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Open Heart Nov 2023Left ventricular hypertrophy (LVH) is frequently seen in association with arterial hypertension and indicates poor prognosis. This study aimed to determine the...
BACKGROUND
Left ventricular hypertrophy (LVH) is frequently seen in association with arterial hypertension and indicates poor prognosis. This study aimed to determine the prevalence of LVH and associated factors in a multiethnic population from Mauritius.
METHODS
Population-based health surveys were performed in 2009 and 2015 and included in total 8961 individuals aged 35-75 years with recorded 12-lead ECG. LVH was defined according to three criteria: Sokolow-Lyon, Cornell voltage and Cornell product. Data were collected about health and lifestyle behaviour. Anthropometry and blood pressure were measured. Fasting levels of blood lipids and glucose were determined, oral glucose tolerance test was performed in people without glucose-lowering medications.
RESULTS
The age-standardised prevalence of LVH was 9% (n=875) according to any of the three ECG criteria. Individuals with LVH were older, more likely to have hypertension, diabetes, known cardiovascular disease (CVD) and elevated levels of cholesterol and creatinine. Further, they were more likely to be of African descent (Creole) and have lower educational level. In a multivariable model, Creole (OR (95% CI)) (1.56 (1.33 to 1.83)), low educational level (1.49 (1.28 to 1.75)), hypertension (3.01 (2.55 to 3.56)), known CVD (1.42 (1.11 to 1.83)) and elevated creatinine (1.08 (1.03 to 1.14)) remained associated with LVH. Individuals with non-treated or uncontrolled hypertension had a higher risk for LVH (3.09 (95% CI 2.57 to 3.71) and 4.07 (95% CI 3.29 to 5.05), respectively), than individuals with well controlled hypertension or normotension.
CONCLUSION
LVH occurs more frequently in individuals with hypertension, as well as in individuals with African ancestry and/or low education level.
Topics: Humans; Hypertrophy, Left Ventricular; Prevalence; Creatinine; Hypertension; Risk Factors; Cardiovascular Diseases; Electrocardiography; Glucose
PubMed: 37935562
DOI: 10.1136/openhrt-2023-002495 -
Cardiovascular Diabetology Jul 2023L-type Ca channel Ca1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac Ca1.2 channels are...
BACKGROUND
L-type Ca channel Ca1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac Ca1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of Ca1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how Ca1.2 channels are alternatively spliced in diabetic heart remains unknown.
METHODS
Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac Ca1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca concentration was monitored by using Fluo-4 AM.
RESULTS
We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased Ca1.2 channel with alternative exon 9* (Ca1.2), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of Ca1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates Ca1.2 channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac Ca1.2 channels. Moreover, GS treatment raises K-triggered intracellular Ca concentration ([Ca]), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates Ca1.2 channel, shifts Ca1.2 window currents to hyperpolarization, increases [Ca] and induces cardiomyocyte hypertrophy.
CONCLUSIONS
AGEs, not glucose, dysregulates Rbfox2 which thereby increases Ca1.2 channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca] in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for Ca1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced Ca1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.
Topics: Animals; Rats; Calcium; Calcium Channels, L-Type; Cardiomegaly; Diabetes Mellitus, Experimental; Glycation End Products, Advanced; Myocytes, Cardiac; RNA Splicing Factors
PubMed: 37415128
DOI: 10.1186/s12933-023-01894-5 -
Vascular Health and Risk Management 2023Hypertension is one of the main preventable cardiovascular (CV) risk factors all over the years, closely related to CV morbidity and mortality. One of the most common... (Review)
Review
Hypertension is one of the main preventable cardiovascular (CV) risk factors all over the years, closely related to CV morbidity and mortality. One of the most common hypertensive target organ damages is hypertensive heart disease (HHD), including left ventricular hypertrophy, which progresses gradually and leads to systolic or diastolic dysfunction of the left ventricular, and finally to end-stage heart failure. Regarding its prevalence and the need for early diagnosis, assessment of heart imaging examination is of major importance. Echocardiography has been used as the standard imaging technique to evaluate HHD for years, providing an accurate evaluation of the left ventricular geometry, along with the systolic and diastolic function. However, nowadays there is a growing interest in cardiovascular magnetic resonance (CMR). Despite the importance of the use of echocardiography in everyday clinical practice, numerous studies have shown the superiority of CMR as an imaging technique for clinical and research purposes, mainly due to its strength to provide an unlimited area of view, as well as the identification and quantification of the type and extent of myocardial fibrosis. Hence, this review aims to analyze the importance of heart imaging in the hypertensive population, with a special interest in CMR imaging.
Topics: Humans; Heart Diseases; Hypertrophy, Left Ventricular; Hypertension; Cardiomyopathies; Magnetic Resonance Imaging
PubMed: 38045022
DOI: 10.2147/VHRM.S436133 -
Kidney360 Aug 2023Higher plasma and urine kidney injury molecule-1, urine monocyte chemoattractant protein-1, and lower urine alpha-1-microglobulin were associated with left ventricular...
KEY POINTS
Higher plasma and urine kidney injury molecule-1, urine monocyte chemoattractant protein-1, and lower urine alpha-1-microglobulin were associated with left ventricular hypertrophy, even after adjustment for confounders. Biomarkers of tubular injury, dysfunction, and inflammation may indicate the severity of kidney pathology and are associated with left ventricular hypertrophy.
BACKGROUND
Left ventricular hypertrophy (LVH) is common in children with CKD and is associated with an increased risk of cardiovascular disease and mortality. We have shown that several plasma and urine biomarkers are associated with increased risk of CKD progression. As CKD is associated with LVH, we sought to investigate the association between the biomarkers and LVH.
METHODS
In the CKD in Children Cohort Study, children aged 6 months to 16 years with an eGFR of 30–90 ml/min per 1.73 m were enrolled at 54 centers in the United States and Canada. We measured plasma biomarkers kidney injury molecule-1 (KIM-1), tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, soluble urokinase-type plasminogen activator receptor and urine KIM-1, monocyte chemoattractant protein-1 (MCP-1), YKL-40, alpha-1-microglobulin (alpha-1m), and epidermal growth factor in stored plasma and urine collected 5 months after enrollment. Echocardiograms were performed 1 year after enrollment. We assessed the cross-sectional association between the log biomarker levels and LVH (left ventricular mass index greater than or equal to the 95th percentile) using a Poisson regression model, adjusted for age, sex, race, body mass index, hypertension, glomerular diagnosis, urine protein-to-creatinine ratio, and eGFR at study entry.
RESULTS
Among the 504 children, LVH prevalence was 12% (=59) 1 year after enrollment. In a multivariable-adjusted model, higher plasma and urine KIM-1 and urine MCP-1 concentrations were associated with a higher prevalence of LVH (plasma KIM-1 prevalence ratio [PR] per log: 1.27, 95% confidence interval [CI], 1.02 to 1.58; urine KIM-1 PR: 1.21, 95% CI, 1.11 to 1.48; and urine MCP-1 PR: 1.18, 95% CI, 1.04 to 1.34). After multivariable adjustment for covariates, lower urine alpha-1m was also associated with a higher prevalence of LVH (PR: 0.90, 95% CI, 0.82 to 0.99).
CONCLUSIONS
Higher plasma and urine KIM-1, urine MCP-1, and lower urine alpha-1m were each associated with LVH prevalence in children with CKD. These biomarkers may better inform risk and help elucidate the pathophysiology of LVH in pediatric CKD.
Topics: Humans; Child; Hypertrophy, Left Ventricular; Inflammation; Renal Insufficiency, Chronic; Kidney Tubules; Biomarkers
PubMed: 37303083
DOI: 10.34067/KID.0000000000000183 -
Cardiovascular Research Dec 2023Regular exercise training benefits cardiovascular health and effectively reduces the risk for cardiovascular disease. Circular RNAs (circRNAs) play important roles in...
AIMS
Regular exercise training benefits cardiovascular health and effectively reduces the risk for cardiovascular disease. Circular RNAs (circRNAs) play important roles in cardiac pathophysiology. However, the role of circRNAs in response to exercise training and biological mechanisms responsible for exercise-induced cardiac protection remain largely unknown.
METHODS AND RESULTS
RNA sequencing was used to profile circRNA expression in adult mouse cardiomyocytes that were isolated from mice with or without exercise training. Exercise-induced circRNA circUtrn was significantly increased in swimming-trained adult mouse cardiomyocytes. In vivo, circUtrn was found to be required for exercise-induced physiological cardiac hypertrophy. circUtrn inhibition abolished the protective effects of exercise on myocardial ischaemia-reperfusion remodelling. circUtrn overexpression prevented myocardial ischaemia-reperfusion-induced acute injury and pathological cardiac remodelling. In vitro, overexpression of circUtrn promoted H9 human embryonic stem cell-induced cardiomyocyte growth and survival via protein phosphatase 5 (PP5). Mechanistically, circUtrn directly bound to PP5 and regulated the stability of PP5 in a ubiquitin-proteasome-dependent manner. Hypoxia-inducible factor 1α-dependent splicing factor SF3B1 acted as an upstream regulator of circUtrn in cardiomyocytes.
CONCLUSION
The circRNA circUtrn is upregulated upon exercise training in the heart. Overexpression of circUtrn can prevent myocardial I/R-induced injury and pathological cardiac remodelling.
Topics: Animals; Humans; Mice; Cardiomegaly; Exercise; Myocardial Reperfusion Injury; Myocytes, Cardiac; RNA, Circular; Ventricular Remodeling; Utrophin
PubMed: 37897547
DOI: 10.1093/cvr/cvad161 -
Journal of Ethnopharmacology Jan 2024Dohongsammul-tang (DH) is a Korean traditional herbal medicine used to alleviate symptoms caused by extravasated blood. It is known to protect against cardiovascular...
ETHNOPHARMACOLOGICAL RELEVANCE
Dohongsammul-tang (DH) is a Korean traditional herbal medicine used to alleviate symptoms caused by extravasated blood. It is known to protect against cardiovascular diseases and promote blood circulation by activating blood circulation to dispel blood stasis. The DH based on the characteristics of its medicinal properties has discovered the potential of alleviating cardiac hypertrophy. Therefore, this study was performed to verify the pharmacological effect of DH on improving cardiovascular disorders and to demonstrate its mutual improvement effect on renal function. Furthermore, aim of this study is founding the new potential beyond the traditional medicinal efficacy of DH, a traditional medicine.
AIM OF THE STUDY
In cardiovascular disease, cardiac hypertrophy refers to a change in the shape of the heart's structure due to pressure overload. It is known that an increase in myofibrils causes thickening of the heart, resulting in high blood pressure. Therefore, suppressing cardiac hypertrophy may be a major factor in lowering the morbidity, mortality, and heart failure associated with cardiovascular disease. Therefore, the study was performed to investigate whether DH, traditionally used, has effects on improving and alleviating cardiac injury and fibrosis caused by cardiac hypertrophy.
MATERIALS AND METHODS
Dohongsamul-tang was composed of 6 herbal medicine and each material were boiled with 4 L distilled water for 2 h. The mixture for dohongsamul-tang centrifuged at 3000 rpm for 10 min and concentrated. The concentrated dohongsamul-tang extraction freeze-dried and sotred at 70 °C. The powder of dohongsamul-tang was diluted with distilled water and administered orally. In this study, pressure overload was induced by tying the transverse aortic arch, which is connected to the left ventricle, to the thickness of a 27G needle by performing a surgical operation. The resulting cardiac hypertrophy and heart remodeling was induced and maintained for 8 weeks.
RESULTS
The study administered propranolol and dohongsamul-tang orally for 10 weeks to investigate their effects on cardiac hypertrophy induced by transverse aortic contraction (TAC) surgery. Results showed that TAC group increased the left ventricle weight and decreased cardiac function, but dohongsamul-tang treatment attenuated these effects. The pressure-volume curve experiment revealed that dohongsamul-tang improved cardiovascular function, which was worsened by TAC group. Dohongsamul-tang treatment also downregulated collagen I and III through the TGF-β/Smad2 signaling pathway and improved hematological biomarkers of cardiac hypertrophy. In addition, dohongsamul-tang treatment improved renal function-related biomarkers, such as blood creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin, which were increased by TAC-induced cardiac hypertrophy.
CONCLUSIONS
Taken together, dohongsamul-tang treatment inhibited cardiac remodeling due to pressure overload in the TAC-induced cardiac hypertrophy model, and this effect is thought to be manifested by improving the functional and morphological changes through the calcineurin/NFATc4 and reducing the cardiac fibrosis by suppressing TGF-β/Smad2 signaling pathways.
Topics: Animals; Mice; Calcineurin; Cardiovascular Diseases; Ventricular Remodeling; Cardiomegaly; Fibrosis; Transforming Growth Factor beta; Plant Extracts; Water; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37453625
DOI: 10.1016/j.jep.2023.116844 -
Transplantation Dec 2023Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ...
BACKGROUND
Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application.
METHODS
Hearts from genetically modified ( GGTA1-KO , hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant.
RESULTS
Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared.
CONCLUSIONS
After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.
Topics: Humans; Animals; Male; Swine; Heterografts; Transplantation, Heterologous; Papio; Insulin-Like Growth Factor I; Ventricular Outflow Obstruction, Left; Antihypertensive Agents; Pilot Projects; Hypertrophy, Left Ventricular; Heart Transplantation
PubMed: 37643028
DOI: 10.1097/TP.0000000000004765 -
Cardiovascular Research Aug 2023The contribution of the right ventricle (RV) to cardiac output is negligible in normal resting conditions when pressures in the pulmonary circulation are low. However,...
The contribution of the right ventricle (RV) to cardiac output is negligible in normal resting conditions when pressures in the pulmonary circulation are low. However, the RV becomes relevant in healthy subjects during exercise and definitely so in patients with increased pulmonary artery pressures both at rest and during exercise. The adaptation of RV function to loading rests basically on an increased contractility. This is assessed by RV end-systolic elastance (Ees) to match afterload assessed by arterial elastance (Ea). The system has reserve as the Ees/Ea ratio or its imaging surrogate ejection fraction has to decrease by more than half, before the RV undergoes an increase in dimensions with eventual increase in filling pressures and systemic congestion. RV-arterial uncoupling is accompanied by an increase in diastolic elastance. Measurements of RV systolic function but also of diastolic function predict outcome in any cause pulmonary hypertension and heart failure with or without preserved left ventricular ejection fraction. Pathobiological changes in the overloaded RV include a combination of myocardial fibre hypertrophy, fibrosis and capillary rarefaction, a titin phosphorylation-related displacement of myofibril tension-length relationships to higher pressures, a metabolic shift from mitochondrial free fatty acid oxidation to cytoplasmic glycolysis, toxic lipid accumulation, and activation of apoptotic and inflammatory signalling pathways. Treatment of RV failure rests on the relief of excessive loading.
Topics: Humans; Heart Ventricles; Stroke Volume; Ventricular Function, Left; Hypertension, Pulmonary; Pulmonary Circulation; Ventricular Function, Right; Ventricular Dysfunction, Right; Pulmonary Artery
PubMed: 37463510
DOI: 10.1093/cvr/cvad108 -
IUBMB Life Nov 2023Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC-induced...
Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC-induced cardiomyopathy (PVC-CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200-220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC-CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC-CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store-operated Ca entry, calcineurin/NFAT pathway, β-myosin heavy chain, and skeletal type α-actin were unaltered in the PVC-CM group. In contrast, pro-hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC-CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti-hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro-hypertrophic factor VEGF-A and its receptor VEGFR2 were significantly elevated in the PVC-CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy.
Topics: Animals; Dogs; Ventricular Premature Complexes; Ventricular Remodeling; Cardiomyopathies; Disease Models, Animal; Hypertrophy
PubMed: 37427864
DOI: 10.1002/iub.2765 -
JAMA Cardiology Nov 2023Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling.
OBJECTIVE
To determine whether activation of β3ARs by repurposing a β3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF.
DESIGN, SETTING, AND PARTICIPANTS
The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022.
INTERVENTION
Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months.
MAIN OUTCOMES AND MEASURES
The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication.
RESULTS
Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial.
CONCLUSIONS
In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02599480.
Topics: Female; Humans; Male; Middle Aged; Adrenergic Agonists; Diabetes Mellitus, Type 2; Heart Failure; Hypertrophy, Left Ventricular; Prospective Studies; Aged
PubMed: 37728907
DOI: 10.1001/jamacardio.2023.3003