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Heart (British Cardiac Society) Jul 2023Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion.... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM.
METHODS
The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics.
CONCLUSION
TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM.
TRIAL REGISTRATION NUMBERS
NCT04706429 and ISRCTN57145331.
Topics: Humans; Trientine; Copper; Cardiomyopathy, Hypertrophic; Heart; Hypertrophy, Left Ventricular; Fibrosis
PubMed: 37137675
DOI: 10.1136/heartjnl-2022-322271 -
Journal of Clinical Medicine Jul 2023Right ventricular failure (RVF) is often caused by increased afterload and disrupted coupling between the right ventricle (RV) and the pulmonary arteries (PAs). After a... (Review)
Review
Right ventricular failure (RVF) is often caused by increased afterload and disrupted coupling between the right ventricle (RV) and the pulmonary arteries (PAs). After a phase of adaptive hypertrophy, pressure-overloaded RVs evolve towards maladaptive hypertrophy and finally ventricular dilatation, with reduced stroke volume and systemic congestion. In this article, we review the concept of RV-PA coupling, which depicts the interaction between RV contractility and afterload, as well as the invasive and non-invasive techniques for its assessment. The current principles of RVF management based on pathophysiology and underlying etiology are subsequently discussed. Treatment strategies remain a challenge and range from fluid management and afterload reduction in moderate RVF to vasopressor therapy, inotropic support and, occasionally, mechanical circulatory support in severe RVF.
PubMed: 37510837
DOI: 10.3390/jcm12144722 -
Circulation Research Jan 2024Cardiac hypertrophy is an intermediate stage in the development of heart failure. The structural and functional processes occurring in cardiac hypertrophy include...
BACKGROUND
Cardiac hypertrophy is an intermediate stage in the development of heart failure. The structural and functional processes occurring in cardiac hypertrophy include extensive gene reprogramming, which is dependent on epigenetic regulation and chromatin remodeling. However, the chromatin remodelers and their regulatory functions involved in the pathogenesis of cardiac hypertrophy are not well characterized.
METHODS
Protein interaction was determined by immunoprecipitation assay in primary cardiomyocytes and mouse cardiac samples subjected or not to transverse aortic constriction for 1 week. Chromatin immunoprecipitation and DNA sequencing (ChIP-seq) experiments were performed on the chromatin of adult mouse cardiomyocytes.
RESULTS
We report that the calcium-activated protein phosphatase CaN (calcineurin), its endogenous inhibitory protein carabin, the STK24 (STE20-like protein kinase 3), and the histone monomethyltransferase, MLL3 (mixed lineage leukemia 3) form altogether a macromolecular complex at the chromatin of cardiomyocytes. Under basal conditions, carabin prevents CaN activation while the serine/threonine kinase STK24 maintains MLL3 inactive via phosphorylation. After 1 week of transverse aortic constriction, both carabin and STK24 are released from the CaN-MLL3 complex leading to the activation of CaN, dephosphorylation of MLL3, and in turn, histone H3 lysine 4 monomethylation. Selective cardiac MLL3 knockdown mitigates hypertrophy, and chromatin immunoprecipitation and DNA sequencing analysis demonstrates that MLL3 is de novo recruited at the transcriptional start site of genes implicated in cardiomyopathy in stress conditions. We also show that CaN and MLL3 colocalize at chromatin and that CaN activates MLL3 histone methyl transferase activity at distal intergenic regions under hypertrophic conditions.
CONCLUSIONS
Our study reveals an unsuspected epigenetic mechanism of CaN that directly regulates MLL3 histone methyl transferase activity to promote cardiac remodeling.
Topics: Animals; Mice; Calcineurin; Cardiomegaly; Chromatin; Epigenesis, Genetic; Histones; Myocytes, Cardiac; Transferases; Ventricular Remodeling
PubMed: 38084599
DOI: 10.1161/CIRCRESAHA.123.323458 -
International Journal of Sports Medicine May 2024Changes in cardiac geometry develop after intense and prolonged training. Left ventricular enlargement, increased relative wall thickness, and growing mass of the left...
Changes in cardiac geometry develop after intense and prolonged training. Left ventricular enlargement, increased relative wall thickness, and growing mass of the left ventricle occur after strenuous exercise. Combat sports such as judo can lead to left ventricular hypertrophy. Previous studies have found that there are differences in left ventricular chamber size and thickness between the sexes, with female athletes having smaller wall diameters and less hypertrophy than male athletes. The research aims to examine heart muscle adaptations and remodeling of cardiac geometry among elite judo athletes and to evaluate differences between males and females. A cross-sectional study included a group of 19 (males n=10, females n=9) professional judokas between 20 and 30 years. Demographic and anthropometric data were collected. Cardiac geometry was determined by two-dimensional transthoracic echocardiography. In terms of left ventricular mass and the left ventricular mass index significant differences were found between male and female judokas (233.44±68.75 g vs. 164.11±16.59 g, p=0.009), (105.16±24.89 vs. 84.66±15.06, p=0.044), respectively. A greater enlargement of the heart muscle is observed in male athletes compared to the female group. Left ventricle enlargement is likely to occur among elite-level judokas.
Topics: Humans; Martial Arts; Female; Male; Cross-Sectional Studies; Hypertrophy, Left Ventricular; Echocardiography; Adult; Sex Factors; Young Adult; Heart Ventricles; Athletes; Ventricular Remodeling; Adaptation, Physiological
PubMed: 38401535
DOI: 10.1055/a-2252-1239 -
Hypertension (Dallas, Tex. : 1979) Nov 2023Left ventricular hypertrophy is a bipolar response, starting as an adaptive response to the hemodynamic challenge, but over time develops maladaptive pathology partly...
BACKGROUND
Left ventricular hypertrophy is a bipolar response, starting as an adaptive response to the hemodynamic challenge, but over time develops maladaptive pathology partly due to microvascular rarefaction and impaired coronary angiogenesis. Despite the profound influence on cardiac function, the mechanotransduction mechanisms that regulate coronary angiogenesis, leading to heart failure, are not well known.
METHODS
We subjected endothelial-specific knockout mice of mechanically activated ion channel, TRPV4 (transient receptor potential cation channel subfamily V member 4; TRPV4) to pressure overload via transverse aortic constriction and examined cardiac function, cardiomyocyte hypertrophy, cardiac fibrosis, and apoptosis. Further, we measured microvascular density and underlying TRPV4 mechanotransduction mechanisms using human microvascular endothelial cells, extracellular matrix gels of varying stiffness, unbiased RNA sequencing, small interfering RNA, Western blot, quantitative-PCR, and confocal immunofluorescence techniques.
RESULTS
We demonstrate that endothelial-specific deletion of TRPV4 preserved cardiac function, cardiomyocyte structure, and reduced cardiac fibrosis compared with TRPV4 mice, 28 days post-transverse aortic constriction. Interestingly, comprehensive RNA sequencing analysis revealed an upregulation of proangiogenic factors (VEGFα [vascular endothelial growth factor α], NOS3 [nitric oxide synthase 3], and FGF2 [fibroblast growth factor 2]) with concomitant increase in microvascular density in TRPV4 hearts after transverse aortic constriction compared with TRPV4. Further, an increased expression of VEGFR2 (vascular endothelial growth factor receptor 2) and activation of the YAP (yes-associated protein) pathway were observed in TRPV4 hearts. Mechanistically, we found that downregulation of TRPV4 in endothelial cells induced matrix stiffness-dependent activation of YAP and VEGFR2 via the Rho/Rho kinase/large tumor suppressor kinase pathway.
CONCLUSIONS
Our results suggest that endothelial TRPV4 acts as a mechanical break for coronary angiogenesis, and uncoupling endothelial TRPV4 mechanotransduction attenuates pathological cardiac hypertrophy by enhancing coronary angiogenesis.
Topics: Animals; Humans; Mice; Cardiomegaly; Disease Models, Animal; Endothelial Cells; Hypertrophy, Left Ventricular; Mechanotransduction, Cellular; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; TRPV Cation Channels; Vascular Endothelial Growth Factor A
PubMed: 37702061
DOI: 10.1161/HYPERTENSIONAHA.123.21528 -
Circulation Jan 2024Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease....
BACKGROUND
Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized.
METHODS
This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension.
RESULTS
The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all <0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002-1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03-1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP.
CONCLUSIONS
Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension.
Topics: Male; Humans; Adult; Middle Aged; Aged; Female; Aldosterone; Ventricular Remodeling; Hypertrophy, Left Ventricular; Renin; Cardiovascular Diseases; Prospective Studies; Cohort Studies; Pulse Wave Analysis; Hypertension; Hyperaldosteronism; Heart Atria
PubMed: 38031887
DOI: 10.1161/CIRCULATIONAHA.123.066389 -
Heart (British Cardiac Society) May 2024Left ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH... (Observational Study)
Observational Study
BACKGROUND
Left ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of patients with FD and no LVH at baseline evaluation.
METHODS
Consecutively referred adult (aged ≥16 years) patients with FD were enrolled into an observational cohort study. Patients were prospectively followed in a specialist cardiomyopathy centre and the primary endpoint was the first detection of LVH (left ventricular mass index (LVMi) ≥115 g/m in men and ≥95 g/m in women).
RESULTS
From a cohort of 393 patients, 214 (aged 35.8±13.8 years; 61 (29%) males) had no LVH at first evaluation. During a median follow-up of 9.4 years (IQR 4.7-12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% CI 6.5% to 16.1%) at 5 years, 29.1% (95% CI 21.5% to 36.7%) at 10 years and 45.0% (95% CI 33.8% to 62.4%) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (HR 1.04 (95% CI 1.02 to 1.06) per 1-year increase, p<0.001), male sex (HR 2.90 (95% CI 1.66 to 5.09), p<0.001) and an abnormal ECG (HR 3.10 (95% CI 1.72 to 5.57), p<0.001). The annual rate of change in LVMi was +2.77 (IQR 1.45-4.62) g/m/year in males and +1.38 (IQR 0.09-2.85) g/m/year in females (p<0.001).
CONCLUSIONS
Approximately one-quarter of patients with FD developed LVH during follow-up. Age, male sex and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.
Topics: Humans; Fabry Disease; Hypertrophy, Left Ventricular; Male; Female; Adult; Incidence; Risk Factors; Middle Aged; Prospective Studies; Young Adult; Sex Factors; Time Factors
PubMed: 38688703
DOI: 10.1136/heartjnl-2023-323783 -
Vascular Pharmacology Dec 2023Hypertension represents a major contributor to the development of coronary artery disease. The pathophysiological mechanisms underlying the link between hypertension and...
Hypertension represents a major contributor to the development of coronary artery disease. The pathophysiological mechanisms underlying the link between hypertension and CAD are complex and include overactivation of neurohormones, accelerated development of the atherosclerotic plaque, endothelial dysfunction, altered intramyocardial coronary circulation, hypertension-mediated cardiac and vascular damage and the relationship between arterial stiffness and coronary perfusion. Blood pressure (BP) reduction is associated with a significant decrease of the risk of coronary events. Therapeutic interventions targeted to reduce BP and to improve endothelial function and coronary microvascular dysfunction, as well as to prevent left ventricular hypertrophy and dysfunction, contribute to reduce the burden of coronary disease and its acute ischemic manifestations.
Topics: Humans; Coronary Artery Disease; Hypertension; Myocardium; Hypertrophy, Left Ventricular; Coronary Circulation
PubMed: 37739329
DOI: 10.1016/j.vph.2023.107230 -
Hypertension (Dallas, Tex. : 1979) Aug 2023Approximately 40% of people with hypertension have left ventricular hypertrophy (LVH) detected by ECG or echocardiography. Because patients with LVH have poor myocardial... (Clinical Trial)
Clinical Trial
BACKGROUND
Approximately 40% of people with hypertension have left ventricular hypertrophy (LVH) detected by ECG or echocardiography. Because patients with LVH have poor myocardial microcirculation, they may be too sensitive to lowering systolic blood pressure (SBP) too much due to a lack of myocardial perfusion pressure. We aimed to investigate whether the average achieved SBP <130 mm Hg may cause harm in patients with LVH in the Valsartan Antihypertensive Long-Term Use Evaluation trial (VALUE).
METHODS
Of the 15 245 VALUE participants, we identified 13 803 patients without cardiovascular events during the first 6 months after randomization. Of these, 2458 patients had electrocardiographic LVH (ECG-LVH). Cox analyses adjusted for age, gender, and baseline variables compared cardiac and all-cause mortality and other prespecified end points for patients who achieved average SBP 130 to 139 mm Hg (No-LVH group n=4863; ECG-LVH group n=929) and <130 mm Hg (No-LVH group n=2107; ECG-LVH group n=305). Reference groups were patients who achieved average SBP ≥140 mm Hg following the first excluded 6 months (No-LVH group n=4375; ECG-LVH group n=1224).
RESULTS
The No-LVH group achieving average SBP <130 mm Hg had a significantly lower incidence of several cardiovascular end points. The ECG-LVH group achieving average SBP <130 mm Hg had higher cardiac mortality (hazard ratio, 1.98 [95% CIs, 1.06-3.70]; =0.032) and all-cause mortality (hazard ratio, 1.74 [95% CIs, 1.17-2.60]; =0.007), and SBP <130 mm Hg was not associated with a reduction in any end point.
CONCLUSIONS
Our findings may be seen as a signal that caution is warranted when treating middle-aged and older patients with electrocardiographic or echocardiographic LVH to SBP <130 mm Hg.
Topics: Aged; Humans; Middle Aged; Antihypertensive Agents; Blood Pressure; Electrocardiography; Hypertension; Hypertrophy, Left Ventricular; Valsartan
PubMed: 37350267
DOI: 10.1161/HYPERTENSIONAHA.123.21454 -
Heart Failure Reviews Sep 2023Studies over recent years have redeveloped our understanding of uremic cardiomyopathy, defined as left ventricular hypertrophy, congestive heart failure, and associated... (Review)
Review
Studies over recent years have redeveloped our understanding of uremic cardiomyopathy, defined as left ventricular hypertrophy, congestive heart failure, and associated cardiac hypertrophy plus other abnormalities that result from chronic kidney disease and are often the cause of death in affected patients. Definitions of uremic cardiomyopathy have conflicted and overlapped over the decades, complicating the body of published evidence, and making comparison difficult. New and continuing research into potential risk factors, including uremic toxins, anemia, hypervolemia, oxidative stress, inflammation, and insulin resistance, indicates the increasing interest in illuminating the pathways that lead to UC and thereby identifying potential targets for intervention. Indeed, our developing understanding of the mechanisms of UC has opened new frontiers in research, promising novel approaches to diagnosis, prognosis, treatment, and management. This educational review highlights advances in the field of uremic cardiomyopathy and how they may become applicable in practice by clinicians. Pathways to optimal treatment with current modalities (with hemodialysis and angiotensin-converting enzyme inhibitors) will be described, along with proposed steps to be taken in research to allow evidence-based integration of developing investigational therapies.
Topics: Humans; Uremia; Cardiomyopathies; Heart Failure; Hypertrophy, Left Ventricular; Cardiomegaly
PubMed: 37173614
DOI: 10.1007/s10741-023-10318-1