Alterations In Cardiac Function Research Articles

Diastolic Dysfunction in Hypertension: A Comprehensive Review of Pathophysiology, Diagnosis, and Treatment.

Diastolic dysfunction refers to impaired relaxation or filling of the ventricles during the diastolic phase of the cardiac cycle. Left ventricular diastolic dysfunction (LVDD) is common in hypertensive individuals and is associated with increased morbidity and mortality. LVDD serves as a critical precursor to heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). The pathophysiology of LVDD in hypertension is complex, involving alterations in cardiac structure and function, neurohormonal activation, and vascular stiffness. While the diagnosis of LVDD relies primarily on echocardiography, management remains challenging due to a lack of specific treatment guidelines for LVDD. This review offers an overview of the pathophysiological mechanisms underlying LVDD in hypertension, diagnostic methods, clinical manifestations, strategies for managing LVDD, and prospects for future research.

Genistein alleviates doxorubicin-induced cardiomyocyte autophagy and apoptosis via ERK/STAT3/c-Myc signaling pathway in rat model.

Doxorubicin (Dox) is a highly effective anti-neoplastic agent. Still, its utility in the clinic has been hindered by toxicities, including vomiting, hematopoietic suppression and nausea, with cardiotoxicity being the most serious side effect. Genistein (Gen) is a natural product with extensive biological effects, including anti-oxidation, anti-tumor, and cardiovascular protection. This study evaluated whether Gen protected the heart from Dox-induced cardiotoxicity and explored the underlying mechanisms. Male Sprague-Dawley (SD) rats were categorized into control (Ctrl), genistein (Gen), doxorubicin (Dox), genistein 20 mg/kg/day + doxorubicin (Gen20 + Dox) and genistein 40 mg/kg/day + doxorubicin (Gen40 + Dox) groups. Six weeks after injection, immunohistochemistry (IHC), transmission electron microscopy (TEM), and clinical cardiac function analyses were performed to evaluate the effects of Dox on cardiac function and structural alterations. Furthermore, each heart histopathological lesions were given a score of 0-3 in compliance with the articles for statistical analysis. In addition, molecular and cellular response of H9c2 cells toward Dox were evaluated through western blotting, Cell Counting Kit-8 (CCK8), AO staining and calcein AM/PI assay. Dox (5 μM in vitro and 18 mg/kg in vivo) was used in this study. In vivo, low-dose Gen pretreatment protected the rat against Dox-induced cardiac dysfunction and pathological remodeling. Gen inhibited extracellular signal-regulated kinase1/2 (ERK1/2)'s phosphorylation, increased the protein levels of STAT3 and c-Myc, and decreased the autophagy and apoptosis of cardiomyocytes. U0126, a MEK1/2 inhibitor, can mimic the effect of Gen in protecting against Dox-induced cytotoxicity both in vivo and in vitro. Molecular docking analysis showed that Gen forms a stable complex with ERK1/2. Gen protected the heart against Dox-induced cardiomyocyte autophagy and apoptosis through the ERK/STAT3/c-Myc signaling pathway.

#1910 Echocardiographic findings in patients with advanced diabetic kidney disease and obstructive sleep apnea

Abstract Background and Aims Obstructive sleep apnea (OSA) is associated with accelerated development of cardiovascular disease. The prevalence of OSA is increased in both type 2 diabetes (DM2) and in chronic kidney disease, and is very high in patients with diabetic kidney disease. However, the contribution of OSA to alterations in cardiac structure and function in diabetic kidney disease remains unknown. We therefore compared cardiac structure and function in diabetic kidney disease patients with or without OSA. Method In a cross-sectional study, 120 patients with DM2, a urine albumin-creatinine ratio (UACR) > 30 mg/g and an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 were tested for OSA. OSA severity was quantified by the apnea-hypopnea-index (AHI). Patients without OSA (AHI < 5 events/hour) were compared to patients with moderate (AHI 15-29 events/hour) or severe OSA (AHI ≥30 events/hour). Transthoracic echocardiography was conducted in all patients to evaluate cardiac structure and function. Linear regression analyses were used to assess the associations between OSA and echocardiographic parameters. Results AHI-data were available for 114 patients; 43 had no OSA, 33 had mild OSA and 38 had moderate-severe OSA. A total of 74 patients (73% men), 39 with no OSA and 35 with moderate-severe OSA, had complete data for both echocardiography and OSA. Their mean age was 71.5 ± 9.4 years, mean eGFR was 32.2 ± 12.3 mL/min/1.73 m2 and the median UACR of 533 (192–1707) mg/g. Age, smoking status, diabetes duration, eGFR, blood pressure, antihypertensive medicine, chronic obstructive pulmonary disease and atrial fibrillation were not significantly different between patients with and without OSA. Patients with moderate-severe OSA had significantly larger left atrial volume index (LAVI) (39.0 ± 19.6 vs. 28.1 ± 10.5 mL/m2, P = 0.0035), left ventricular mass index (LVMI) (49.2 ± 12.0 vs. 41.8 ± 9.7, g/m2, P = 0.0043), and right ventricular diameter (34.3 ± 5.8 vs. 28.4 ± 4.4 mm, P < 0.0001) compared to those without OSA (Fig. 1). Global longitudinal strain (GLS) was significantly reduced in OSA patients (−14.9 ± 3.1 vs. −16.6 ± 2.8, P = 0.0196), while no difference was observed in LV ejection fraction (54.4 ± 8.1 vs. 56.5 ± 6.2, p = 0.21). The association between OSA and LAVI, LVMI, right ventricular diameter and GLS remained significant after adjustment for age, sex, eGFR and mean arterial pressure. Conclusion Moderate-severe OSA is independently associated with alterations in cardiac structure and function in patients with diabetic kidney disease and reduced renal function. OSA could be an independent contributor to the development of heart failure in patients with diabetic kidney disease.

#2246 Cardiovascular changes and outcomes across the early CKD spectrum: a UK Biobank cardiovascular MRI substudy

Abstract Background and Aims Chronic kidney disease (CKD) patients are at a significant risk of accelerated cardiovascular (CV) disease (CVD), which increases as glomerular filtration rate (GFR) declines. The prevalence of CVD in early CKD is high but there is lack of data on early myocardial changes in this group of patients. We investigated the associations of early CKD with alterations in cardiac structure and function and adverse CV outcomes using cardiovascular magnetic resonance (CMR) imaging. Method We used measures of CMR analysis from participants in the UK Biobank CMR imaging substudy to extract information on morphology and function of the four heart chambers. Early CKD was defined as an estimated GFR with cystatin (eGFRcys) between 60 and 90 ml/min. Patients with left ventricular ejection fraction <50%, history of CVD, eGFRcys < 60 ml/min, uACR > 3 mg/mmol, and those on renal replacement therapy were excluded. The association between early CKD and CMR parameters was analysed in 5 linear regression models: unadjusted, age adjusted, sociodemographic adjusted, sociodemographic and lifestyle adjusted, and a fully adjusted model also including clinical characteristics. Cox regression analyses were used to determine association between mildly decreased eGFR and adverse CV outcomes (myocardial infarction, stroke, CV death, and a composite CV outcome). Results A total of 33 124 individuals [17 825 (53.8%) women, age 64 (11) years] who received CMR imaging between 2014 and 2019 and fulfilled the inclusion criteria were identified: 19,919 with no CKD and 13,205 with early CKD. Participants with early CKD were more likely to be older, males and smokers. In the fully adjusted model, early CKD was associated with structural changes in the left ventricle (LV) [mass −1.04 g (−1.75 to −0.33), end-diastolic volume −2.69 mL (−4.01 to −1.38), end-systolic volume −0.95 mL (−1.30 to −0.60)], right ventricle (RV) [end-diastolic volume −3.24 mL (−4.67 to −1.82), end-systolic volume −1.73 mL (−2.55 to −0.91)], right atrium (maximum volume −2.81 mL (−4.09 to −1.53), minimal volume −1.46 mL (−2.30 to −0.62)]. Early CKD was also associated with a change in LV global circumference strain [-0.16 (−0.31 to −0.01)] but it was not associated with changes in the left atrium parameters or functional parameters [LV ejection fraction 0.21 (−0.05 to 0.48), RV ejection fraction 0.21 (−0.07 to 0.49)]. These changes were not associated with adverse CV outcomes on multivariable analyses (HR for MI 1.35, 95% CI 0.94-1.94; HR for stroke 0.98, 95% CI 0.63-1.50). Conclusion In a low-risk general population (without known CVD and with preserved LV ejection fraction) mildly reduced kidney function, as measured with eGFRcys, was associated with smaller LV and RV volumes, larger LV mass, and impaired LV global circumference strain. This early cardiac remodelling was not associated with adverse CV outcomes, but the event rate was very small during follow up. These findings suggest that cardiomyopathy associated with early CKD is not a regional condition of the left ventricle but affects the heart globally.

Dental pulp stem cells ameliorate D-galactose-induced cardiac ageing in rats.

Ageing is a key risk factor for cardiovascular disease and is linked to several alterations in cardiac structure and function, including left ventricular hypertrophy and increased cardiomyocyte volume, as well as a decline in the number of cardiomyocytes and ventricular dysfunction, emphasizing the pathological impacts of cardiomyocyte ageing. Dental pulp stem cells (DPSCs) are promising as a cellular therapeutic source due to their minimally invasive surgical approach and remarkable proliferative ability. This study is the first to investigate the outcomes of the systemic transplantation of DPSCs in a D-galactose (D-gal)-induced rat model of cardiac ageing. Methods. Thirty 9-week-old Sprague-Dawley male rats were randomly assigned into three groups: control, ageing (D-gal), and transplanted groups (D-gal + DPSCs). D-gal (300 mg/kg/day) was administered intraperitoneally daily for 8 weeks. The rats in the transplantation group were intravenously injected with DPSCs at a dose of 1 × 106 once every 2 weeks. The transplanted cells migrated to the heart, differentiated into cardiomyocytes, improved cardiac function, upregulated Sirt1 expression, exerted antioxidative effects, modulated connexin-43 expression, attenuated cardiac histopathological alterations, and had anti-senescent and anti-apoptotic effects. Our results reveal the beneficial effects of DPSC transplantation in a cardiac ageing rat model, suggesting their potential as a viable cell therapy for ageing hearts.

Transcriptomic profiling and regulatory pathways of cardiac resident macrophages in aging

Cardiovascular diseases are an array of age-related disorders, and accumulating evidence suggests a link between cardiac resident macrophages (CRMs) and the age-related disorders. However, how does CRMs alter with aging remains elusive. In the present study, aged mice (20 months old) have been employed to check for their cardiac structural and functional alterations, and the changes in the proportion of CRM subsets as well, followed by sorting of CRMs, including C-C Motif Chemokine Receptor 2 (CCR2)+ and CCR2– CRMs, which were subjected to Smart-Seq. Integrated analysis of the Smart-Seq data with three publicly available single-cell RNA-seq datasets revealed that inflammatory genes were drastic upregulated for both CCR2+ and CCR2– CRMs with aging, but genes germane to wound healing were downregulated for CCR2– CRMs, suggesting the differential functions of these two subsets. More importantly, inflammatory genes involved in damage sensing, complement cascades, and phagocytosis were largely upregulated in CCR2– CRMs, implying the imbalance of inflammatory response upon aging. Our work provides a comprehensive framework and transcriptional resource for assessing the impact of aging on CRMs with a potential for further understanding cardiac aging.

Interval training suppresses nod-like receptor protein 3 inflammasome activation to improve cardiac function in myocardial infarction rats by hindering the activation of the transforming growth factor-β1 pathway

ObjectiveMyocardial infarction (MI) -induced cardiac dysfunction can be attenuated by aerobic exercises. This study explored the mechanism of interval training (IT) regulating cardiac function in MI rats, providing some theoretical basis for clarifying MI pathogenesis and new ideas for clinically treating MI.MethodsRats were subjected to MI modeling, IT intervention, and treatments of the Transforming growth factor-β1 (TGF-β1) pathway or the nod-like receptor protein 3 (NLRP3) activators. Cardiac function and hemodynamic indicator alterations were observed. Myocardial pathological damage and fibrosis, reactive oxygen species (ROS) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, MDA content, inflammasome-associated protein levels, and inflammatory factor levels were assessed. The binding between TGF-β1 and receptor was detected.ResultsMI rats exhibited decreased left ventricle ejection fraction (LVEF), left ventricle fractional shortening (LVFS), left ventricular systolic pressure (LVSP), positive and negative derivates max/min (dP/dt max/min) and increased left ventricular end-systolic pressure (LVEDP), a large number of scar areas in myocardium, disordered cell arrangement and extensive fibrotic lesions, increased TGF-β1 and receptor binding, elevated ROS level and MDA content and weakened SOD, CAT and GSH-Px activities, and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and cleaved-caspase-1 levels, while IT intervention caused ameliorated cardiac function. IT inactivated the TGF-β1 pathway to decrease oxidative stress in myocardial tissues of MI rats and inhibit NLRP3 inflammasome activation. Activating NLRP3 partially reversed IT-mediated improvement on cardiac function in MI rats.ConclusionIT diminished oxidative stress in myocardial tissues and suppressed NLRP3 inflammasome activation via inactivating the TGF-β1 pathway, thus improving the cardiac function of MI rats.

Association of attenuated leptin signaling pathways with impaired cardiac function under prolonged high-altitude hypoxia

Cardiovascular function and adipose metabolism were markedly influenced under high altitudes. However, the interplay between adipokines and heart under hypoxia remains to be elucidated. We aim to explore alterations of adipokines and underlying mechanisms in regulating cardiac function under high altitudes. We investigated the cardiopulmonary function and five adipokines in Antarctic expeditioners at Kunlun Station (4,087 m) for 20 days and established rats exposed to hypobaric hypoxia (5,000 m), simulating Kunlun Station. Antarctic expeditioners exhibited elevated heart rate, blood pressure, systemic vascular resistance, and decreased cardiac pumping function. Plasma creatine phosphokinase-MB (CK-MB) and platelet-endothelial cell adhesion molecule-1 (sPecam-1) increased, and leptin, resistin, and lipocalin-2 decreased. Plasma leptin significantly correlated with altered cardiac function indicators. Additionally, hypoxic rats manifested impaired left ventricular systolic and diastolic function, elevated plasma CK-MB and sPecam-1, and decreased plasma leptin. Chronic hypoxia for 14 days led to increased myocyte hypertrophy, fibrosis, apoptosis, and mitochondrial dysfunction, coupled with reduced protein levels of leptin signaling pathways in myocardial tissues. Cardiac transcriptome analysis revealed leptin was associated with downregulated genes involved in rhythm, Na+/K+ transport, and cell skeleton. In conclusion, chronic hypoxia significantly reduced leptin signaling pathways in cardiac tissues along with significant pathological changes, thus highlighting the pivotal role of leptin in regulation of cardiac function under high altitudes.

Myocardial function, mechanics and work by echocardiography in adolescents with severe obesity.

Obesity and its metabolic complications can impact the heart's structure and function in childhood, although demonstrating this impact has been challenging. New echocardiographic parameters such as left atrial strain (LAε) and left ventricular strain (LVε), as well as myocardial work (MW), could reveal subclinical alterations in cardiac function. The aim is to evaluate the feasibility of these parameters in adolescents with severe obesity and explore their associations with body fat, metabolic comorbidities, and physical capacity. This is a cross-sectional study in adolescents with obesity who underwent echocardiography with analysis of LAε, LVε and MW using speckle tracking. Feasibility and association with anthropometry, body fat percentage, comorbidities and cardiopulmonary test were analyzed. Twenty adolescents were recruited, 13 (65%) were males, median age 14.2 (interquartile range: 12.9-14.9) years old. The median Z-score for BMI (zBMI) was +3.03 (2.87-3.14), 14 (70%) had severe obesity (zBMI ≥+3), 12 (60%) body fat ≥95th percentile, 9 (45%) high blood pressure (HBP) and 8 (40%) metabolic syndrome. The analysis of the echocardiographic parameters was feasible in 95% (LAε) and 100% (LVε and MW). LVε was lower in adolescents with vs. without metabolic syndrome: 17.8% (17.5-19.3%) vs. 19.3% (18.3-20.3%), P = 0.046; and with vs. without HBP 17.8% (17.5-18.6%) vs. 19.7% (18.4-20.3%), P = 0.02. Those with body fat ≥95th percentile had lower LAε and MW parameters, without association with cardiopulmonary test. Echocardiographic evaluation of LAε, LVε and MW is feasible in adolescents with severe obesity. A higher proportion of body fat and the presence of comorbidities are associated with alterations in these new echocardiographic functional parameters suggesting myocardial impact of higher metabolic compromise.

Bone Mechanical Loading Reduces Heart Rate and Increases Heart Rate Variability via the Autonomic Nervous System in Anesthetized Mice

Mechanical loading of bone creates interstitial fluid flow and shear stress within the bone lacunocanalicular system, leading to alterations of bone size and mass. Bone plays an important role as an endocrine organ, releasing endocrine signaling molecules that impact systemic physiology. Further, the central and peripheral nervous systems regulate bone mass in response to strain through alterations in autonomic tone. This suggests the potential for interplay between bone and other organs via endocrine signaling and autonomic innervation. In this study, our group investigated this potential interplay by focusing on bone and heart. We hypothesized that mechanical bone loading of mice in vivo would result in altered cardiac function. To test this hypothesis, we performed acute in vivo mechanical loading on right leg tibias of anesthetized TOPGAL and CD-1 mice. Tibias underwent compressive cyclic loading (a sine wave) that modulates between -0.3N and -9.0N for 300 cycles at 2 Hz. Cardiac function was monitored with lead II electrocardiogram (ECG) data, heart rate (HR), and heart rate variability (HRV). Immediate, transient reduction in resting HR (0.93 ± 0.013 fold change from baseline, n=6-7, p<0.01 compared to control) was achieved during tibial loading in 6-month-old male and female mice, with concurrent increase in HRV (1.24 ± 0.11 fold change from baseline, n=6-7, p<0.01). Both HR and HRV returned to baseline levels upon completion of the loading process. ECG measurements, QRS and corrected QT (QTc), were not found to be altered (p>0.05) during loading and 30 minutes following loading. In further studies, 1N-2N did not produce a decrease in HR, while 3N (0.92 ± 0.077 fold change from baseline, n=12, p<0.05) and 9N (0.93 ± 0.061 fold change from baseline, n=13, p<0.05) decreased HR. There was decreased magnitude and responsiveness with aging to 11 months old at 3N and 9N (p>0.05), suggesting the response may weaken with age. The immediate, transient nature of the changes to resting HR and HRV suggest a neural mechanism for this response. To test this mechanism, we inhibited local neuronal afferent activity by injecting lidocaine (2.5mg/kg) near the tibia prior to loading. In doing so, the decrease in HR during loading was significantly diminished (vehicle 0.90 ± 0.060 vs. lidocaine 0.97 ± 0.042 fold change from baseline, n=7-8, p<0.05). To test the efferent arm of the response, mice were injected with the parasympathetic, muscarinic acetylcholine receptor antagonist atropine (2mg/kg), or the sympathetic, β1/β2 receptor antagonist propranolol (10mg/kg). Propranolol significantly inhibited the HR decrease during loading (vehicle 0.88 ± 0.095 vs. propranolol 0.98 ± 0.026 fold change from baseline, n=7-8, p<0.05), while atropine did not (n=8-11, p>0.05). These findings suggest that reductions in sympathetic tone on the heart during bone loading led to the decrease in HR. In conclusion, this study uncovered a reflexive neural connection between bone and heart that is affected by age and mediated by afferent neurons in the tibia and alterations in efferent sympathetic tone to the heart. These findings provide new knowledge that builds on the current science of bone remodeling and its regulation. This study was funded by HRSA Medical Student Education Grant T99HP39202 and NIH P01AG039355. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Insulin Treatment Does Not Prevent EARLY Autonomic Cardiovascular and Diastolic Dysfunctions in Streptozotocin-Induced Diabetic Rats.

Recent studies have found increased cardiovascular mortality risk in patients with type 1 diabetes when compared to normoglycemic people, even when they were kept under good glycemic control. However, the mechanisms underlying this condition have yet to be fully understood. Using streptozotocin (STZ)-induced diabetic rats, we evaluated the effects of insulin replacement therapy on cardiac, autonomic, inflammatory, and oxidative stress parameters. Daily treatment with insulin administrated subcutaneously in the STZ-diabetic rats showed a reduction in hyperglycemia (>250 mg/dL) to normalized values. The insulin treatment was effective in preventing alterations in cardiac morphometry and systolic function but had no impact on diastolic function. Also, the treatment was not able to prevent the impairment of baroreflex-tachycardic response and systolic arterial pressure variability (SAP-V). A correlation was found between improvement of these autonomic parameters and higher levels of IL-10 and lower levels of oxidized glutathione. Our findings show that insulin treatment was not able to prevent diastolic, baroreflex, and SAP-V dysfunction, suggesting an outstanding cardiovascular risk, even after obtaining a good glycemic control in STZ-induced diabetic rats. This study shed light on a relatively large population of diabetic patients in need of other therapies to be used in combination with insulin treatment and thus more effectively manage cardiovascular risk.

Evaluation of Alterations in Basic Cardiac Functions in Operators of Artisanal Refineries in Rivers State, Nigeria

The impact of numerous artisanal refineries on the populace in Niger Delta region has been a great source of mainly health, economic and environmental concerns. Thus, the present study comparatively assessed the alterations of basic cardiac functions that may be associated with the operation of artisanal refineries (OAR) in Rivers State of Nigeria. This cross-sectional survey used a multi-stage sampling technique (including purposive and snowball tools) to recruit 203 (including 120 OAR-exposed and 83 non-OAR exposed) consenting and apparently healthy adult male and female subjects. With the use of the electrocardiographic (ECG) machine, the basic ECG indices were recorded from the study subjects. Quantitative data obtained from the subjects were subjected to statistical analyses using the Statistical Package for Social Sciences (SPSS) version 21.0. The result indicated significantly (P<0.0) elevated heart rates in the OAR-exposed subjects when compared to their non-OAR-exposed counterparts. Amongst the various ECG features, the exposed subjects predominantly presented with left atrial enlargement (LAE) (male exposed=57% and female exposed =46.3%) as against none in the unexposed group. And there was no significant association of the incidences of Abnormal/clinical ECG Features between the actively exposed (OAR operators) and passively exposed (residents in same city who are non-OAR operators) subjects. In conclusion, the operation of artisanal refineries in our locale may potentially predispose its operators to significant elevation of heart rate and incidences of abnormal ECG features.

First trimester screening identifies maternal cardiac maladaptation at mid-gestation.

First, a logistic regression model, based on maternal demographic characteristics and medical history and blood pressure at 11-13 weeks' gestation, can identify about 70% of women who develop future chronic hypertension (CH) in the three years following pregnancy, at screen positive rate of 10%. Second, at mid-gestation women who subsequently develop hypertensive disorders of pregnancy (HDP) have increased peripheral vascular resistance and mild cardiac functional and morphological alterations and these cardiovascular abnormalities persist for at least 2 years after delivery. To examine whether the use of the first-trimester risk for subsequent development of CH can help to identify women at high risk for cardiovascular maladaptation at mid-gestation. Prospective observational study in 3812 women with singleton pregnancies women attending for a routine hospital visit at 11+0 to 13+6 weeks' gestation and again at 19+1 to 23+3 weeks at King's College Hospital, London, UK between August 2019 and August 2020. The first-trimester visit included recording of maternal demographic characteristics and medical history and measurement of systolic and diastolic blood pressure. At mid-gestation detailed maternal cardiovascular assessment was carried out. The association of risk for development of CH, determined from first-trimester assessment, and cardiovascular indices at mid-gestation was examined. Women who are at high-risk for development of future CH, compared to those at low-risk, had a higher incidence of hypertensive disorders of pregnancy (HDP). In addition, high-risk women, had reduced systolic and diastolic function at mid-gestation. Among women with HDP, those who were high-risk for future CH, compared to those at low-risk, also had worse cardiac function at mid-gestation. Use of a model for first-trimester prediction of subsequent development of CH can identify women who show evidence of cardiac maladaptation at mid-gestation. Further studies are needed to clarify whether women who screen as high-risk for future CH, compared to those at low-risk, have reduced cardiac function beyond pregnancy. This article is protected by copyright. All rights reserved.

Characterizing the Causal Pathway From Childhood Adiposity to Right Heart Physiology and Pulmonary Circulation UsingLifecourse Mendelian Randomization.

Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging. In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end-diastolic volume: β=0.24 [95% CI, 0.15-0.33]; P=3×10-7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat-free mass and childhood height, respectively. Our findings suggest that, although childhood body size has a long-term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse.

Serum metabolite signatures of cardiac function and morphology in individuals from a population-based cohort

BackgroundChanges in serum metabolites in individuals with altered cardiac function and morphology may exhibit information about cardiovascular disease (CVD) pathway dysregulations and potential CVD risk factors. We aimed to explore associations of cardiac function and morphology, evaluated using magnetic resonance imaging (MRI) with a large panel of serum metabolites.MethodsCross-sectional data from CVD-free individuals from the population-based KORA cohort were analyzed. Associations between 3T-MRI-derived left ventricular (LV) function and morphology parameters (e.g., volumes, filling rates, wall thickness) and markers of carotid plaque with metabolite profile clusters and single metabolites as outcomes were assessed by adjusted multinomial logistic regression and linear regression models.ResultsIn 360 individuals (mean age 56.3 years; 41.9% female), 146 serum metabolites clustered into three distinct profiles that reflected high-, intermediate- and low-CVD risk. Higher stroke volume (relative risk ratio (RRR): 0.53, 95%-CI [0.37; 0.76], p-value < 0.001) and early diastolic filling rate (RRR: 0.51, 95%-CI [0.37; 0.71], p-value < 0.001) were most strongly protectively associated against the high-risk profile compared to the low-risk profile after adjusting for traditional CVD risk factors. Moreover, imaging markers were associated with 10 metabolites in linear regression. Notably, negative associations of stroke volume and early diastolic filling rate with acylcarnitine C5, and positive association of function parameters with lysophosphatidylcholines, diacylphosphatidylcholines, and acylalkylphosphatidylcholines were observed. Furthermore, there was a negative association of LV wall thickness with alanine, creatinine, and symmetric dimethylarginine. We found no significant associations with carotid plaque.ConclusionsSerum metabolite signatures are associated with cardiac function and morphology even in individuals without a clinical indication of CVD.

Long-term cardiovascular assessment of women who had a pregnancy complicated by a hypertensive disorder.

Women with hypertensive disorders of pregnancy (HDP) are at increased risk of developing hypertension and cardiovascular disease later in life. However, from studies so far, it is difficult to define whether this association reflects preexisting maternal cardiovascular risk or merely reflect a potentially causal relationship between HDP and later cardiovascular risk. We performed detailed cardiovascular assessment in women at mid-gestation, prior to development of a HDP and at 2 years post-partum aiming to identify cardiovascular changes prior to development of HDP and to assess persistent cardiovascular alterations long after the HDP event. This was a prospective observational study in which we performed detailed cardiovascular assessment at mid-gestation and at median of 2.3 years (interquartile range 2.1 to 2.4 years) post-partum. We examined 112 women who developed a HDP and 451 women whose pregnancy was not complicated by hypertension. We used conventional and more advanced echocardiographic techniques, i.e. speckle tracking, to accurately determine left ventricular systolic and diastolic function. We used M-mode measurements to determine left ventricular remodeling and estimate left ventricular mass. Maternal vascular status was assessed using ophthalmic artery Doppler and by calculating peak systolic velocity (PSV) ratio, as a marker of peripheral vascular resistance. At mid-gestation, women who subsequently developed HDP had increased ophthalmic artery PSV ratio. These women also had mild cardiac functional and morphological alterations which were mostly accounted for by maternal cardiovascular risk factors. At 2 years post-partum, women who experienced HDP, compared to those who did not, had cardiovascular abnormalities with reduction in left ventricular systolic and diastolic function which remained after multivariable analysis. Longitudinal analysis demonstrated that the evolution of cardiovascular changes in the HDP and non-HDP groups was similar. Mild cardiac functional and morphological alterations precede the development of HDP and such changes persist for at least 2 years postpartum. The cardiac changes are likely to be the consequence of preexisting maternal cardiovascular risk factors rather than an adverse consequence of HDP. This article is protected by copyright. All rights reserved.

Aldosterone Effect on Cardiac Structure and Function.

Cardiac remodelling could be a key mechanism in aldosteronemediated cardiovascular morbidity and mortality. Experimental and clinical evidence has demonstrated that aldosterone causes cardiac structural remodelling and dysfunction by its profibrotic and pro-hypertrophic effects, which result mainly from the direct effects on myocardial collagen deposition, inflammation, and oxidative stress. Clinical studies have investigated the aldosterone effects on the heart in different clinical conditions, including general population, essential hypertension, primary aldosteronism, heart failure, and atrial fibrillation. Robust findings indicate that aldosterone or the activation of the cardiac mineralocorticoid receptor can cause damage to myocardial tissue by mechanisms independent of the blood pressure, leading to tissue hypertrophy, fibrosis, and dysfunction. Aldosterone-mediated cardiovascular morbidity and mortality mainly result from cardiac structural and functional alterations. In different clinical settings, aldosterone can induce cardiac structural remodelling and dysfunction via several pathological mechanisms, including cardiac fibrosis, inflammation, and oxidative stress. Aldosterone antagonists could effectively decrease or reverse the detrimental aldosterone-mediated changes in the heart.

The TTN p. Tyr4418Ter mutation causes cardiomyopathy in human and mice.

To generate a mouse model carrying TTNtv Y4370* simulating the newly discovered human heterozygous nonsense TTNtv c.13254T>G (p.Tyr4418Ter) to supplement and improve the functional evidence of pathogenic mutation TTNtv c.13254T>G on the pathogenic type of dilated cardiomyopathy. We generated 4 mice carrying TTNtv p. Y4370* through CRISPR/Cas-mediated genome engineering. Monthly serological detection, bimonthly echocardiography, and histology evaluation were carried out to observe and compare alterations of cardiac structure and function between 4 TTN+/- mice and 4 wild-type (WT) mice. For the two-month-old TTN+/- mice, serum glutamic-oxalacetic transaminase (AST), lactic dehydrogenase (LDH), and creatine kinase (CK) were significantly increased, the diastolic Left Ventricular Systolic Anterior Wall (LVAW), and the LV mass markedly rose, with the left ventricular volume displaying an increasing trend and Ejection Fraction (EF) and Fractional Shortening (FS) showing a decreasing trend. Besides, the histological evaluation showed that cardiac fibrosis level and positive rate of cardiac mast cell of TTN+/- mice were obviously increased compared with WT mice. TTNtv Y4370* could lead to cardiac structure and function alterations in mice, supplementing the evidence of TTNtv c.13254T>G pathogenicity in human.

Maternal cardiovascular function in midgestation is related to placental angiogenesis.

To investigate whether angiogenic markers of placental function are associated with maternal cardiac function and hemodynamic responses at 19-23 weeks' gestation, controlling for maternal risk factors and pregnancy complications. This was a prospective study of women with singleton pregnancy attending King's College Hospital, London, UK, for a routine hospital visit at 19-23 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure (MAP), maternal heart rate, serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). We also performed maternal echocardiography to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. Our cohort included 4006 women. Lower PlGF values were significantly associated with higher MAP (P < 0.0001), lower maternal heart rate (P < 0.0001), lower mitral valve s' mean velocity (P = 0.027) and higher left atrial area (P = 0.022) after adjustment for maternal characteristics and pregnancy complications. sFlt-1 was associated positively with relative wall thickness (P = 0.012), whereas sFlt-1/PlGF ratio was associated negatively with mitral valve A (P = 0.006) and positively with left atrial area (P = 0.015) and MAP (P = 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors based on their obstetric and medical history. A continuous association of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present in midgestation, independently of pre-existing maternal risk factors and pregnancy complications. Impaired placental function appears to be related to mild systolic and diastolic dysfunction and cardiac remodeling. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Platelets modulate cardiac remodeling via the collagen receptor GPVI after acute myocardial infarction.

Platelets play an important role in cardiovascular diseases. After acute myocardial infarction, platelets display enhanced activation and migrate into the infarct zone. Furthermore, platelets trigger acute inflammation and cardiac remodeling leading to alterations in scar formation and cardiac function as observed in thrombocytopenic mice. GPVI is the major collagen receptor in platelets and important for platelet activation and thrombus formation and stability. Antibody induced deletion of GPVI at the platelet surface or treatment of mice with recombinant GPVI-Fc results in reduced inflammation and decreased infarct size in a mouse model of AMI. However, the role of GPVI has not been fully clarified to date. In this study, we found that GPVI is not involved in the inflammatory response in experimental AMI using GPVI deficient mice that were analyzed in a closed-chest model. However, reduced platelet activation in response to GPVI and PAR4 receptor stimulation resulted in reduced pro-coagulant activity leading to improved cardiac remodeling. In detail, GPVI deficiency in mice led to reduced TGF-β plasma levels and decreased expression of genes involved in cardiac remodeling such as Col1a1, Col3a1, periostin and Cthrc1 7 days post AMI. Consequently, collagen quality of the scar shifted to more tight and less fine collagen leading to improved scar formation and cardiac function in GPVI deficient mice at 21d post AMI. Taken together, this study identifies GPVI as a major regulator of platelet-induced cardiac remodeling and supports the potential relevance of GPVI as therapeutic target to reduce ischemia reperfusion injury and to improve cardiac healing.