Sex differences in gene expression in response to ischemia in the human myocardium

Abstract and KeywordsBackgroundSex differences exist in the prevalence, presentation, and outcomes of ischemic heart disease. Females have higher risk of heart failure post myocardial infarction relative to males and the female sex is an independent risk factor for hospital and operative mortality after cardiac surgery. However, the mechanisms underlying this sexual dimorphism remain unclear. We examined sex differences in human myocardial gene expression in response to ischemia.MethodsLeft ventricular biopsies from 68 male and 46 female patients undergoing aortic valve replacement surgery were obtained at baseline and after a median 74 minutes of cold cardioplegic arrest/ischemia and respective transcriptomes were quantified by RNA-Seq. Sex-specific responses to ischemia were quantified by differential gene expression, expression quantitative trait loci (eQTL) and pathway and functional analysis. Cell-type enrichment analysis. was used to obtain an estimate of the identity and relative proportions of different cell types present in each sample.ResultsA sex-specific response to ischemia was observed for 271 genes. Functional annotation analysis revealed sex-specific modulation of the oxytocin signaling pathway and common pathway of fibrin clot formation. The eQTL analysis identified variant-by-sex interaction eQTLs at baseline and post-ischemia, indicative of sex differences in the genotypic effects on gene expression, and cell-type enrichment analysis showed sex-bias in proportion of specific cell types.ConclusionIn response to myocardial ischemia, the human left ventricle demonstrates changes in gene expression that differ between the sexes. These differences provide insight into the sexual dimorphism of ischemic heart disease and may aid in the development of sex-specific therapies that reduce myocardial injury.

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Single-cell dissection of live human hearts in ischemic heart disease and heart failure reveals cell-type-specific driver genes and pathways

10.1101/2021.06.23.449672 ◽

2021 ◽

Author(s):

Suvi Linna-Kuosmanen ◽

Eloi Schmauch ◽

Kyriakitsa Galani ◽

Carles A. Boix ◽

Lei Hou ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Single Cell ◽

Human Heart ◽

Cell Types ◽

Ischemic Heart ◽

Cell Type ◽

Cell Type Specific

Ischemic heart disease is the single most common cause of death worldwide with an annual death rate of over 9 million people. Genome-wide association studies have uncovered over 200 genetic loci underlying the disease, providing a deeper understanding of the causal mechanisms leading to it. However, in order to understand ischemic heart disease at the cellular and molecular level, it is necessary to identify the cell-type-specific circuits enabling dissection of driver variants, genes, and signaling pathways in normal and diseased tissues. Here, we provide the first detailed single-cell dissection of the cell types and disease-associated gene expression changes in the living human heart, using cardiac biopsies collected during open-heart surgery from control, ischemic heart disease, and ischemic and non-ischemic heart failure patients. We identify 84 cell types/states, grouped in 12 major cell types. We define markers for each cell type, providing the first extensive reference set for the live human heart. These major cell types include cardiovascular cells (cardiomyocytes, endothelial cells, fibroblasts), rarer cell types (B lymphocytes, neurons, Schwann cells), and rich populations of previously understudied layer-specific epicardial and endocardial cells. In addition, we reveal substantial differences in disease-associated gene expression at the cell subtype level, revealing arterial pericytes as having a central role in the pathogenesis of ischemic heart disease and heart failure. Our results demonstrate the importance of high-resolution cellular subtype mapping in gaining mechanistic insight into human cardiovascular disease.

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Direct results of percutaneous coronary interventions in patients with chronic ischemic heart disease and left ventricular dysfunction

Kreativnaya kardiologiya ◽

10.15275/kreatkard.2017.01.05 ◽

2017 ◽

Vol 1 (10) ◽

pp. 45-55

Author(s):

Bagrat Alekyan ◽

◽

Yurii Buziashvili ◽

Elena Golukhova ◽

Olga Bockeria ◽

...

Keyword(s):

Heart Disease ◽

Ischemic Heart Disease ◽

Left Ventricular Dysfunction ◽

Ventricular Dysfunction ◽

Left Ventricular ◽

Ischemic Heart ◽

Percutaneous Coronary Interventions ◽

Chronic Ischemic Heart Disease ◽

Percutaneous Coronary ◽

Direct Results

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Glutamine Is Cardioprotective in Patients with Ischemic Heart Disease following Cardiopulmonary Bypass

The Heart Surgery Forum ◽

10.1532/hsf98.20111074 ◽

2011 ◽

Vol 14 (6) ◽

pp. 384 ◽

Cited By ~ 17

Author(s):

Vladimir V. Lomivorotov ◽

Sergey M. Efremov ◽

Vladimir A. Shmirev ◽

Dmitry N. Ponomarev ◽

Vladimir N. Lomivorotov ◽

...

Keyword(s):

Heart Disease ◽

Placebo Group ◽

Cardiopulmonary Bypass ◽

Ischemic Heart Disease ◽

Troponin I ◽

Left Ventricular ◽

Ischemic Heart ◽

Left Ventricular Ejection ◽

Study Group ◽

Cardioprotective Effects

Background: The aim of the present study was to investigate the cardioprotective effects of the perioperative use of N(2)-L-alanyl-L-glutamine (GLN) in patients with ischemic heart disease (IHD) who undergo their operations under cardiopulmonary bypass (CPB).Methods: This double-blind, placebo-controlled, randomized study included 50 patients who underwent cardiac surgery with CPB. Exclusion criteria were a left ventricular ejection fraction <50%, diabetes mellitus, <3 months since the onset of myocardial infarction, and emergency surgery. Patients in the study group (n = 25) received 0.4 g/kg GLN (Dipeptiven, 20% solution) per day. Patients in the control group (n = 25) were administered a placebo (0.9% NaCl). The primary end point was the dynamics of troponin I at the following stages: (1) prior to anesthesia, (2) 30 minutes after CPB, (3) 6 hours after CPB, (4) 24 hours after surgery, and (5) 48 hours after surgery. Secondary end points included measurements of hemodynamics with a Swan-Ganz catheter.Results: On the first postoperative day after the surgery, the median troponin I level was significantly lower in the study group than in the placebo group: 1.280 ng/mL (interquartile range [IQR], 0.840-2.230 ng/mL) versus 2.410 ng/mL (IQR, 1.060-6.600 ng/mL) (P = .035). At 4 hours after cardiopulmonary bypass (CPB), the median cardiac index was higher in the patients in the study group: 2.58 L/min per m2 (IQR, 2.34-2.91 L/min per m2) versus 2.03 L/min per m2 (IQR, 1.76-2.32 L/min per m2) (P = .002). The median stroke index also was higher in the patients who received GLN: 32.8 mL/m2 (IQR, 27.8-36.0 mL/m2) versus 26.1 mL/m2 (IQR, 22.6-31.8 mL/m2) (P = .023). The median systemic vascular resistance index was significantly lower in the study group than in the placebo group: 1942 dyn�s/cm5 per m2 (IQR, 1828-2209 dyn�s/cm5 per m2) versus 2456 dyn�s/cm5 per m2 (IQR, 2400-3265 dyn�s/cm5 per m2) (P = .001).Conclusion: Perioperative administration of GLN during the first 24 hours has cardioprotective effects in IHD patients following CPB. This technique enhances the troponin concentration at 24 hours after surgery and is associated with improved myocardial function.

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PULMONARY VASCULAR RESISTANCE BY ECHOCARDIOGRAPHY-DOPPLER IN ISCHEMIC HEART DISEASE WITH LEFT VENTRCULAR SYSTOLIC DYSFUNCTION

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2017.5.11 ◽

2017 ◽

pp. 89-94

Author(s):

Ke Toan Tran ◽

Thi Thuy Hang Nguyen

Keyword(s):

Heart Disease ◽

Ischemic Heart Disease ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Tricuspid Valve ◽

Left Ventricular ◽

Ischemic Heart ◽

Left Ventricular Ejection ◽

S Wave ◽

Echocardiography Doppler

Objective: To determine pulmonary vascular resistance (PVR) by echocardiography - Doppler and to find correlation between pulmonary vascular resistance with left ventricular EF, PAPs, TAPSE, tissue S-wave of the tricuspid valve in patients with ischemic heart disease. Subjects and Methods: We studied on 82 patients with ischemic heart disease and EF<40% including 36 females, 46 males. Patients were estimated for pulmonary vascular resistance, EF, PAPs, TAPSE, tissue S-wave of the tricuspid valve by echocardiographyDoppler. Results: 64.6% of patients are increased PVR, average of PVR is 3.91 ± 1.85 Wood units and it is increasing with NYHA severity. There are negative correlations between pulmonary vascular resistance with left ventricular ejection fraction (r = - 0.545; p <0.001), TAPSE index (r= -0.590; p <0.001) and tissue S-wave of the tricuspid valve (r = -0.420; p <0.001); positive correlation with systolic pulmonary artery pressure (r = 0.361, p = 0.001), Conclusions: Increased PVR is the primary mechanism for pulmonary hypertension and right heart failure in patients with left heart disease. Determination of PVR in patients with left ventricular dysfunction by echocardiography is important in clinical practice. Key words: Echocardiography-Doppler; Pulmonary vascular resistance; ischemic heart disease

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Digital Subtraction High-Frame-Rate Echocardiography in Detecting Delayed Onset of Regional Left Ventricular Relaxation in Ischemic Heart Disease

Circulation ◽

10.1161/01.cir.91.2.304 ◽

1995 ◽

Vol 91 (2) ◽

pp. 304-312 ◽

Cited By ~ 46

Author(s):

Hiroya Kondo ◽

Tohru Masuyama ◽

Ken Ishihara ◽

Toshiaki Mano ◽

Kazuhiro Yamamoto ◽

...

Keyword(s):

Heart Disease ◽

Ischemic Heart Disease ◽

Left Ventricular ◽

Frame Rate ◽

Ischemic Heart ◽

Digital Subtraction ◽

High Frame Rate ◽

Left Ventricular Relaxation ◽

Delayed Onset ◽

Ventricular Relaxation

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Major Left Bundle Branch Block and Coronary Heart Disease—Are There Any Differences between the Sexes?

Journal of Clinical Medicine ◽

10.3390/jcm10112284 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2284

Author(s):

Diana Gurzău ◽

Alexandra Dădârlat-Pop ◽

Bogdan Caloian ◽

Gabriel Cismaru ◽

Horaţiu Comşa ◽

...

Keyword(s):

Risk Factors ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Left Bundle Branch Block ◽

Left Ventricular ◽

Ischemic Heart ◽

Left Ventricular Ejection ◽

Bundle Branch Block ◽

Microvascular Angina ◽

Ventricular Ejection Fraction

Left bundle branch block is not a benign pathology, and its presence requires the identification of a pathological substrate, such as ischemic heart disease. Left bundle branch block appears to be more commonly associated with normal coronary arteries, especially in women. The objectives of our study were to describe the particularities of left bundle branch block in women compared to men with ischemic heart disease. Result: We included seventy patients with left bundle branch block and ischemic heart disease, with a mean age of 67.01 ± 8.89 years. There were no differences in the profile of risk factors, except for smoking and uric acid. The ventricular depolarization (QRS) duration was longer in men than women (136.86 ± 8.32 vs. 132.57 ± 9.19 msec; p = 0.018) and also men were observed to have larger left ventricular diameters. Left bundle branch block duration was directly associated with ventricular diameters and indirectly associated with left ventricular ejection fraction value, especially in women (R = −0.52, p = 0.0012 vs. R = −0.50, p = 0.002). In angiography, 80% of women had normal epicardial arteries compared with 65.7% of men; all these patients presented with microvascular dysfunction. Conclusion: The differences between the sexes were not so obvious in terms of the presence of risk factors; instead, there were differences in electrocardiographic, echocardiographic, and angiographic aspects. Left bundle branch block appears to be a marker of microvascular angina and systolic dysfunction, especially in women.

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