Mechanisms of Sinoatrial Node Dysfunction in Heart Failure with Preserved Ejection Fraction
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE184120 | GEO | 2022/05/18
REPOSITORIES: GEO
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Project description:Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats) or cardiometabolic syndrome (in ZSF1 obese rats). Mechanistically, this effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics, as evidenced by cardiac trasncriptome and metabolome analyses. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium ATPase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.
2021-02-11 | GSE163665 | GEO
Project description:Heart failure affects 2–3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics will show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction ≥ 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group. <br> Sequencing data from clinical patients fall under GDPR regulations of sharing of personal data and will be made available through EGA-SE.
2019-03-02 | E-MTAB-7454 | biostudies-arrayexpress
Project description:As patients with heart failure with preserved ejection fraction (HFpEF) present with multiple comorbidities, we hypothesized, that metabolic syndrome in aging animals could lead to the development of diastolic dysfunction and HFpEF. HFpEF is a common complex morbid syndrome for which there are currently little evidence-based therapies. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.
2022-02-02 | GSE189190 | GEO
Project description:Male Dahl salt sensitive and Lewis rats (n=3 each) were fed an 8% NaCl diet starting at 5 weeks of age for 8 weeks. Total RNA was isolated with TRIzol reagent from DS and LEW kidneys and was subjected to microarray analysis. Experiment Overall Design: Male Dahl salt sensitive and Lewis rats (n=3 each) were fed an 8% NaCl diet starting at 5 weeks of age for 8 weeks. Total RNA was isolated with TRIzol reagent from DS and LEW kidneys and was subjected to microarray analysis. The resulting data were analyzed with GeneChip Operating Software ver1.4. Three independent experiments comparing expressions between salt-loaded Dahl salt sensitive and salt-loaded Lewis rats were performed.
2007-11-29 | E-GEOD-4800 | biostudies-arrayexpress
Project description:BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure patients. Clinically, HFpEF prevalence show age and gender biases. Although the majority of HFpEF patients are elderly, there is an emergence of young HFpEF patients. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. METHODS AND RESULTS: HFpEF dietary regimen (HFD + L-NAME) was used to induce HFpEF in wildtype and telomerase RNA knockout mice (mTRG2 and mTRG3), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in mTRG2 (at 6-weeks) and mTRG3 (at 4-weeks) compared to wildtype (8-weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that p53 is necessary for the development of HFpEF. CONCLUSIONS: Here we demonstrate that p53 activation is critical for the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 prevents HFpEF upon HFD + L-NAME challenge.
2022-07-06 | GSE195482 | GEO
Project description:Serum and glucocorticoid-induced kinase 1 (SGK1) activates the epithelial sodium channel (eNaC) in tubules. We examined renal SGK1 abundance in salt-adaptation and in salt-sensitive hypertension. Sprague-Dawley and Dahl salt-sensitive rats were placed on either 8% or 0.3% NaCl diets for 10 days. Plasma aldosterone levels were approximately 2.5-fold greater on 0.3% versus 8% NaCl diets in both rat strains. Both serum and glucocorticoid-induced kinase 1 transcript and protein abundance were less (P<0.01) in Sprague-Dawley rats and greater (P<0.01) in Dahl salt-sensitive rats on 8% versus 0.3% NaCl diets. The cDNA sequences of serum and glucocorticoid-induced kinase 1 in both strains of rat were the same. The present results provide evidence that the abundance of serum and glucocorticoid-induced kinase 1 in rat kidney may play a role in salt adaptation and the pathogenesis of hypertension and suggests that aldosterone is not the primary inducer of SGK1 in the Sprague-Dawley rat. Keywords = Rattus norvegicus, Sprague Dawley, Dahl SS/Jr, kidney, NaCl diet Keywords: other
2004-02-14 | GSE599 | GEO
Project description:Benidipine hydrochloride is a long-acting calcium channel blocker and is used for the treatment of hypertension and angina pectoris. The cardioprotective effects of benidipine have been shown in several animal and clinical studies. We examined the effect of the dihydropyridine calcium channel blocker (CCB) benidipine on the gene expression profile in heart by DNA microarray. Dahl salt-sensitive (DS) rats were fed with normal diet (0.19% NaCl) or a high-salt diet (8% NaCl) from 7 weeks of age. Benidipine (4mg/kg) or vehicle (0.5% w/v methylcellulose 400cP) was administered orally after the start of the feeding. DS rats fed the high-salt diet showed an increase in systolic blood pressure (SBP), which was accompanied by the gain of heart weight. SBP was significantly lower in the benidipine group than in the vehicle group. The weight of heart was significantly decreased in the benidipine group. Keywords: Diseased state and drug effect analysis
2009-06-16 | GSE8201 | GEO
Project description:Benidipine hydrochloride is a long-acting calcium channel blocker and is used for the treatment of hypertension and angina pectoris. The cardioprotective effects of benidipine have been shown in several animal and clinical studies. We examined the effect of the dihydropyridine calcium channel blocker (CCB) benidipine on the gene expression profile in heart by DNA microarray. Dahl salt-sensitive (DS) rats were fed with normal diet (0.19% NaCl) or a high-salt diet (8% NaCl) from 7 weeks of age. Benidipine (4mg/kg) or vehicle (0.5% w/v methylcellulose 400cP) was administered orally after the start of the feeding. DS rats fed the high-salt diet showed an increase in systolic blood pressure (SBP), which was accompanied by the gain of heart weight. SBP was significantly lower in the benidipine group than in the vehicle group. The weight of heart was significantly decreased in the benidipine group. Experiment Overall Design: Three samples were analyzed, the hearts of rat with normal diet (normal), high-salt diet plus vehicle (control), high-salt diet plus Benidipine (Benidipine). We use 2 arrays: control vs. normal and Benidipine vs. control. Replicates and dye swaps were not performed.
2009-06-23 | E-GEOD-8201 | biostudies-arrayexpress
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-17 | GSE249409 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-18 | GSE249412 | GEO