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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, particularly heart failure with preserved ejection fraction. 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. [ABSTRACT FROM AUTHOR]

Left ventricular (LV) diastolic dysfunction, atrial fibrillation (AF), and heart failure with preserved ejection fraction (HFpEF) share common risk factors and are closely related to one another and to adverse cardiovascular events. Exertional dyspnoea in patients with AF should trigger a comprehensive LV diastolic function evaluation since AF frequently precedes incident HFpEF. An echocardiographic assessment of LV diastolic function in patients with AF is challenging, mainly because of variability in cycle length, the absence of atrial contraction, and the frequent occurrence of left atrial enlargement regardless of LV filling pressures (LVFPs). The algorithm of the 2016 recommendations for the evaluation of LV diastolic function cannot be directly applied in this setting. This review discusses the modalities available for diastolic function assessment and HFpEF diagnosis in patients with AF. Based on currently available data, a reasonable clinical target of diastolic function evaluation in AF would be to reach a binary conclusion: LVFP elevated or not. Recently, a two-step algorithm that combined several echocardiographic parameters plus the inclusion of body mass index has been proposed to differentiate normal from elevated LVFP in patients with AF. The echocardiographic evaluation must be complemented by a thorough clinical evaluation along with natriuretic peptides and cardiac catheterization in selected cases. If a diagnosis of HFpEF cannot be ascertained, a close follow-up for timely identification of diastolic dysfunction markers, along with monitoring and correction of modifiable risk factors, is recommended. [ABSTRACT FROM AUTHOR]

Cardiac remodelling is often most profound in male athletes and in athletes with the greatest volumes of endurance training and is characterized by chamber enlargement and a mild-to-modest hypertrophy. The diastolic filling of the left ventricle (LV) is a complex process including the early recoil of the contracted LV, the active relaxation of the myocardium, the compliance of the myocardium, the filling pressures, and heart rate. Echocardiography is the cornerstone for the clinical assessment of LV diastolic function. LV diastolic function is usually enhanced in elite endurance athletes characterized by improved early filling of the ventricle, while it is preserved or enhanced in other athletes associated with the type of training being performed. This allows for the high performance of any endurance athlete. Typical findings when using resting echocardiography for the assessment of LV diastolic function in endurance athletes include a dilated LV with normal or mildly reduced LV ejection fraction (EF), significantly enlarged left atrium (LA) beyond the commonly used cut-off of 34 mL/m2, and a significantly elevated E/A ratio. The early-diastolic mitral annular velocity and the E-wave peak velocity are usually normal. Importantly, interpretation of the echocardiographic indices of LV diastolic function should always consider the clinical context and other parameters of systolic and diastolic functions. In the absence of an underlying pathology, single measurements outside the expected range for similar athletes will often not represent the pathology. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the left ventricular wall, diastolic dysfunction, and fibrosis, and is associated with mutations in genes encoding sarcomere proteins. While in vitro studies have used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study HCM, these models have not examined the multicellular interactions involved in fibrosis. Using engineered cardiac microtissues (CMTs) composed of HCM-causing MYH7-variant hiPSC-CMs and wild-type fibroblasts, we observed cell-cell cross-talk leading to increased collagen deposition, tissue stiffening, and decreased contractility dependent on fibroblast proliferation. hiPSC-CM conditioned media and single-nucleus RNA sequencing data suggested that fibroblast proliferation is mediated by paracrine signals from MYH7-variant cardiomyocytes. Furthermore, inhibiting epidermal growth factor receptor tyrosine kinase with erlotinib hydrochloride attenuated stromal activation. Last, HCM-causing MYBPC3-variant CMTs also demonstrated increased stromal activation and reduced contractility, but with distinct characteristics. Together, these findings establish a paracrine-mediated cross-talk potentially responsible for fibrotic changes observed in HCM. [ABSTRACT FROM AUTHOR]

Galectin-3 and Suppression of tumorigenicity-2 (ST2) are known markers of cardiac fibrosis. We investigated the prognostic value of fibrotic markers for the development of diastolic dysfunction and long-term outcome in patients suffering an ST-elevated myocardial infarction (STEMI). We analyzed 236 patients from the GIPS-III cohort with available echocardiographic studies and plasma measurements at hospitalization and after 4 months follow-up. Adjusted logistic mixed effects modelling revealed no association between the occurrence of diastolic dysfunction over time with abnormal plasma levels of galectin-3 and ST2. We observed no differences regarding survival outcome at follow-up of 5 years between patients with normal versus abnormal values in both galectin-3 (P = 0.75), and ST2 (P = 0.85). In conclusion, galectin-3 and sST2 were not associated with the development of diastolic dysfunction in non-diabetic patients that presented with a STEMI. [ABSTRACT FROM AUTHOR]

(1) Background: Pregnancy induces significant physiological adaptations with substantial impacts on the cardiovascular system. Hypertensive disorders of pregnancy (HDPs) are connected to significant risks of maternal and fetal complications, contributing significantly to morbidity and mortality across the globe. This study focuses on evaluating autonomic dysfunction by analyzing heart rate variability (HRV) and assessing cardiac performance through global longitudinal strain (GLS) using speckle tracking echocardiography, as well as examining diastolic function in pregnant women with HDP compared to healthy pregnant controls. (2) Methods: A case–control study was conducted involving pregnant women diagnosed with gestational hypertension (GH), preeclampsia (PE), or severe preeclampsia (SPE) as the case group, and healthy pregnant women as the control group. HRV was measured to evaluate autonomic function, GLS was assessed using speckle tracking echocardiography, and diastolic function was evaluated through standard echocardiographic parameters. Data were analyzed to compare cardiac performance and autonomic regulation between the HDP and control group, as well as among the different HDP subgroups. (3) Results: The HDP group exhibited significantly reduced HRV parameters compared to healthy controls, indicating notable autonomic dysfunction. Speckle tracking echocardiography revealed lower GLS among women with HDP, particularly in those with SPE, compared to the control group. Diastolic dysfunction was also present in the HDP group. (4) Conclusions: HRV and GLS are valuable non-invasive tools for detecting autonomic dysfunction and cardiac performance impairments in pregnant women with hypertensive disorders. These findings suggest that autonomic and cardiac dysfunctions are prevalent in HDP. [ABSTRACT FROM AUTHOR]

Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients. [ABSTRACT FROM AUTHOR]

The pathophysiology underlying impaired LV function in PAH remains unclear, with some studies implicating intrinsic myocardial dysfunction and others pointing to LV underfilling. Evaluation of pulmonary vein area (PVA) and flow may offer novel, mechanistic insight by distinguishing elevated LV filling pressure common in myocardial dysfunction from LV underfilling. This study aimed to elucidate LV filling physiology in PAH by assessing PVA and flow using cardiac magnetic resonance (CMR) and compare pulmonary vein flow in PAH with HFrEF as a model representing elevated filling pressures, in addition to healthy controls. Patients with PAH or heart failure with reduced ejection fraction (HFrEF) referred for CMR were retrospectively reviewed, and healthy controls were included as reference. Pulmonary vein S, D and A-wave were compared between groups. Associations between pulmonary vein area (PVA) by CMR and echocardiographic indices of LV filling pressure were evaluated. Nineteen patients with PAH, 25 with HFrEF and 24 controls were included. Both PAH and HFrEF had lower ejection fraction and S-wave velocity than controls. PAH displayed smaller LV end-diastolic volumes than controls, while HFrEF demonstrated larger PVA and higher A-wave reversal. PVA was associated with mitral E/e′ ratio (r2 = 0.10; p = 0.03), e′ velocity (r2 = 0.23; p = 0.001) and left atrial volume (r2 = 0.07; p = 0.005). Among PAH, PVA was not associated with LV-GLS. A PVA cut-off of 2.3cm2 displayed 87% sensitivity and 72% specificity to differentiate HFrEF and PAH (AUC = 0.82). PAH displayed lower pulmonary vein S-wave velocity, smaller LV volume and reduced function compared with controls. Reduced LV function in PAH may be owing to underfilling rather than intrinsic myocardial disease. PVA demonstrates promise as a novel, non-invasive imaging marker to assess LV filling status. [ABSTRACT FROM AUTHOR]

Background: A high-fat diet (HFD) contributes to various metabolic disorders and obesity, which are major contributors to cardiovascular disease. As an essential regulator for heart homeostasis, cardiac resident macrophages may go awry and contribute to cardiac pathophysiology upon HFD. Thus, to better understand how HFD induced cardiac dysfunction, this study intends to explore the transcriptional and functional changes in cardiac resident macrophages of HFD mice. Methods: C57BL/6J female mice that were 6 weeks old were fed with HFD or normal chow diet (NCD) for 16 weeks. After an evaluation of cardiac functions by echocardiography, mouse hearts were harvested and cardiac resident CCR2- macrophages were sorted, followed by Smart sequencing. Bioinformatics analysis including GO, KEGG, and GSEA analyses were employed to elucidate transcriptional and functional changes. Results: Hyperlipidemia and obesity were observed easily upon HFD. The mouse hearts also displayed more severe fibrosis and diastolic dysfunction in HFD mice. Smart sequencing and functional analysis revealed metabolic dysfunctions, especially lipid-related genes and pathways. Besides this, antigenpresentation-related gene such as Ctsf and inflammation, particularly for NFkB signaling and complement cascades, underwent drastic changes in cardiac resident macrophages. GO cellular compartment analysis was also performed and showed specific organelle enrichment trends of the involved genes. Conclusion: Dysregulated metabolism intertwines with inflammation in cardiac resident macrophages upon HFD feeding in mice, and further research on crosstalk among organelles could shed more light on potential mechanisms. [ABSTRACT FROM AUTHOR]

Thyroid hormones modulate the cardiovascular system. However, the effects of subclinical thyroid dysfunction and euthyroidism on cardiac function remain unclear. We investigated the association between left ventricular (LV) diastolic dysfunction and subclinical thyroid dysfunction or thyroid hormones within the reference range. This cross-sectional study included 26,289 participants (22,197 euthyroid, 3,671 with subclinical hypothyroidism, and 421 with subclinical thyrotoxicosis) who underwent regular health check-ups in the Republic of Korea. Individuals with thyroid stimulating hormone (TSH) levels > 4.2 µIU/mL and normal free thyroxine (FT4, 0.78–1.85 ng/dL) and triiodothyronine (T3, 76–190 ng/dL) levels were defined as having subclinical hypothyroidism. Individuals with serum TSH levels < 0.4 µIU/mL and normal FT4 and T3 levels were defined as having subclinical thyrotoxicosis. The cardiac structure and function were evaluated using echocardiography. LV diastolic dysfunction with normal ejection fraction (EF) was defined as follows: EF of > 50% and (a) E/e' ratio > 15, or (b) E/e' ratio of 8–15 and left atrial volume index ≥ 34 mL/m2. Subclinical hypothyroidism was significantly associated with cardiac indices regarding LV diastolic dysfunction. The odds of having LV diastolic dysfunction was also increased in participants with subclinical hypothyroidism (adjusted odds ratio [AOR] 1.36, 95% confidence interval [CI], 1.01–1.89) compared to euthyroid participants. Subclinical thyrotoxicosis was not associated with LV diastolic dysfunction. Among the thyroid hormones, only serum T3 was significantly and inversely associated with LV diastolic dysfunction even within the normal range. Subclinical hypothyroidism was significantly associated with LV diastolic dysfunction, whereas subclinical thyrotoxicosis was not. Serum T3 is a relatively important contributor to LV diastolic dysfunction compared to TSH or FT4. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the leading cause of morbimortality in Europe and worldwide. CVD imposes a heterogeneous spectrum of cardiac remodelling, depending on the insult nature, that is, pressure or volume overload, ischaemia, arrhythmias, infection, pathogenic gene variant, or cardiotoxicity. Moreover, the progression of CVD‐induced remodelling is influenced by sex, age, genetic background and comorbidities, impacting patients' outcomes and prognosis. Cardiac reverse remodelling (RR) is defined as any normative improvement in cardiac geometry and function, driven by therapeutic interventions and rarely occurring spontaneously. While RR is the outcome desired for most CVD treatments, they often only slow/halt its progression or modify risk factors, calling for novel and more timely RR approaches. Interventions triggering RR depend on the myocardial insult and include drugs (renin–angiotensin–aldosterone system inhibitors, beta‐blockers, diuretics and sodium–glucose cotransporter 2 inhibitors), devices (cardiac resynchronization therapy, ventricular assist devices), surgeries (valve replacement, coronary artery bypass graft), or physiological responses (deconditioning, postpartum). Subsequently, cardiac RR is inferred from the degree of normalization of left ventricular mass, ejection fraction and end‐diastolic/end‐systolic volumes, whose extent often correlates with patients' prognosis. However, strategies aimed at achieving sustained cardiac improvement, predictive models assessing the extent of RR, or even clinical endpoints that allow for distinguishing complete from incomplete RR or adverse remodelling objectively, remain limited and controversial. This scientific statement aims to define RR, clarify its underlying (patho)physiologic mechanisms and address (non)pharmacological options and promising strategies to promote RR, focusing on the left heart. We highlight the predictors of the extent of RR and review the prognostic significance/impact of incomplete RR/adverse remodelling. Lastly, we present an overview of RR animal models and potential future strategies under pre‐clinical evaluation. [ABSTRACT FROM AUTHOR]

Aims Age-related changes in cardiac structure and function are well recognized and make the clinical determination of abnormal left ventricular (LV) diastolic dysfunction (LVDD) particularly challenging in the elderly. We investigated whether a deep neural network (DeepNN) model of LVDD, previously validated in a younger cohort, can be implemented in an older population to predict incident heart failure (HF). Methods and results A previously developed DeepNN was tested on 5596 older participants (66–90 years; 57% female; 20% Black) from the Atherosclerosis Risk in Communities Study. The association of DeepNN predictions with HF or all-cause death for the American College of Cardiology Foundation/American Heart Association Stage A/B (n = 4054) and Stage C/D (n = 1542) subgroups was assessed. The DeepNN-predicted high-risk compared with the low-risk phenogroup demonstrated an increased incidence of HF and death for both Stage A/B and Stage C/D (log-rank P < 0.0001 for all). In multi-variable analyses, the high-risk phenogroup remained an independent predictor of HF and death in both Stages A/B {adjusted hazard ratio [95% confidence interval (CI)] 6.52 [4.20–10.13] and 2.21 [1.68–2.91], both P < 0.0001} and Stage C/D [6.51 (4.06–10.44) and 1.03 (1.00–1.06), both P < 0.0001], respectively. In addition, DeepNN showed incremental value over the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) guidelines [net re-classification index, 0.5 (CI 0.4–0.6), P < 0.001; C -statistic improvement, DeepNN (0.76) vs. ASE/EACVI (0.70), P < 0.001] overall and maintained across stage groups. Conclusion Despite training with a younger cohort, a deep patient-similarity–based learning framework for assessing LVDD provides a robust prediction of all-cause death and incident HF for older patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a simple but effective nomogram to predict risk of septic cardiomyopathy (SCM) in the intensive care unit (ICU). We analyzed data from patients who were first admitted to the ICU for sepsis between 2008 and 2019 in the MIMIC-IV database, with no history of heart disease, and divided them into a training cohort and an internal validation cohort at a 7:3 ratio. SCM is defined as sepsis diagnosed in the absence of other cardiac diseases, with echocardiographic evidence of left (or right) ventricular systolic or diastolic dysfunction and a left ventricular ejection fraction (LVEF) of less than 50%. Variables were selected from the training cohort using the Least Absolute Shrinkage and Selection Operator (LASSO) regression to develop an early predictive model for septic cardiomyopathy. A nomogram was constructed using logistic regression analysis and its receiver operating characteristic (ROC) and calibration were evaluated in two cohorts. A total of 1562 patients participated in this study, with 1094 in the training cohort and 468 in the internal validation cohort. SCM occurred in 13.4% (147 individuals) in the training cohort, 16.0% (75 individuals) in the internal validation cohort. After adjusting for various confounding factors, we constructed a nomogram that includes SAPS II, Troponin T, CK-MB index, white blood cell count, and presence of atrial fibrillation. The area under the curve (AUC) for the training cohort was 0.804 (95% CI 0.764–0.844), and the Hosmer–Lemeshow test showed good calibration of the nomogram (P = 0.288). Our nomogram also exhibited good discriminative ability and calibration in the internal validation cohort. Our nomogram demonstrated good potential in identifying patients at increased risk of SCM in the ICU. [ABSTRACT FROM AUTHOR]

The evidence about the associations of leukocyte telomere length (LTL) and intermediary cardiovascular phenotypes with adverse cardiovascular outcomes is inconclusive. This study assessed these relationships with cardiovascular imaging, electrocardiography, and the risks of sudden cardiac death (SCD), coronary events, and heart failure (HF) admission. We conducted a cross-sectional analysis of UK Biobank participants enrolled between 2006 and 2010. LTL was measured using quantitative polymerase chain reactions. Electronic health records were used to determine the incidence of SCD, coronary events, and HF admission. Cardiovascular measurements were made using cardiovascular magnetic resonance imaging and machine learning. The associations of LTL with SCD, coronary events, and HF admission and cardiac magnetic resonance imaging, electrocardiogram parameters of 33,043 and 19,554 participants were evaluated by multivariate regression. The median (interquartile range) follow-up period was 11.9 (11.2–12.6) years. Data was analyzed from January to May 2023. Among the 403,382 white participants without coronary artery disease or HF, 181,637 (45.0%) were male with a mean age of 57.1 years old. LTL was independently negatively associated with a risk of SCD (LTL third quartile vs first quartile: hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.72–0.92), coronary events (LTL third quartile vs first quartile: HR: 0.88, 95% CI: 0.84–0.92), and HF admission (LTL fourth quartile vs first quartile: HR: 0.84, 95% CI: 0.74–0.95). LTL was also independently positively associated with cardiac remodeling, specifically left ventricular mass index, left-ventricular-end systolic and diastolic volumes, mean left ventricular myocardial wall thickness, left ventricular stroke volume, and with electrocardiogram changes along the negative degree of T-axis. Cross-sectional study results showed that LTL was positively associated with heart size and cardiac function in middle age, but electrocardiography results did not show these associations, which could explain the negative association between LTL and risk of SCD, coronary events, and HF admission in UK Biobank participants. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a multifaceted pathogenesis disease and the exact mechanisms driving HFpEF have not been completely elucidated. Pressure overload hypertrophy (POH) related fibroblasts and M2 macrophages in HFpEF myocardium have been recently identified and are now of great interest. Sympathetic overdrive has also been implicated in HFpEF. This study is designed to dynamically observe the potential roles of aforementioned mechanisms in pathological remodeling and cardiac dysfunction in chronic PO rats. Surgical constriction of the abdominal aorta was used for induction of HFpEF. Echocardiography, electrocardiogram, hemodynamic measurement, hematoxylin and eosin staining, Masson staining, immunohistochemistry and immunofluorescence were performed to assess the changes in heart dysfunction, cardiac remodeling and driving mechanisms at different time points (2, 18, 24 weeks). The PO induced HFpEF model was well established, which was confirmed by the persistent increase in carotid artery systolic and diastolic blood pressure, and left ventricle hypertrophy at the corresponding postoperative stage. Meanwhile, PO hypertrophy gradually developed into HFpEF, associated with QT and QTc intervals prolongation, normal systolic (EF was maintained at >50%) but impaired diastolic function (increasing LVEDP and LV -dP/dtmin, abnormal E/A ratio), increased myocytes size, and observed relatively slight inflammatory infiltration but robust reactive fibrosis. IHC staining further confirmed that macrophages (CD68) but not neutrophils (MPO) or T cells (CD3) accounted for a predominant proportion of infiltrating cells. Mechanistically, we found that the infiltrating macrophages in the heart expressed high levels of CD206 which was simultaneously adjacent to POH fibroblasts appeared to overexpression of α-SMA in PO rats at late stages. Interestingly, we distinguished two different POHF sub-populations during PO induced HFpEF development, according to non overlapping signals of α-SMA and PDGFRα/β proteins. Additionally, PO led to a pronounced exaggeration in sympathetic fibers at all time points. These findings suggest that the establishing model here begins with cardiac sympathetic overdrive, subsequently along with immune cells especially M2 macrophage accumulation and fibroblast heterogeneity at later stages is associated with the development of cardiac maladaptive remodeling and diastolic dysfunction thus further progression to HFpEF. [ABSTRACT FROM AUTHOR]

The effects of conditioning on cardiac function in young horses is still unknown. For this reason, this study evaluated the left ventricular (LV) function of young horses by echocardiography after six weeks of conditioning. Fourteen untrained young purebred Arabian horses were evaluated at rest and after a stress test (ST) before and after a six-week conditioning program. There was an increase in V4 (p < 0.001) after conditioning, as well as a reduction in both heart rate (HR) at rest and peak HR during the ST (p < 0.001). There was also a reduction in internal diameter, along with an increase in interventricular septal, free wall and mean thicknesses and LV mass (p < 0.05). After the ST, the conditioned animals showed higher values of velocity time integral, stroke volume, systolic and cardiac indices, ejection (ET) and deceleration times (DT), end-diastolic volume, time to onset of radial myocardial velocity during early diastole and time to peak of transmitral flow velocity, in addition to reduced pre-ejection period (PEP), PEP/ET ratio and mean velocity of circumferential fiber shortening (p < 0.05). The conditioning protocol promoted physiological adaptations that indicate an improvement in the animals' aerobic capacity associated with an enhanced left ventricular function. [ABSTRACT FROM AUTHOR]

Guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) is a cytoplasmic enzyme that catalyzes the synthesis of GDP-mannose, a crucial substrate for several glycosylation pathways. Reports of pathogenic variants in the GMPPB gene are infrequent. As of April 2023, 109 cases with pathogenic variants in the GMPPB gene have been reported worldwide. Here, we present two siblings born of consanguineous parentage from Southern India. This is a retrospective study on genetically confirmed siblings with GMPPB pathogenic variants. The siblings, a 15-year-old girl, and a 13-year-old boy, presented with progressive limb-girdle weakness and cataracts from early childhood. The girl had exertion-induced breathlessness and mental subnormality. Creatine kinase levels were 5750 and 4320 IU/L. An echocardiogram of the heart revealed global hypokinesia, moderate left ventricular dysfunction, and mild mitral regurgitation with dilation of the left atrium and left ventricle in the girl child. Exome sequencing showed a homozygous pathogenic variant (NM_021971.4 (GMPPB): c.358A>G (p.Met120Val) in Exon 4 of GMPPB gene in both the siblings. Thus, we report an unusual early onset LGMD phenotype of GMPPB-related disorder with cardiac involvement and cataracts from a single family. [ABSTRACT FROM AUTHOR]

Background: Children and adolescents with insulin-dependent diabetes mellitus (IDDM) are at high risk of metabolic disorders that may interfere with lipid metabolism and predispose to dyslipidemia. Objective: To detect the incidence of dyslipidemia and associated factors in children with IDDM in Diyala. Patients and Methods: This was a case-control study that included a total of 100 children with type 1 diabetes mellitus(T1DM) and 100 age- and gender-matched non-diabetic children who presented to the Pediatric Department/Al-Batool Teaching Hospital during the period from April 2022 to April 2023. Demographic data included the child's age, gender, weight, mother's educational level, mother's job, child's educational level, school attendance, and physical activity. Clinical data included systolic and diastolic blood pressure, HbA1c, family history of illness, disease duration, type of insulin, and insulin dose. Fasting lipid profile and hemoglobin A1c investigations were done for the study groups, and the data were statistically analyzed. Results: The overall dyslipidemia in IDDM children and controls was 46% and 8%, respectively, with a highly significant difference. The mean age and weight in diabetic patients with dyslipidemia were 8.23±3.63 years and 28.96±13.31 kg, respectively, which was higher than that of normolipidemic diabetic patients (10.72±3.23 years and 34.22±12.14 kg, respectively) with significant differences. Furthermore, 28.26% of mothers of dyslipidemia-.diabetic patients were employed, compared with only 11.11% of normolipidemic-diabetic patients, a significant difference. A family history of DM was reported in 47.83% and 27.78% of dyslipidemic and normolipidemic diabetic patients, respectively, with a significant difference. Conclusion: The incidence of dyslipidemia among diabetic children in Diyala is 46%. Older age, increased body weight, and a mother's job as an employer are significantly associated with the development of dyslipidemia in insulin-dependent diabetes mellitus patients. [ABSTRACT FROM AUTHOR]

Aims Depending on volume status, secondary tricuspid regurgitation (sTR) has a strong dynamic component. In contrast, associated structural dilatation of the tricuspid annulus and the right heart chambers may be less volume dependent. This study aimed to assess the prognostic value of right heart remodelling in isolated severe sTR (isoTR). Methods and results A total of 36 000 patients from the longitudinal echocardiographic database of our tertiary centre were screened for severe isoTR [vena contracta (VC) ≥ 7 mm] in the absence of atrial fibrillation (AF), other valve disease, and/or reduced systolic left ventricular function. Echocardiographic examinations were re-read, focusing on right ventricular (RV) parameters and on quantitative and qualitative parameters of isoTR. All-cause mortality was defined as the primary endpoint. Two hundred and sixteen patients fulfilled the inclusion criteria. Severe TR was predominant; only few were classified in the new grades massive [ n = 23 (10%)] and torrential TR [ n = 4 (2%)]. During a median follow-up of 35 months (20–53), all-cause mortality was 31% (n = 67). Multivariate Cox regression analysis revealed no association of VC, effective regurgitant orifice area, or regurgitant volume with all-cause mortality. However, indexed RV end-diastolic diameter (P < 0.001), indexed right atrial dimensions (P = 0.019), and particularly tricuspid valve (TV) annulus diameter diastole index (P = 0.002) and TV annulus diameter systole index (P = 0.001) were significantly associated with outcome. Conclusion Severe isolated TR in the absence of AF is a rare finding with a grim prognosis. Tricuspid annular diameter dimensions rather than quantitative measures of TR proved to be of significant prognostic value indicating a continuous remodelling leading to a 'point of no return' with a dismal outcome. [ABSTRACT FROM AUTHOR]

Emerging evidence has documented that circadian rhythm disorders could be related to cardiovascular diseases. However, there is limited knowledge on the direct adverse effects of circadian misalignment on the heart. This study aimed to investigate the effect of chronic circadian rhythm disorder on heart homeostasis in a mouse model of consistent jetlag. The jetlag model was induced in mice by a serial 8-h phase advance of the light cycle using a light-controlled isolation box every 4 days for up to 3 months. Herein, we demonstrated for the first time that chronic circadian rhythm disorder established in the mouse jetlag model could lead to HFpEF-like phenotype such as cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction, following the attenuation of the Clock-sGC-cGMP-PKG1 signaling. In addition, clock gene knock down in cardiomyocytes induced hypertrophy via decreased sGC-cGMP-PKG signaling pathway. Furthermore, treatment with an sGC-activator riociguat directly attenuated the adverse effects of jetlag model-induced cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction. Our data suggest that circadian rhythm disruption could induce HFpEF-like phenotype through downregulation of the clock-sGC-cGMP-PKG1 signaling pathway. sGC could be one of the molecular targets against circadian rhythm disorder-related heart disease. [ABSTRACT FROM AUTHOR]

Left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD) are highly prevalent predictors of cardiovascular disease in individuals with chronic kidney disease (CKD). Vitamin D, particularly 25-hydroxyvitamin D [25(OH)D], deficiency has been reported to be associated with cardiac structure and function in CKD patients. In the current study, we investigated the association between 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of 25(OH)D, and LVH/LVDD in CKD patients. We enrolled 513 non-dialysis CKD patients. The presence of LVH and LVDD was determined using transthoracic echocardiography. In multivariable analysis, serum 1,25(OH)2D levels, but not serum 25(OH)D, were independently associated with LVH [odds ratio (OR): 0.90, 95% confidential interval (CI): 0.88–0.93, P < 0.001]. Additionally, age, systolic blood pressure, and intact parathyroid hormone levels were independently associated with LVH. Similarly, multivariable analysis demonstrated that serum 1,25(OH)2D levels, but not 25(OH)D levels, were independently associated with LVDD (OR: 0.88, 95% CI: 0.86–0.91, P < 0.001) with systolic blood pressure showing independent association with LVDD. The optimal cut-off values for serum 1,25(OH)2D levels for identifying LVH and LVDD were determined as ≤ 12.7 pg/dl and ≤ 18.1 pg/dl, respectively. Our findings suggest that serum 1,25(OH)2D levels have independent association with LVH and LVDD in CKD patients, underscoring their potential as biomarkers for these conditions in this patient population. [ABSTRACT FROM AUTHOR]

Background: Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD. Results: We included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 × 10−5, for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC] = 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD. Conclusion: In this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity. E59jTaJp--U2oUtePgjZu8 Video Abstract [ABSTRACT FROM AUTHOR]

Background: The cardiac manifestations of COVID-19 have been described in patients with acute respiratory distress syndrome (ARDS) admitted to intensive care unit (ICU). The presence and impact of right ventricular (RV) diastolic function and performance has not been studied in this population yet. We describe the prevalence of RV diastolic dysfunction, assessed by the pulmonary valve pre-ejection A wave (PV A wave), and the RV systo-diastolic interaction, using the RV total isovolumic time (t-IVT), in COVID-19 ARDS. Results: Prospective observational study enrolling patients with moderate to severe COVID-19 ARDS admitted to ICU who underwent a transthoracic echocardiogram within 24 h of ICU admission and at least a second one during the ICU stay. Respiratory, hemodynamic and biochemistry parameters were collected. 163 patients (age 61.0 ± 9.3 years, 72% males) were enrolled. 36 patients (22.1%) had RV dysfunction, 45 (27.1%) LV systolic dysfunction. 73 patients (44.7%) had PV A wave. The RV t-IVT correlated with TAPSE at ICU admission (p < 0.002; r – 0.61), presence of PV A wave (p < 0.001; r 0.78), peak inspiratory pressure (PIP) (p < 0.001; r 0.42), PEEP (p < 0.001; r 0.68), dynamic driving pressure (DDP) (p < 0.001; r 0.58), and PaO2/FiO2 ratio (p < 0.01; r − 0.35). The presence of PV A wave was associated with higher PIP (p < 0.001; r 0.45), higher PEEP (p < 0.001; r 0.56), higher DDP (p < 0.01, r 0.51), and lower PaO2/FiO2 ratio (p < 0.001; r – 0.49). Conclusions: RV t-IVT and the presence of PV A wave are non-invasive means to describe a significant RV diastolic dysfunction and may be consider descriptive signs of RV performance in COVID-19 ARDS. [ABSTRACT FROM AUTHOR]

Background: Otolith organ acts complementarily with the autonomic nervous system to maintain blood pressure. However, the effect of blood pressure variability in the autonomic nervous system on otolith organ has not yet been determined. This study aimed to verify the hypothesis that blood pressure variability in the autonomic nervous system affects the recurrence of benign paroxysmal positional vertigo (BPPV), which is the most common disease of the vestibular organs, by using the head-up tilt test (HUTT). Methods: This study included 432 patients diagnosed with idiopathic BPPV. The follow-up period for all patients was 12 months. Age, sex, hypertension, diabetes and recurrence were analyzed. The HUTT parameters were divided into a group of patients whose average diastolic blood pressure increased in the upright position compared to supine position during the HUTT (DBP1) and a group of patients whose average diastolic blood pressure decreased in the upright position compared to supine position during the HUTT (DBP2). Model selection, general loglinear analysis, and logit loglinear analysis were performed using a hierarchically progressing loglinear analysis. Results: In summary, the group with increased average diastolic blood pressure (DBP1) showed a higher tendency for BPPV recurrence compared to the group with decreased diastolic blood pressure (DBP2) in the upright position during the HUTT, although the difference was not statistically significant (p = 0.080). However, in males, the DBP1 group demonstrated a significantly higher recurrence rate of BPPV than the DBP2 group during the HUTT (95% CI, -20.021 to -16.200; p < 0.001). Conclusions: It is presumed that poor autonomic nervous system response through vestibulosympathetic reflex maintains elevated diastolic blood pressure in the upright position during the HUTT. This variability is assumed to affect the recurrence of BPPV. [ABSTRACT FROM AUTHOR]

Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed IKv1.5 with IC50 of 3.08 μM, preferentially blocked the hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited INav1.5 with IC50 of 3.30 μM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K+ current (Iss) and transient outward K+ current (Ito), but without inhibition of L-type Ca2+ current (ICa,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits IKv1.5 and INav1.5 in vitro and reduces AF susceptibility in isolated rat hearts and rats. [ABSTRACT FROM AUTHOR]

Background: In people, obesity is a risk factor for cardiovascular disease, associated with systemic hypertension, cardiac remodelling and systolic and diastolic dysfunction. Weight reduction can reverse myocardial remodelling and reduce risk of subsequent cardiovascular disease. In cats, far less is known regarding the effects of obesity and subsequent weight reduction on cardiovascular morphology and function. This prospective study aimed to assess cardiac morphology and function, heart rate variability, cardiac biomarkers and body composition before and after controlled weight reduction in cats with obesity. Body composition analysis (by dual energy x-ray absorptiometry, DEXA) and cardiovascular assessment (echocardiography, systemic arterial systolic blood pressure, electrocardiography, plasma cardiac biomarkers) were performed prior to weight management in twenty cats with obesity. These investigations were repeated in eleven cats that reached target weight. Results: At baseline, systemic hypertension was not documented, but the majority of cats with obesity (15 out of 19) showed echocardiographic evidence of diastolic dysfunction. Eleven of 20 cats had increased maximal end-diastolic septal or left ventricular free wall thickness (≥ 6.0 mm) at baseline. Median (interquartile range) percentage of weight lost in the cats reaching target weight was 26% (17–29%), with a median reduction in body fat mass of 45% (26–64%). Both the end-diastolic left ventricular free wall (median magnitude of change -0.85 mm, IQR -0.05 mm to -1.55 mm, P = 0.019; median percentage reduction 14.0%) and end-diastolic interventricular septum (median magnitude of change -0.5 mm, IQR -0.2 mm to -1.225 mm, P = 0.047; median percentage reduction 7.9%) thickness decreased after weight reduction. Following weight reduction, pulsed wave tissue Doppler imaging of the left ventricular free wall was consistent with improved diastolic function in 4 out of 8 cats, however there was no significant difference in overall diastolic function class. Further, there was no change in heart rate variability or cardiac biomarkers with weight reduction. Conclusion: An increase in left ventricular wall thickness and diastolic dysfunction were common echocardiographic features in cats with obesity within our study and may be reversible with successful weight and fat mass loss. Further studies are required to clarify the clinical consequences of these findings. [ABSTRACT FROM AUTHOR]

Background: Careful interpretation of the relation between phenotype changes of the heart and gene variants detected in dilated cardiomyopathy (DCM) is important for patient care and monitoring. Objective: We sought to assess the association between cardiac-related genes and whole-heart myocardial mechanics or morphometrics in nonischemic dilated cardiomyopathy (NIDCM). Methods: It was a prospective study consisting of patients with NIDCM. All patients were referred for genetic testing and a genetic analysis was performed using Illumina NextSeq 550 and a commercial gene capture panel of 233 genes (Systems Genomics, Cardiac-GeneSGKit®). It was analyzed whether there are significant differences in clinical, two-dimensional (2D) echocardiographic, and magnetic resonance imaging (MRI) parameters between patients with the genes variants and those without. 2D echocardiography and MRI were used to analyze myocardial mechanics and morphometrics. Results: The study group consisted of 95 patients with NIDCM and the average age was 49.7 ± 10.5. All echocardiographic and MRI parameters of myocardial mechanics (left ventricular ejection fraction 28.4 ± 8.7 and 30.7 ± 11.2, respectively) were reduced and all values of cardiac chambers were increased (left ventricular end-diastolic diameter 64.5 ± 5.9 mm and 69.5 ± 10.7 mm, respectively) in this group. It was noticed that most cases of whole-heart myocardial mechanics and morphometrics differences between patients with and without gene variants were in the genes GATAD1, LOX, RASA1, KRAS, and KRIT1. These genes have not been previously linked to DCM. It has emerged that KRAS and KRIT1 genes were associated with worse whole-heart mechanics and enlargement of all heart chambers. GATAD1, LOX, and RASA1 genes variants showed an association with better cardiac function and morphometrics parameters. It might be that these variants alone do not influence disease development enough to be selective in human evolution. Conclusions: Combined variants in previously unreported genes related to DCM might play a significant role in affecting clinical, morphometrics, or myocardial mechanics parameters. [ABSTRACT FROM AUTHOR]

Investigating ventricular diastolic properties is crucial for understanding the physiological cardiac functions in organisms and unraveling the pathological mechanisms of cardiovascular disorders. Ventricular stiffness, a fundamental parameter that defines ventricular diastolic functions in chordates, is typically analyzed using the end‐diastolic pressure–volume relationship (EDPVR). However, comparing ventricular stiffness accurately across chambers of varying maximum volume capacities has been a long‐standing challenge. As one of the solutions to this problem, we propose calculating a relative ventricular stiffness index by applying an exponential approximation formula to the EDPVR plot data of the relationship between ventricular pressure and values of normalized ventricular volume by the ventricular weight. This article reviews the potential, utility, and limitations of using normalized EDPVR analysis in recent studies. Herein, we measured and ranked ventricular stiffness in differently sized and shaped chambers using ex vivo ventricular pressure‐volume analysis data from four animals: Wistar rats, red‐eared slider turtles, masu salmon, and cherry salmon. Furthermore, we have discussed the mechanical effects of intracellular and extracellular viscoelastic components, Titin (Connectin) filaments, collagens, physiological sarcomere length, and other factors that govern ventricular stiffness. Our review provides insights into the comparison of ventricular stiffness in different‐sized ventricles between heterologous and homologous species, including non‐model organisms. [ABSTRACT FROM AUTHOR]

Introduction: Menopause is associated with reduced nitric oxide (NO) bioavailability and lower tolerance against myocardial ischemia-reperfusion (IR) injury. This study investigated whether long-term nitrate administration provides resistance against myocardial IR injury in ovariectomized (OVX) rats. Method: After ovariectomy, female rats were assigned to the OVX and the OVX + nitrate groups (n = 14/group); the latter group consumed nitrate (100 mg/L) for 9 months. At month 9, each group was divided into two subgroups (n = 7/subgroup), of which one subgroup was exposed to myocardial IR (IR+ hearts) and the other was not exposed (IR-hearts). The hearts of rats were isolated, and NO metabolite (NOx), oxidative stress indices, and mRNA expressions of endothelial (eNOS), inducible (iNOS), and neuronal (nNOS) NO synthases, as well as markers of apoptosis, were measured in the IR- and IR+ hearts. In the IR+ hearts, cardiac function indices (CFI) and the infarct size were also measured. Results: Nitrate increased catalase activity (97%) and eNOS expression (2.94-fold) in the IR-hearts. In the IR+ hearts, nitrate reduced left ventricular (LV) enddiastolic pressure (11.6%) and infarct size (26.2%) and increased recovery of LV developed pressure (44.0%) and peak rate of positive (28.9%) and negative (15.4%) changes in LV pressure. In addition, in the IR+ hearts, nitrate increased eNOS and B-cell lymphoma-2 (Bcl-2) as well as decreased iNOS, Bcl-2 associated X protein (Bax), caspase-3, caspase-8, caspase-9, and tumor necrosis factor-a (TNF-a) expression. Nitrate increased total antioxidant capacity (TAC) and catalase (CAT) activity and decreased malondialdehyde (MDA) levels at month nine in serum and IR+ hearts. Conclusion: The favorable effects of nitrate against IR injury were associated with higher eNOS and Bcl-2 expression, CAT activity, TAC, and lower iNOS, Bax, caspase-3, caspase-8, caspase-9 and TNF-a expression, and MDA in the heart tissue. Nitrate preconditioning alleviated IR-induced myocardial injury in OVX rats; this effect was associated with eNOS upregulation before IR and the blunting of OVX-induced eNOS downregulation, iNOS upregulation, apoptosis, and oxidative stress in heart tissue after IR. [ABSTRACT FROM AUTHOR]

To maintain efficient myocardial function, optimal coordination between ventricular contraction and the arterial system is required. Exercise-based cardiac rehabilitation (CR) has been demonstrated to improve left ventricular (LV) function. This study aimed to investigate the impact of CR on ventricular-arterial coupling (VAC) and its components, as well as their associations with changes in LV function in patients with acute myocardial infarction (AMI) and preserved or mildly reduced ejection fraction (EF). Effective arterial elastance (EA) and index (EAI) were calculated from the stroke volume and brachial systolic blood pressure. Effective LV end-systolic elastance (ELV) and index (ELVI) were obtained using the single-beat method. The characteristic impedance (Zc) of the aortic root was calculated after Fourier transformation of both aortic pressure and flow waveforms. Pulse wave separation analysis was performed to obtain the reflection magnitude (RM). An exercise-based, outpatient cardiac rehabilitation (CR) program was administered for up to 6 months. Twenty-nine patients were studied. However, eight patients declined to participate in the CR program and were subsequently classified as the non-CR group. At baseline, E' velocity showed significant associations with EAI (beta -0.393; P = 0.027) and VAC (beta -0.375; P = 0.037). There were also significant associations of LV global longitudinal strain (LV GLS) with EAI (beta 0.467; P = 0.011). Follow-up studies after a minimum of 6 months demonstrated a significant increase in E' velocity (P = 0.035), improved EF (P = 0.010), and LV GLS (P = 0.001), and a decreased EAI (P = 0.025) only in the CR group. Changes in E' velocity were significantly associated with changes in EAI (beta -0.424; P = 0.033). Increased aortic afterload and VA mismatch were associated with a negative impact on both LV diastolic and systolic function. The outpatient CR program effectively decreased aortic afterload and improved LV diastolic and systolic dysfunction in patients with AMI and preserved or mildly reduced EF. [ABSTRACT FROM AUTHOR]

Background: Right cardiac chamber remodeling is widespread in patients with connective tissue disease (CTD). Serum uric acid (SUA) is considered a potential independent risk factor for cardiovascular disease, and elevated SUA levels are often observed in patients with CTD. The correlation between SUA levels and right cardiac chamber remodeling remains unclear. This study investigated the association of SUA with right cardiac chamber remodeling as assessed by cardiac magnetic resonance feature-tracking (CMR-FT) in CTD patients. Methods and results: In this cross-sectional study, a total of 104 CTD patients and 52 age- and sex-matched controls were consecutively recruited. All individuals underwent CMR imaging, and their SUA levels were recorded. The patients were divided into three subgroups based on the tertiles of SUA level in the present study. CMR-FT was used to evaluate the right atrial (RA) longitudinal strain and strain rate parameters as well as right ventricular (RV) global systolic peak strain and strain rate in longitudinal and circumferential directions for each subject. Univariable and multivariable linear regression analyses were used to explore the association of SUA with RV and RA strain parameters. Compared with the controls, the CTD patients showed significantly higher SUA levels but a lower RV global circumferential strain (GCS) and RA phasic strain parameters (all p < 0.05), except the RA booster strain rate. RV GCS remained impaired even in CTD patients with preserved RV ejection fraction. Among subgroups, the patients in the third tertile had significantly impaired RV longitudinal strain (GLS), RV GCS, and RA reservoir and conduit strain compared with those in the first tertile (all p < 0.05). The SUA levels were negatively correlated with RV GLS and RV GCS as well as with RA reservoir and conduit strain and strain rates (the absolute values of b were 0.250 to 0.293, all P < 0.05). In the multivariable linear regression analysis, the SUA level was still an independent determinant of RA conduit strain (b = -0.212, P = 0.035) and RV GCS (b = 0.207, P = 0.019). Conclusion: SUA may be a potential risk factor of right cardiac chamber remodeling and is independently associated with impaired RA conduit strain and RV GCS in CTD patients. [ABSTRACT FROM AUTHOR]

keeping rabbits as pets and their use in laboratory research increased the need for studying heart diseases and treatments in rabbits. Pimobendan is one of the most common medications used in cardiac diseases and is anecdotal in rabbits. The first step toward the approval of pimobendan in rabbits is assessing the potential for beneficial effects on cardiac function through echocardiographic functional parameters. This study aimed to determine the effects of pimobendan on echocardiographic parameters. Eleven rabbits were included in this study. Echocardiographic examinations were performed before and after pimobendan administration for each rabbit. The LV morphological and functional parameters were compared between study time points. Pimobendan resulted in changes in several echocardiographic variables in the rabbits, including FS and an increase in EF, SV, LVPWs, and LA end-systolic (p = 0.0001, p = 0.0001, p = 0.0284, p = 0.0272, and p = 0.0007, respectively). Moreover, LVIDs and end-systolic volume decreased (p = 0.0343 and p = 0.038). The changes in some parameters were not significant, such as LVIDd, LVPWd, end-diastolic volume, LA max, Mitral annulus diameter, and LA/Ao. FS, which indicates an increase in the power of heart contraction and consequently an improvement in heart function, increased in this study after pimobendan administration. Therefore, it can be concluded that pimobendan improves cardiac functions. Further studies are required to investigate whether pimobendan has similar effects in rabbits with cardiac diseases. [ABSTRACT FROM AUTHOR]

Lean patients with NAFLD may develop cardiac complications independently of pre-existent metabolic disruptions and comorbidities. To address the underlying mechanisms independent of the development of obesity, we used a murine model of hepatic mitochondrial deficiency. The liver-heart axis was studied as these mice develop microvesicular steatosis without obesity. Our results unveil a sex-dependent phenotypic remodeling beyond liver damage. Males, more than females, show fasting hypoglycemia and increased insulin sensitivity. They exhibit diastolic dysfunction, remodeling of the circulating lipoproteins and cardiac lipidome. Conversely, females do not manifest cardiac dysfunction but exhibit cardiometabolic impairments supported by impaired mitochondrial integrity and β-oxidation, remodeling of circulating lipoproteins and intracardiac accumulation of deleterious triglycerides. This study underscores metabolic defects in the liver resulting in significant sex-dependent cardiac abnormalities independent of obesity. This experimental model may prove useful to better understand the sex-related variability, notably in the heart, involved in the progression of lean-NAFLD. A genetic mouse model of lean-NAFLD reveals that male exhibit a more severe hepatic phenotype with increased macrophage infiltration, FGF21 concentration and sustained hypoglycemia associated with cardiac diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Early identification of women at high risk for cardiovascular diseases (CVD), with subsequent monitoring, will allow for improved clinical outcomes and generally better quality of life. This study aimed to identify the associations between early menopause, abnormal diastolic function, and clinical outcomes. This retrospective study included 795 menopausal women from is a nationwide, multicenter, registry of patients with suspected angina visiting outpatient clinic. The patients into two groups: early and normal menopause (menopausal age ≤ 45 and > 45 years, respectively). If participants met > 50% of the diastolic function criteria, they were classified as having normal diastolic function. Multivariable-adjusted Cox models were used to test associations between menopausal age and clinical outcomes including the incidence of major adverse cardiovascular events (MACE), over a median follow-up period of 771 days. Early menopause was associated with increased waist circumference (p = 0.001), diabetes prevalence (p = 0.003), obstructive coronary artery disease (p = 0.005), abnormal diastolic function (p = 0.003) and greater incidences of MACE, acute coronary syndrome, and hospitalization for heart failure. In patients with abnormal diastolic function, early menopause increased MACE risk significantly, with no significant difference in normal diastolic function. These findings highlight early menopause and abnormal diastolic function as being potential risk markers in women for midlife CVD events. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options. While lactate, a byproduct of glycolysis, is known to be significantly elevated in type 2 diabetes, its specific role in DCM remains uncertain. This study reveals an abnormal upregulation of monocarboxylate transporter 4 (MCT4) on the plasma membrane of cardiomyocytes in type 2 diabetes, leading to excessive lactate efflux from these cells. The disruption in lactate transport homeostasis perturbs the intracellular lactate-pyruvate balance in cardiomyocytes, resulting in oxidative stress and inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased lactate efflux augments histone H4K12 lactylation in macrophages, facilitating inflammatory infiltration within the microenvironment. In vivo experiments have demonstrated that inhibiting MCT4 effectively alleviates myocardial oxidative stress and pathological damage, reduces inflammatory macrophage infiltration, and enhances cardiac function in type 2 diabetic mice. Furthermore, a clinical prediction model has been established, demonstrating a notable association between peripheral blood lactate levels and diastolic dysfunction in individuals with type 2 diabetes. This underscores the potential of lactate as a prognostic biomarker for DCM. Ultimately, our findings highlight the pivotal involvement of MCT4 in the dysregulation of cardiac energy metabolism and macrophage-mediated inflammation in type 2 diabetes. These insights offer novel perspectives on the pathogenesis of DCM and pave the way for the development of targeted therapeutic strategies against this debilitating condition. [ABSTRACT FROM AUTHOR]

New or mild heart failure (HF) is mainly caused by left ventricular dysfunction. We hypothesised that gene expression differ between the left (LV) and right ventricle (RV) and secondly by type of LV dysfunction. We compared gene expression through myocardial biopsies from LV and RV of patients undergoing elective coronary bypass surgery (CABG). Patients were categorised based on LV ejection fraction (EF), diastolic function and NT-proBNP into pEF (preserved; LVEF ≥ 45%), rEF (reduced; LVEF < 45%) or normal LV function. Principal component analysis of gene expression displayed two clusters corresponding to LV and RV. Up-regulated genes in LV included natriuretic peptides NPPA and NPPB, transcription factors/coactivators STAT4 and VGLL2, ion channel related HCN2 and LRRC38 associated with cardiac muscle contraction, cytoskeleton, and cellular component movement. Patients with pEF phenotype versus normal differed in gene expression predominantly in LV, supporting that diastolic dysfunction and structural changes reflect early LV disease in pEF. DKK2 was overexpressed in LV of HFpEF phenotype, potentially leading to lower expression levels of β-catenin, α-SMA (smooth muscle actin), and enhanced apoptosis, and could be a possible factor in the development of HFpEF. CXCL14 was down-regulated in both pEF and rEF, and may play a role to promote development of HF. [ABSTRACT FROM AUTHOR]

Heart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA‐203 (miR‐203) as a senescence‐associated microRNA that regulates NAD+ homeostasis. We found that the blood miR‐203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR‐203 (TgN (miR‐203)) showed resistance to aging‐induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR‐203 significantly prevented D‐gal‐induced cardiomyocyte senescence and mitochondrial damage, while miR‐203 knockdown aggravated these effects. Mechanistically, miR‐203 inhibited PARP1 expression by targeting its 3′UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR‐203 as a genetic tool for anti‐heart aging by restoring NAD+ function in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT prolongation, torsades de pointes, pericardial effusion, and hypotension, as well as chronic conditions, such as hypertension, and systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovascular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovascular side effect continues even after the causative medication is stopped, it is referred to as a cardiotoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even at very low medication dosages, and can present as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome, and myocarditis caused by cancer therapy. [ABSTRACT FROM AUTHOR]

Developing effective anti-fibrotic therapies for heart diseases holds the potential to address unmet needs in several cardiac conditions, including heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and cardiotoxicity induced by cancer therapy. The inhibition of the primary fibrotic regulator, transforming growth factor (TGF) β, represents an efficient strategy for mitigating fibrosis in preclinical models. However, translating these findings into clinical benefits faces challenges due to potential adverse effects stemming from TGF-β's physiological actions in inflammation and tissue homeostasis. Various strategies exist for inhibiting TGF-β, each associated with a distinct risk of adverse effects. Targeting TGF-β directly or through its signaling pathway proves efficient in reducing fibrosis. However, direct TGF-β blockade may lead to uncontrolled inflammation, especially following myocardial infarction, while interference with the signaling pathway may compromise structural integrity, resulting in issues like insufficient wound healing or ventricular dilatation. Influencing TGF-β activity through interacting signaling pathways, for instance by inhibitors of the renin–angiotensin–aldosterone-system, is insufficiently potent in reducing fibrosis. Targeting activators of latent TGF-β, including ADAMTS enzymes, thrombospondin, and integrins, emerges as a potentially safer strategy to reduce TGF-β-induced fibrosis but it requires the identification of appropriate targets. Encouragement is drawn from promising agents developed for fibrosis in other organs, fueling hope for similar breakthroughs in treating cardiac fibrosis. Such advances depend on overcoming obstacles for the implementation of anti-fibrotic strategies in patients with heart disease, including fibrosis quantification. In this review, insights garnered from interventional and mechanistic studies, obtained through a non-systemic search spanning preclinical and clinical evidence, are summarized to pinpoint the most promising targets for further exploration and development. [ABSTRACT FROM AUTHOR]

The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice. [ABSTRACT FROM AUTHOR]

Periodontal disease (PD) is considered a risk factor for cardiovascular events. However, its relationship to chronic heart failure (CHF) is unclear. The aim was to compare cardiac and inflammatory parameters in CHF patients with (PG) versus without periodontitis (NPG). The following parameters were recorded in 58 patients: periodontal screening and recording (PSR), troponin T, NT-proBNP, C-reactive protein (CRP), interleukin-6 (IL-6), blood pressure, heart rate, ejection fraction (EF), ventricular systolic and diastolic function parameters, incremental test, and three questionnaires (Mediterranean Diet Adherence Screener, MEDAS; Oral Health Impact Profile, OHIP-14; Patient Health Questionnaire, PHQ). The serum levels of NT-proBNP and troponin T were significantly higher in the PG, and the left ventricular systolic and diastolic function parameters were significantly lower. The correlation analysis showed age as the only independent risk factor for periodontitis and cardiac biomarkers. No significant group differences were found in the MEDAS, OHIP-14, and PHQ scores, or in CRP, IL-6, and cardiocirculatory parameters. Overall, the BMI correlated significantly with the mean PSR and total cholesterol. The occurrence of increased PSR together with increased age and cardiac risk parameters does not exclude an association between periodontitis and CHF, though no positive correlation was calculated. Periodontitis may be a modifiable risk factor for CHF. Its treatment may help to control the inflammatory burden. [ABSTRACT FROM AUTHOR]

This article discusses a pilot study that examined the impact of weaning from mechanical ventilation on right ventricular function in patients with prolonged mechanical ventilation. The study used a specific imaging technique to measure the strain on the right ventricular wall during the weaning process. The results showed that there was no significant difference in the strain values between different ventilation methods, but higher baseline strain values were associated with successful weaning. The study suggests that it is important to consider right ventricular function during the weaning process and that the imaging technique used may be helpful in assessing this function. [Extracted from the article]

Background: Left ventricular (LV) diastolic dysfunction is an independent predictor of future cardiovascular events. Early detection of patients with LV diastolic dysfunction can improve clinical outcomes through active management. However, the assessment of diastolic function is very complicated, and there are currently lack of effective biomarkers to assess the risk of LV diastolic dysfunction. Connective tissue growth factor (CTGF) plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the associations between plasma CTGF level and the risk of LV diastolic dysfunction in this study and judge its effectiveness in diagnosing LV diastolic dysfunction. Methods: A total of 169 patients with overt hyperthyroidism were included. LV diastolic function was evaluated and the subjects were divided into normal LV diastolic function group and LV diastolic dysfunction group. Routine clinical medical data, biochemical data, thyroid related parameters and echocardiographic parameters were recorded for analysis. Results: Compared with normal LV diastolic function group, the LV diastolic dysfunction group had higher age and BMI, as well as lower heart rate, lower serum albumin, lower eGFR, higher serum TgAb and BNP level, and the incidences of hypertension were also higher (all P <0.05). Circulating plasma CTGF levels in the LV diastolic dysfunction group were significantly higher (normal LV diastolic function group: 7.026 [5.567-8.895], LV diastolic dysfunction group: 8.290 [7.054-9.225] ng/ml, median [(Interquartile range)], P = 0.004); Compared with the lowest quartile group, the crude odds ratios (OR) of LV diastolic dysfunction in the second, third, and fourth quartile group were 3.207, 5.032 and 4.554, respectively (all P<0.05). After adjustment for the potentially confounding variables, the adjusted OR values of the third and fourth quartile group had no obvious change. The results of ROC showed that the plasma CTGF had the largest area under the ROC curve, and the value was 0.659 (P = 0.005). Conclusion: The level of circulating plasma CTGF in the LV diastolic dysfunction group was significantly increased. Plasma CTGF level is an independent risk factor for LV diastolic dysfunction. Compared with serum BNP level, the plasma CTGF level may have auxiliary diagnostic value for LV diastolic dysfunction in hyperthyroid patients. [ABSTRACT FROM AUTHOR]

Aims Haemodynamic forces (HDFs) provided a feasible method to early detect cardiac mechanical abnormalities by estimating the intraventricular pressure gradients. The novel advances in assessment of HDFs using routine cardiac magnetic resonance (CMR) cines shed new light on detection of preclinical dysfunction. However, definition of normal values for this new technique is the prerequisite for application in the clinic. Methods and results A total of 218 healthy volunteers [38.1 years ± 11.1; 111 male (50.9%)] were recruited and underwent CMR examinations with a 3.0T scanner. Balanced steady state free precession breath hold cine images were acquired, and HDF assessments were performed based on strain analysis. The normal values of longitudinal and transversal HDF strength [root mean square (RMS)] and ratio of transversal to longitudinal HDF were all evaluated in overall population as well as in both genders and in age-specific groups. The longitudinal RMS values (%) of HDFs were significantly higher in women (P < 0.05). Moreover, the HDF amplitudes significantly decreased with ageing in entire heartbeat, systole, diastole, systolic/diastolic transition, and diastolic deceleration, while increased in atrial thrust. In multivariable linear regression analysis, age, heart rate, and global longitudinal strain emerged as independent predictors of the amplitudes of longitudinal HDFs in entire heartbeat and systole, while left ventricular end-diastole volume index was also independently associated with longitudinal HDFs in diastole and diastolic deceleration (P < 0.05 for all). Conclusion Our study provided comprehensive normal values of HDF assessments using CMR as well as presented with specific age and sex stratification. HDF analyses can be performed with excellent intra- and inter-observer reproducibility. [ABSTRACT FROM AUTHOR]

Cardiovascular magnetic resonance (CMR)-derived hemodynamic force (HDF) analyses have been introduced recently enabling more in-depth cardiac function evaluation. Inter-study reproducibility is important for a widespread clinical use but has not been quantified for this novel CMR post-processing tool yet. Serial CMR imaging was performed in 11 healthy participants in a median interval of 63 days (range 49–87). HDF assessment included left ventricular (LV) longitudinal, systolic peak and impulse, systolic/diastolic transition, diastolic deceleration as well as atrial thrust acceleration forces. Inter-study reproducibility and study sample sizes required to demonstrate 10%, 15% or 20% relative changes of HDF measurements were calculated. In addition, intra- and inter-observer analyses were performed. Intra- and inter-observer reproducibility was excellent for all HDF parameters according to intraclass correlation coefficient (ICC) values (> 0.80 for all). Inter-study reproducibility of all HDF parameters was excellent (ICC ≥ 0.80 for all) with systolic parameters showing lower coeffients of variation (CoV) than diastolic measurements (CoV 15.2% for systolic impulse vs. CoV 30.9% for atrial thrust). Calculated sample sizes to detect relative changes ranged from n = 12 for the detection of a 20% relative change in systolic impulse to n = 200 for the detection of 10% relative change in atrial thrust. Overall inter-study reproducibility of CMR-derived HDF assessments was sufficient with systolic HDF measurements showing lower inter-study variation than diastolic HDF analyses. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). Methods: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. Results: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07–0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3− 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. Conclusions: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. Trial registration: ClinicalTrials.gov NCT05023941. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is the leading cause of death in Cushing's syndrome (CS). Primary bilateral macro - nodular adrenal hyperplasia (PBMAH), is a rare cause of CS that is clinically distinct from the other common types of CS, but cardiac characteristics have been poorly studied. Methods: The clinical data, steroid hormones and echocardiographic variables of 17 patients with PBMAH were collected. Twenty-one CS patients with cortisol-producing adenoma (CPA) were collected as controls. The similarities and differences of clinical and cardiac features between the two groups were compared. Results: In the PBMAH group, the proportion of female was lower (35.30 vs 100.00%), the age was older (55.76 ± 2.42 years vs 39.57 ± 2.72 years), and the course of disease was longer -13.00 (5.00, 21.50) years vs 1.58 (1.00, 5.00) years'. The proportion of PBMAH patients with hypertension was higher than that of CPA patients (100.00% vs 61.90%). Plasma cortisol and 24h urinary free cortisol (24h UFC) were lower in PBMAH patients than that in CPA patients-morning cortisol 19.50 (15.35, 24.48) mg/dL vs 28.30 (22.88, 29.89) mg/dL, 24h UFC 106.20 (65.35, 156.58) vs 506.23 (292.53, 712.18) mg2. The PBMAH group had longer right ventricular diameter (24.06 ± 1.23 mm vs 20.48 ± 0.83 mm), left atrial diameter (39.41 ± 1.15 mm vs 32.86 ± 0.76 mm), and a higher rate of diastolic dysfunction (76.50% vs 38.10%) than the CPA group. Univariate regression analysis showed that combination of hypertension and duration of hypertension had significant effects on left atrial diameter (b=6.383, P=0.001; b = 0.276, P<0.001, respectively) and E/A ratios (b=-0.496, P< 0.001; b=0.022, P<0.001, respectively). Multivariate regression analysis showed that corticosterone level had a significant effect on systolic blood pressure (b=6.712, P=0.025). Conclusion: Comparing to the CPA, ventricular diastolic dysfunction was common in PBMAH patients under relatively lower cortisol level. PBMAH had high corticosterone levels which may play a role in the development of hypertension and further cardiac changes. [ABSTRACT FROM AUTHOR]

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five‐day within‐subject, double‐blind, placebo‐controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3–5) and completed self‐reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post‐dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing. [ABSTRACT FROM AUTHOR]