (Ang II)-induced cardiac left ventricular hypertrophy has yet to be investigated. We therefore determined whether RAGE has a role in regulating pathological cardiac hypertrophy. Protein abundance was estimated using Western blotting and intracellular ROS level and phospho-p65 were detected using fluorescence microscopy. Enzyme-linked immunosorbent assay was used to detect HMGB1 and IL-1β. All in vitro experiments were performed using H9C2 cells. To induce cardiomyocyte hypertrophy, 300nM Ang II was treated for 48h and 2µg/ml sRAGE was treated 1h prior to addition of Ang II. sRAGE attenuated Ang II-induced cardiomyocyte hypertrophy by downregulating RAGE and angiotensin II type 1 receptor expression. Secretion levels of high motility group box 1 and interleukin-1β, estimated from a cell culture medium, were significantly reduced by sRAGE. Activated PKCs and ERK1/2, important signals in left ventricular hypertrophy (LVH) development, were downregulated by sRAGE treatment. Furthermore, we found that nuclear factor-κB and NOD-like receptor protein 3 (NLRP3) were associated with RAGE-mediated cardiomyocyte hypertrophy. In the context of these results, we conclude that RAGE induces cardiac hypertrophy through the activation of the PKCs-ERK1/2 and NF-κB-NLRP3-IL1β signaling pathway, and suggest that RAGE-NLRP3 may be an important mediator of Ang II-induced cardiomyocyte hypertrophy. In addition, we determined that inhibition of RAGE activation with soluble RAGE (sRAGE) has a protective effect on Ang II-induced cardiomyocyte hypertrophy.

Western diet increases cardiac ceramide content in healthy and hypertrophied hearts

Background and aimsObesity and cardiac left ventricular hypertrophy (LVH) are recognised independent risk factors in the development of heart failure (HF). However, the combination of these factors may exacerbate the onset of cardiovascular disease by mechanisms as yet unclear. LVH leads to significant cellular remodelling, including alterations in metabolism which may result in an inappropriate accumulation of lipids and eventual lipotoxicity and apoptosis. The aim of the study was to determine the impact of dietary manipulation on cardiac metabolism in the obese and hypertrophied heart. Methods and resultsLVH was induced via aortic constriction (AC) in an experimental model of cardiac hypertrophy and animals subjected to 9 weeks of dietary manipulation with either a standard, high fat, or a sucrose containing Western-style diet (SD, HFD and WD, respectively). This latter diet resulted in accelerated weight gain in both LVH/AC and control animals. LVH was greater in AC animals fed a WD, and both control and AC animals from this diet showed a significant reduction in cardiac fatty acid oxidation and increased triacylglycerol content. Ceramide content was significantly increased in the WD groups, with no additional effect of LVH. Comparison with a model of HF induced by exposure to Doxorubicin and WD showed exacerbated remodelling of cardiac ceramide species leading to increased C16 and C18 content. ConclusionsThese findings highlight the inappropriate accumulation and re-distribution of cardiac ceramide species in a diet-induced model of obesity and LVH, potentially increasing susceptibility to cell death. The combination of increased fat and sugar leads to greater pathological remodelling and may explain why this diet pattern is consistently linked with poor cardiovascular outcomes.

Amalaki rasayana, a traditional Indian drug enhances cardiac mitochondrial and contractile functions and improves cardiac function in rats with hypertrophy

We evaluated the cardioprotective effect of Amalaki Rasayana (AR), a rejuvenating Ayurvedic drug prepared from Phyllanthusemblica fruits in the reversal of remodeling changes in pressure overload left ventricular cardiac hypertrophy (LVH) and age-associated cardiac dysfunction in male Wistar rats. Six groups (aging groups) of 3 months old animals were given either AR or ghee and honey (GH) orally; seventh group was untreated. Ascending aorta was constricted using titanium clips in 3 months old rats (N = 24; AC groups) and after 6 months, AR or GH was given for further 12 months to two groups; one group was untreated. Histology, gene and protein expression analysis were done in heart tissues. Chemical composition of AR was analyzed by HPLC, HPTLC and LC-MS. AR intake improved (P < 0.05) cardiac function in aging rats and decreased LVH (P < 0.05) in AC rats as well as increased (P < 0.05) fatigue time in treadmill exercise in both groups. In heart tissues of AR administered rats of both the groups, SERCA2, CaM, Myh11, antioxidant, autophagy, oxidative phosphorylation and TCA cycle proteins were up regulated. ADRB1/2 and pCREB expression were increased; pAMPK, NF-kB were decreased. AR has thus a beneficial effect on myocardial energetics, muscle contractile function and exercise tolerance capacity.

Valporic acid enhances the Atrial Natriuretic Peptide (ANP) mediated anti-hypertrophic activity by modulating the Npr1 gene transcription in H9c2 cells in vitro

The present study was aimed to determine whether stimulating Npr1 gene activity using Valporic acid (VA), a small short chain fatty acid molecule can enhance ANP mediated anti-hypertrophic activity in isoproterenol (ISO) – treated H9c2 cells in vitro. H9c2 cells were treated with ISO (10−5 M) and co-treated with VA (10−5 M) in the presence and absence of ANP (10−8M), for 48h. ATRA (10−5 M) was used as a positive inducer of Npr1 gene transcription. The mRNA expression of Npr1 and PKG-I genes, proto-oncogenes (c-fos, c-jun and c-myc) and hypertrophic markers (ANP, BNP, α-sk and β-MyHC), genes were determined by quantitative PCR (qPCR). The protein profiling of NPR-A, PKG-I and cGMP were evaluated by Western blot, immunofluorescence and ELISA respectively. A marked reduction in the level of expression of Npr1 (3- fold) and PKG-I (2.5-fold) genes and increased expression of proto-oncogenes (p< 0.001, respectively) and hypertrophic marker genes (p<0.001, respectively) were noticed in the ISO-treated H9c2 cells as compared with control cells. In contrast, the VA treated cells showed maximal Npr1 gene expression (3.5-fold) as compared with ATRA treated cells (2 fold), which is well correlated with the intracellular cGMP levels (80% vs 60%) and reduced (2.5-fold) HDAC −1&−2 mRNA expression. Furthermore, VA or ATRA treatment effectively reversed the ISO-induced altered expression of Npr1 and PKG-I genes, proto-oncogenes, and hypertrophic markers genes. Interestingly, the results of the present study suggest that ANP mediated anti-hypertrophic activity was enhanced with either VA (p<0.001) or ATRA (p<0.01) co-treatment. Together, we conclude that VA in combination with ANP can be a novel therapeutical approach for the treatment and management of left ventricular cardiac hypertrophy.

The impact of depression and cardiophobia on quality of life in patients with essential hypertension.

Patients with chronic conditions like hypertension may experience many negative emotions which endorse the development of anxiety and depression symptomatology, thus they increase their risk for poor quality of life. Several studies have shown an association between symptoms of psychological distress and hypertension. In this study we aimed to quantify the link between depression, cardiophobia and quality of life in hypertensive patients. A cross-sectional design was employed. A sample of 197 hypertensive patients (89 men-108 women, mean age 53 years, SD=12 ranged 25-78) from a university outpatient hypertension clinic in Greece participated. Ninety-four (47.7%) of the participants suffered from essential grade I hypertension; 68 (34.5%) were grade II; 16 (8.1%) were categorized as grade III, while only 11 (5.6%) patients were recorded as normotensives with high normal values. The questionnaires included: (a) question for the recording of social-demographic characteristics and clinical features, (b) The Short Form (SF-36) Health Survey, (c) The Beck Depression Inventory -I, and (d) The Cardiac Anxiety Questionnaire. There were no significant differences between the two genders with exception of marital status (p=0.010), dyslipidemia (p=0.050), grade of hypertension (p=0.014), cardiac left ventricular hypertrophy (p=0.004), renal failure (p=0.043) and stroke (p=0.024). Lower levels of quality of life and higher levels of depression and cardiophobia were observed compared to the general population. There were no significant differences on psychological measures between the two sexes (p>0.05). Cardiophobia was positively related to depressive symptomatology (r=0.533, p=0.000) while negatively to both physical and mental health summary measures of SF-36 health survey (r=-0.467, p=0.000 r=-0.537, p=0.000 respectively). Multiple linear regression models found that for psychical health depression and cardiac anxiety, avoidance activities had an influence on levels of quality of life in hypertensive patients, after controlling for age and other socio-demographic variables and clinical characteristics (Beta=-0.133, p=0.007, Beta=-0.364 p=0.000 and Beta=-0.167 p=0.006, respectively). For mental component summary depression and cardiophobia, heart focused attention had also impact on mental health in hypertensives (Beta=-0.438, p=0.016, Beta=-0.564, p=0.000 and Beta=-0.223, p=0.037, respectively) after adjustments. Heart focused anxiety symptoms-as avoidance activities and/or attention and monitoring cardiac activity, are related to hypertensive patients' present deteriorated depressive symptoms and levels of quality of life. Both depressive symptomatology and heart focused anxiety may be a mechanism partly responsible for hypertensive patients' present impaired levels of quality of life.

Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay

BackgroundA homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which...

Accuracy of the Electrocardiograph in Detecting Cardiac Left Ventricular Hypertrophy in Pediatric Patients with Aortic Valve Disease

Background: Left ventricular hypertrophy (LVH) is a pathological remodeling of myocardial tissue occurring in response to an increase in cardiac workload. The most significant cause of LVH in the pediatric population is aortic valve disease, which includes aortic valve stenosis and insufficiency. Though LVH can arise naturally in response to strenuous exercise, it has clinical utility as a marker of hypertension and heart disease. LVH can be detected using certain voltage criteria via electrocardiogram (ECG), though this approach typically exhibits poor sensitivity. The current gold standard for LVH identification is echocardiogram – however, waiting times and operator skill are significant variables in echocardiographic diagnosis of LVH. This study evaluates the sensitivity and specificity of various voltage criteria for LVH in this population, and whether amalgamating criteria can boost their accuracy. Methods: A retrospective chart review was conducted to look at the echocardiograms and electrocardiograms (ECGs) of 62 pediatric patients with aortic valve disease seen at McMaster University Medical Centre. Patient ECGs were analyzed for LVH using a number of voltage criteria: those established by the Journal of American College of Cardiology’s (JACC) standards for pediatric LVH, criteria utilized for adult LVH, and Cornell adult voltage criteria. To determine the suitability of these indices in identifying LVH via ECG, we analyzed sensitivity, specificity and negative predictive value (NPV) of each set of criteria using echocardiograms carried out within 2 months as a gold standard. Results: Our results identify Cornell Female voltage criteria as bearing the highest sensitivity (81.94%) in identifying LVH in this population, while JACC pediatric criteria demonstrated the highest specificity (77.29%). Using Cornell Female voltage criteria as a sensitive screening tool, we then applied JACC pediatric criteria (chosen for its high specificity). The combined criteria (JACCCF) demonstrated higher sensitivity and specificity (88.64% and 83.33%, respectively) than either criteria used in isolation. Conclusion: Cornell Female voltage criteria demonstrated the highest sensitivity in this population, though it is typically not utilized in a pediatric setting. Utilizing Cornell Female criteria as a screening tool in tandem with JACC criteria for its specificity yielded a set of highly specific and sensitive criteria. This approach bears promise in pediatric patients with aortic valve disease, and should be explored in other populations with LVH.

Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats.

Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.

Electrocardiogram Derived QRS Duration >120 ms is Associated With Elevated Plasma Homocysteine Levels in a Rural Australian Cross-Sectional Population.

Homocysteine levels in the low to moderate range for cardiovascular risk have been previously associated with left ventricular cardiac hypertrophy (LVH). Electrocardiogram (ECG) derived QRS duration has also been used as an epidemiological screening marker for cardiac hypertrophy risk. QRS duration cut offs have not been previously modeled to assess homocysteine levels in community populations. Our aims are to determine if QRS duration is associated with an elevated homocysteine level in a cross-sectional Australian aging rural population.A retrospective study design utilizing a rural health diabetic screening clinic database containing observational data from the period January 9, 2002 till September 25, 2012. One hundred seventy-eight individuals (>21 years of age) from the database were included in the study. Inclusion criteria included being nondiabetic and having both a QRS duration measure and a matching homocysteine level within the same subject. All participants were from the Albury-Wodonga area, with a mean age of >64 years for both sexes.Mean population homocysteine plasma levels were 10.4 μmol/L (SD = 3.6). The mean QRS duration was 101.8 ms (SD = 17.4). Groups were stratified on the basis of QRS duration (≤120 ms [n = 157] and >120 ms [n = 21]). QRS duration subgroup (≤120 ms vs >120 ms) mean differences across homocysteine levels were 10.1 μmol/L (SD = 3.3) and 12.2 μmol/L (SD = 4.7), respectively (P = 0.016). Other ECG parameters (PQ interval, QTc interval, and QT dispersion) measurements were not significantly associated with differences in plasma homocysteine (P = not significant).We conclude that in community populations homocysteine may be moderately elevated when QRS durations are >120 ms. Small additional increases in homocysteine levels may suggest a risk factor for ECG diagnosis of LVH.

Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function.

Decreased nitric oxide (NO) bioavailability underlies a number of cardiovascular pathologies, including hypertension. The shear stress exerted by flowing blood is the main determinant of NO release. Rap1 promotes integrin- and cadherin-mediated signaling. Here, we show that Rap1 is a critical regulator of NO production and endothelial function. Rap1 deficiency in murine endothelium attenuates NO production and diminishes NO-dependent vasodilation, leading to endothelial dysfunction and hypertension, without deleterious effects on vessel integrity. Mechanistically, Rap1 is activated by shear stress, promotes the formation of the endothelial mechanosensing complex-comprised of PECAM-1, VE-cadherin and VEGFR2- and downstream signaling to NO production. Our study establishes a novel paradigm for Rap1 as a regulator of mechanotransduction.

Clinical Implications

HomeHypertensionVol. 60, No. 5Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Nov 2012https://doi.org/10.1161/HYP.0b013e31827679abHypertension. 2012;60:1087Blood Pressure Characteristics and Early Onset Preeclampsia (page 1338)Download figureDownload PowerPointSome women develop preeclampsia very early in their pregnancy. Interestingly, such women are also more likely to have a family history of preeclampsia, develop preeclampsia again in subsequent pregnancies, and have a higher risk of later cardiovascular disease. These observations raise the possibility that women develop early onset preeclampsia because they have distinct, heritable, physiological traits that predispose them to both preeclampsia and later cardiovascular disease. In this issue of Hypertension, Lazdam et al report distinct differences in blood pressure characteristics during pregnancy, and <13 years later, in women who develop early onset preeclampsia. They demonstrate for the first time that compared with those with late-onset preeclampsia or normotensive pregnancies, such women have persistently higher blood pressure 6 weeks after delivery, a substantially greater increase in blood pressure over the next decade relative to levels during pregnancy, and significantly higher nocturnal blood pressures in later life. Lazdam et al then studied blood pressure in the offspring and found that those born to the pregnancies complicated by early onset disease had 6 mm Hg higher systolic blood pressure compared with those born to either late-onset disease or normotensive pregnancy. Characterization of the biology that underlies these distinct variations in blood pressure behavior may identify pathways for novel interventions. Furthermore, a diagnosis of early onset disease seems to identify individuals who may warrant targeted blood pressure surveillance.Determinants of Adolescent Left Ventricular Mass (page 1266)Cardiac left ventricular hypertrophy is a strong independent predictor of cardiovascular disease morbidity and mortality in adulthood. Left ventricular growth and geometric remodeling in adolescence may have long-term consequences on cardiovascular health in later life. However, factors influencing left ventricular mass in early life are poorly characterized. The determinants of left ventricular mass and patterns of geometric remodeling in healthy adolescents with specific emphasis on birth size and growth in early childhood were studied. Left ventricular measurements were obtained with echocardiography in 418 adolescents at 15 years of age in a prospective atherosclerosis prevention study, Special Turku Coronary Risk Factor Intervention Project (STRIP). Birth weight was directly associated with left ventricular mass, regardless of sex and current weight, pulse pressure, and physical activity level. Growth in early childhood was not associated with left ventricular mass in adolescence. Adolescents who were overweight had 17 g greater left ventricular mass than those with normal body mass index. The results indicate that birth weight has a long-lasting impact on left ventricular mass and normal body weight is beneficial for cardiac structure in adolescents, whereas weight gain during the first 2 years of life does not associate with adolescent left ventricular mass. These data extend the knowledge of the determinants of left ventricular mass from early life to adolescence, relevant for the prevention of cardiovascular disease.Is Blood Pressure Variability a Risk Factor? (page 1138)Download figureDownload PowerPointAttempts to anchor blood pressure variability as an established cardiovascular risk factor span ≈30 years. Recent findings challenge the concept of usual blood pressure and led to the proposition to consider blood pressure variability in the diagnosis, treatment, and monitoring of patients with hypertension. Because these findings originated from post hoc analyses within the context of clinical trials in selected high-risk patients or in patients with a history of stroke, confirmation from an unbiased population sample was necessary. In this issue of Hypertension, results from the prospective Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) indicate that systolic blood pressure variability does not have any independent prognostic significance over and beyond mean systolic pressure. These findings from 2944 randomly recruited participants, representative of a general population, and followed up for a median of 12 years, suggest that what matters most in the management of hypertension is to reduce the blood pressure level, as recommended in current guidelines. FLEMENGHO results do not support blood pressure variability as an independent risk factor. Previous Back to top Next FiguresReferencesRelatedDetails November 2012Vol 60, Issue 5 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/HYP.0b013e31827679ab Originally publishedNovember 1, 2012 PDF download Advertisement

Risk factors affecting cardiac left-ventricular hypertrophy and systolic and diastolic function in the chronic phase of allogeneic hematopoietic cell transplantation

Chronic impairment of cardiac function can be an important health risk and impair the quality of life, and may even be life-threatening for long-term survivors of allogeneic hematopoietic cell transplantation (HCT). However, risk factors for and/or the underlying mechanism of cardiac dysfunction in the chronic phase of HCT are still not fully understood. We retrospectively investigated factors affecting cardiac function and left-ventricular hypertrophy (LVH) in the chronic phase of HCT. Sixty-three recipients who survived for >1 year after receiving HCT were evaluated using echocardiography. Based on simple linear regression models, high-dose TBI-based conditioning was significantly associated with a decrease in left-ventricular ejection fraction and the early peak flow velocity/atrial peak flow velocity ratio, following HCT (coefficient=-5.550, P=0.02 and coefficient=-0.268, P=0.02, respectively). These associations remained significant with the use of multiple linear regression models. Additionally, the serum ferritin (s-ferritin) level before HCT was found to be a significant risk factor for LVH on multivariable logistic analysis (P=0.03). In conclusion, our study demonstrated that a myeloablative regimen, especially one that involved high-dose TBI, impaired cardiac function, and that a high s-ferritin level might be associated with the development of LVH in the chronic phase of HCT.

Desmodium gangeticum root extract attenuates isoproterenol-induced cardiac hypertrophic growth in rats

Context: Desmodium gangeticum (L) DC (Fabaceae; DG), a medicinal plant that grows in tropical habitats, is widely used to treat various ailments including digestive and inflammatory disorders. Aims: To investigate the possible cardioprotective activity of a DG root extract against isoproterenol (ISO)-induced left ventricular cardiac hypertrophy (LVH) in adult Wistar rats. Methods: Daily intraperitoneal administration of ISO (10 mg/kg body weight, single injection) for 7 days induced LVH in rats. The LVH rats were post-treated orally with DG (100 mg/kg body weight) for a period of 30 days. Thereafter, changes in heart weight (HW) and body weight (BW), HW/BW ratio, percent of hypertrophy, collagen accumulation, activities of matrix metalloproteinase (MMP) -2 and -9, superoxide dismutase (SOD) and catalase (CAT) enzymes, and the level of an oxidative stress marker, lipid peroxide (LPO), were determined. Results: HW/BW ratio, an indicator of hypertrophic growth, was significantly reduced in DG root post-treated LVH rats as compared with that for the non-treated LVH rats. The altered levels of ventricular LPO, collagen, MMPs-2 and -9, and antioxidant enzymes in the ISO-treated animals reverted back to near normal upon DG treatment. Further, the anti-hypertrophic activity of DG was comparable to that of the standard drug losartan (10 mg/kg). Conclusions: The results of the present study suggest that the aqueous root extract of DG exhibited anti-hypertrophic activity in-vivo by inhibiting ISO-induced ROS generation and MMP activities.

Modulation of impact of high fat diet in pathological and physiological left ventricular cardiac hypertrophy by fluvastatin

The male wistar rats were kept at high fat diet for 90 days and subjected to partial abdominal aortic constriction (PAAC) at 62nd and continued up to 90th day. Similarly, rats were kept at high fat diet for 90 days and subjected to chronic swimming training (CST) at 46th day and continued up to 90th day. Obesity was assessed by %age change in body weight, WHR ratio and adiposity index whereas cardiac hypertrophy was assessed by using index of cardiac hypertrophy, i.e., left ventricular weight, left ventricular weight to body weight, (LVW/BW), left ventricular wall thickness (LVWT), cardiomyocyte diameter, LV, protein content and collagen content. Further, mean arterial blood pressure (MABP) was also recorded. Oxidative stress was assessed by measuring the levels of thiobarbituric acid reactive species (TBARS), levels of superoxide anion generation and levels of reduced glutahione in left ventricular tissue. The PAAC and CST increased the index of cardiac hypertrophy. Moreover, PAAC has significantly increased MABP. Fluvastatin, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, significantly attenuated PAAC induced left ventricular cardiac hypertrophy and MABP whereas no significant change was observed in CST-induced cardiac hypertrophy. Furthermore, fluvastatin significantly attenuated the oxidative stress by decreasing the levels of TBARS and superoxide anion generation and increasing the levels of reduced glutathione. These results suggest that fluvastatin prevented the PAAC-induced cardiac hypertrophy.

Hepcidin mutation in a β-thalassemia major patient with persistent severe iron overload despite chelation therapy

Hepcidin, a 25 amino acid peptide expressed in the liver, has been shown to have a major role in iron homeostasis controlling iron release from reticuloendothelial and intestinal epithelial cells. Human hepcidin is encoded as a prohormone called pre-prohepcidin (84 amino acid) containing a consensus furin cleavage site preceding the C-terminal 25 amino acid bioactive peptide. It is induced by inflammation and iron and decreased by hypoxia and anemia [1]. b-Thalassemia major (TM) is a hereditary hemolytic anemia resulting from the reduction or complete absence of b-globin chain synthesis. Patients with TM and other refractory anemias receiving regular blood transfusions become iron overloaded at the rate of approximately 0.3– 0.5 mg/kg body weight per day. Indeed, iron overload results from transfusional iron and increased intestinal absorption due to inefficient erythropoiesis. Hepcidin mRNA expression was found to be decreased in the liver of C57Bl/6 Hbb (a murine model of thalassemia major) and in patients with thalassemia major urinary hepcidin was disproportionately suppressed in regard to iron burden [2]. In thalassemia major, low hepcidin levels result in increased iron absorption and greater release of stored iron into the circulation and contribute to iron accumulation in liver, endocrine glands and heart. Iron chelator deferoxamine (DFO) reduces iron burden in TM, but limitations of its infusion have stimulated the design of oral chelators which result in better compliance. Thus, almost all TM patients achieve an acceptable iron status. We report a TM case in which mutations in hepcidin could have interfered with distribution and removal of body iron by chelators. The patient was a 23-year-old woman, homozygous for b39 thalassemia major, regularly transfused since 1 year of age, receiving an average of 4 units of packed red cells monthly (corresponding to 7.5 g/year of iron) and chelated by subcutaneous infusion of DFO (40 mg/kg day, 6 days/ week) since early infancy. In her record, a persistent high iron burden was documented despite chelation treatment. The patient developed hypothyroidism and hypogonadotropic hypogonadism and was on hormonal replacement therapy. The echocardiography evaluation showed a slight cardiac left ventricular hypertrophy and an ejection fraction of 66%. Liver iron concentration was estimated at 20 years by Superconducting Quantum Interference Device biomagnetic liver susceptometry method (SQUID-BLS). Despite chelation treatment, the iron concentration evidenced by SQUID was at very high levels (5,230 lg/g liver dw). At the time of the study, non-transferrin-bound iron (NTBI), detected by high-performance liquid chromatography (HPLC) [3], was 3.66 lM (normal value -0.70 ± 0.50); serum ferritin levels and transferrin saturation, measured by standards method, were 4,323 ng/mL and 110%, respectively (normal values 150 ± 100, 35 ± 15). Genomic DNA was isolated from leukocytes by standard method. Exons 1–3 of hepcidin gene were amplified with different pairs of primers: the first pair amplified exon 1, including the promoter and 50-UTR region, the second L. Duca P. Delbini I. Nava M. D. Cappellini Department of Internal Medicine, Maggiore Policlinico, Mangiagalli and Regina Elena Foundation IRCCS, University of Milan, Milan, Italy