[The effect of sodium-glucose cotransporter type 2 inhibitors on left ventricular diastolic function: current status and prospects].

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). Impaired left ventricular (LV) diastolic function (DF) is an important element in the pathogenesis of HFpEF. Experimental studies have found intracellular mechanisms for the so-called diastolic effects in gliflozins. Studies using laboratory models of experimental HFpEF have demonstrated a positive effect of dapagliflozin and empagliflozin on the elastic properties of cardiomyocyte myofilaments, the dynamics of myocardial fibrosis, and intracellular sodium and calcium homeostasis. The significance of anti-inflammatory, antioxidant properties of gliflozins in improving the cardiomyocyte DF has been experimentally established. The effect of SGLT2 inhibitors on LV DF in patients at high risk for cardiovascular diseases and their complications, that has been demonstrated in relatively small clinical studies, is due to primary cardiac and secondary effects. Results of individual studies confirmed the protective (in relation to myocardial relaxation) properties of gliflozins in the conditions of a diastolic stress test. The regression of LV diastolic dysfunction associated with the SGLT2 inhibitor treatment found in small observational studies is important in the context of the significant beneficial effect of empagliflozin and dapagliflozin on the prognosis of cardiovascular diseases that has been demonstrated in large randomized clinical trials in patients with HFpEF.

Epicardial adipose tissue volume highly correlates with left ventricular diastolic dysfunction in endogenous Cushing's syndrome.

BACKGROUND: Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS: A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS: A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION: CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

This study explored the potential risk factors of LVDD in endogenous CS by incorporating body composition parameters. EATV was identified as an independent risk factor for LVDD. Targeted therapeutic interventions to reduce excessive cortisol-induced EAT accumulation may be promising to mitigate the risk of LVDD development in patients with CS.

[The relevance of diastolic reserve of the left ventricle in patients with type 2 diabetes mellitus (literature review).]

Type 2 diabetes mellitus is one of the most common non-infectious diseases in the world. Among people with type 2 diabetes, patients of the older age group. An in understanding of the early cardiovascular manifestations of diabetes occupies an important place in international research and prevention programs, given that cardiac vascular complications are the cause of death in patients with diabetes. Recent studies evaluating left ventricular diastolic dysfunction as a characteristic predictor of diabetic cardiomyopathy by echocardiography. In accordance with the recommendations for diastolic dysfunction, have shown that the algorithm of the informative algorithm is used to determine left ventricular diastolic dysfunction in patients with prognosis in predicting cardiovascular complications.

Right ventricular diastolic adaptation to pressure overload in different rat strains.

Different rat strains are used in various animal models of pulmonary hypertension and right ventricular (RV) failure. No systematic assessment has been made to test differences in RV response to pressure overload between rat strains. We compared RV adaptation to pulmonary trunk banding (PTB) in Wistar (W), Sprague Dawley (SD), and Fischer344 (F) rats by hemodynamic profiling focusing on diastolic function. Age-matched male rat weanlings were randomized to sham surgery (W-sham, n = 5; SD-sham, n = 4; F-sham, n = 4) or PTB (W-PTB, n = 8; SD-PTB, n = 8; F-PTB, n = 8). RV function was evaluated after 5 weeks by echocardiography, cardiac MRI, and invasive pressure-volume measurements. PTB caused RV failure and increased RV systolic pressures four-fold in all three PTB groups compared with sham. W- and SD-PTB had a 2.4-fold increase in RV end-systolic volume index compared with sham, while F-PTB rats were less affected. Diastolic and right atrial impairment were evident by increased RV end-diastolic elastance, filling pressure, and E/e' in PTB rats compared with sham, again F-PTB the least affected. In conclusions, PTB caused RV failure with signs of diastolic dysfunction. Despite a similar increase in RV systolic pressure, F-PTB rats showed less RV dilatation and a more preserved diastolic function compared with W- and SD-PTB.

The association between TSH and thyroid hormones in the normal or subclinical dysfunction range with left ventricular diastolic dysfunction.

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.

Correlations of Serum Lipid Parameters and Atherogenic Indices With Left Ventricular Diastolic Dysfunction Among Apparently Healthy Patients With Type 2 Diabetes Mellitus: A Multicenter In-Hospital Cross-Sectional Study.

Background: In adolescents with Type 1 diabetes, lipid ratios are predictors of left ventricular diastolic dysfunction (LVDD). However, whether this also applies to adults with Type 2 Diabetes Mellitus (T2DM) is unclear. This study is aimed at assessing the correlations of serum lipid parameters and atherogenic indices with LVDD in patients with T2DM. Methods: This cross-sectional study included 203 patients with T2DM aged 59.9 ± 13.6 years (111 males, sex ratio: 1 : 2 in favor of males) from eight randomly selected urban hospitals. Demographic information was collected, an anthropometric assessment was performed, and blood pressure was measured. Fasting blood samples were obtained to assess total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), glucose, and glycated hemoglobin. The atherogenic index of plasma (AIP), Castelli Risk Index I (CRI-I), Castelli Risk Index II (CRI-II), atherogenic coefficient, and non-HDL-C were determined using specific formulas. Diastolic function was assessed using echocardiography as per the 2016 updated guidelines of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI). Results: Approximately 47.8% of the participants had LVDD. Compared with participants with normal diastolic function, those with LVDD were more likely to be older than 55 years (p < 0.001), tended to have obesity (p = 0.045), had a higher risk of developing dyslipidemia (p = 0.041), and higher AIP and CRI-II (p < 0.05) levels while having similar low HDL-C and hypertriglyceridemia frequencies. In the multivariate model adjusting for age, high AIP (adjusted odds ratio [aOR], 3.37; 95% confidence interval [CI], 1.22-5.34) and high CRI-II (aOR: 3.80; 95% CI: 2.25-6.35) were independent determinants of LVDD. Conclusions: These results highlight the importance of considering atherogenic indices, primarily AIP and CRI-II in the management of T2DM patients. High AIP and high CRI-II could serve as surrogate markers of LVDD, an early cardiovascular manifestation in patients with T2DM.

Left Atrial Strain for assessment of left ventricle diastolic dysfunction in acute coronary syndrome patients.

INTRODUCTION: Patients with acute coronary syndrome (ACS) have a high incidence of Left ventricle diastolic dysfunction (DD). Latest algorithms for the assessment of DD lay on 2D parameters and describe a grading to quantify its severity. However, there persists a "gray zone" of values in which DD remains indeterminate. AIM: to analyze the diagnostic value of Left atrium strain (LAS) for categorization of LV DD and assessment of LV filling pressures in ACS patients. METHODS: Cross-sectional study that prospectively evaluated 105 patients presenting ACS with preserved LV ejection fraction (LVEF). Patients were divided in 4 groups according to the DD grade. Mean values of LAS, corresponding to three phases of atrial function: reservoir (LASr), conduit (LAScd) and contraction (LASct), were obtained by speckle-tracking echocardiography. RESULTS: Mean age was 60±10 years, with a gender ratio of 6.14. LASr and LASct were significantly lower according to DD severity (p combined=0.021, p combined=0.034; respectively). E/e' ratio was negatively correlated to LASr (r= - 0.251; p= 0.022) and LASct (r= -0.197; p=0.077). Left atrial volume index (LAVI) was also negatively correlated to LASr (r= -0.294, p= 0.006) and LASct (r= -0.3049, p=0.005). Peak tricuspid regurgitation was negatively correlated to LASr (r=-0.323, p=0.017) and LASct (r=-0.319, p=0.020). Patients presenting elevated LV filling pressures had lower LASr and LASct (p=0.049, p=0.022, respectively) compared to patients witn normal LV filling pressures. ROC curve analysis showed that a LASr < 22% (Se= 75%, Sp= 73%) and a LASct < 13% (Se= 71%, Sp=58%) can increase the likelihood of DD grade II or III by 4.6 (OR= 4.6; 95% CI: 1.31-16.2; p=0.016) and 3.7 (OR= 3.7; 95% CI: 1.06-13.1; p= 0.047), respectively. CONCLUSION: LAS is a valuable tool, which can be used to categorize DD in ACS patients.

Left atrial stiffness index - an early marker of left ventricular diastolic dysfunction in patients with coronary heart disease.

AIMS: To evaluate the correlation between left atrial stiffness index (LASI) and left ventricular diastolic function in patients with coronary heart disease (CHD) by Autostrain LA technique. METHODS: This was a retrospective analysis that included a total of 82 CHD patients who had suitable image quality for left atrial strain measurement. According to the 2016 ASE/EACVI guidelines for the echocardiographic assessment of diastolic dysfunction, the patients were divided into three groups: normal left ventricular diastolic function group (n = 26), indeterminate left ventricular diastolic function (n = 36), and left ventricular diastolic dysfunction (LVDD) (n = 20). The left atrial conduit strain (LAScd), Left atrial contractile strain (LASct), left atrial reservoir strain (LASr) and its derived parameters, including LASI and left atrial filling index (LAFI), were compared among the three groups. Furthermore, we conduct a correlation analysis between LASI and left ventricular diastolic function in patients with CHD. RESULTS: LASr and LAScd in normal group were higher than those in indeterminate group, LASr and LAScd in indeterminate group were higher than those in LVDD group, LASI in normal group was lower than that in indeterminate group, and LASI in indeterminate group was lower than that in LVDD group (P < 0.001). LASct in both normal and indeterminate groups was higher than that in LVDD group (P < 0.05). The LAFI of normal group was lower than that of indeterminate group and LVDD group (P < 0.001). LASI was positively correlated with E/e'(r = 0.822) (P < 0.001). LASr and E/e' were negatively correlated (r = -0.637) (P < 0.001). CONCLUSION: LASI is closely related to the changes of left ventricular diastolic function in CHD patients.

Lower diastolic tension may be indicative of higher proarrhythmic propensity in failing human cardiomyocytes.

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.

Clinical Significance of Exercise Pulmonary Hypertension With a Negative Diastolic Stress Test for Suspected Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF. METHODS AND RESULTS: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e' (exE/e') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/e'<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/e'≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/e'<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/e'<15 but a high slope had NT-proBNP levels and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope. CONCLUSIONS: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

Diastolic dysfunction in Alzheimer's disease model mice is associated with Aß-amyloid aggregate formation and mitochondrial dysfunction.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease caused by the deposition of Aß aggregates or neurofibrillary tangles. AD patients are primarily diagnosed with the concurrent development of several cardiovascular dysfunctions. While few studies have indicated the presence of intramyocardial Aß aggregates, none of the studies have performed detailed analyses for pathomechanism of cardiac dysfunction in AD patients. This manuscript used aged APPSWE/PS1 Tg and littermate age-matched wildtype (Wt) mice to characterize cardiac dysfunction and analyze associated pathophysiology. Detailed assessment of cardiac functional parameters demonstrated the development of diastolic dysfunction in APPSWE/PS1 Tg hearts compared to Wt hearts. Muscle function evaluation showed functional impairment (decreased exercise tolerance and muscle strength) in APPSWE/PS1 Tg mice. Biochemical and histochemical analysis revealed Aß aggregate accumulation in APPSWE/PS1 Tg mice myocardium. APPSWE/PS1 Tg mice hearts also demonstrated histopathological remodeling (increased collagen deposition and myocyte cross-sectional area). Additionally, APPSWE/PS1 Tg hearts showed altered mitochondrial dynamics, reduced antioxidant protein levels, and impaired mitochondrial proteostasis compared to Wt mice. APPSWE/PS1 Tg hearts also developed mitochondrial dysfunction with decreased OXPHOS and PDH protein complex expressions, altered ETC complex dynamics, decreased complex activities, and reduced mitochondrial respiration. Our results indicated that Aß aggregates in APPSWE/PS1 Tg hearts are associated with defects in mitochondrial respiration and complex activities, which may collectively lead to cardiac diastolic dysfunction and myocardial pathological remodeling.

Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.

Cardiac diastolic dysfunction by cigarette smoking is associated with mitochondrial integrity in the heart.

Cigarette smoking behaviors are harmful and cause one out of ten deaths due to cardiovascular disease. As population sizes grow and number of cigarette smokers increases, it is vital that we understand the mechanisms leading to heart failure in cigarette smokers. We have reported that metabolic regulation of a histone deacetylase, SIRT1, modulates cardiovascular and mitochondrial function under stress. Given this conclusion, we hypothesized that chronic cigarette smoking led to cardiovascular dysfunction via a reduction SIRT1. Mice were randomly organized into smoking or nonsmoking groups, and the smoking group received cigarette smoke exposure for 16 weeks. Following 16-week exposure, diastolic function of the heart was impaired in the smoking group as compared to sham, indicated by a significant increase in E/e'. The electrical function of the heart was also impaired in the smoking group compared to the sham group, indicated by increased PR interval and decreased QTc interval. This diastolic dysfunction was not accompanied by increased fibrosis in mouse hearts, although samples from human chronic smokers indicated increased fibrosis compared to their nonsmoker counterparts. As well as diastolic dysfunction, mitochondria from the 16-week smoking group showed significantly impaired function, evidenced by significant decreases in all parameters measured by the mitochondrial stress test. We further found biochemical evidence of a significantly decreased level of SIRT1 in left ventricles of both mouse and human smoking groups compared to nonsmoking counterparts. Data from this study indicate that decreased SIRT1 levels by cigarette smoking are associated with diastolic dysfunction caused by compromised mitochondrial integrity.

Detecting elevated left ventricular end diastolic pressure from simultaneously measured femoral pressure waveform and electrocardiogram.

Objective.Instantaneous, non-invasive evaluation of left ventricular end-diastolic pressure (LVEDP) would have significant value in the diagnosis and treatment of heart failure. A new approach called cardiac triangle mapping (CTM) has been recently proposed, which can provide a non-invasive estimate of LVEDP. We hypothesized that a hybrid machine-learning (ML) method based on CTM can instantaneously identify an elevated LVEDP using simultaneously measured femoral pressure waveform and electrocardiogram (ECG).Approach.We studied 46 patients (Age: 39-90 (66.4 ± 9.9), BMI: 20.2-36.8 (27.6 ± 4.1), 12 females) scheduled for clinical left heart catheterizations or coronary angiograms at University of Southern California Keck Medical Center. Exclusion criteria included severe mitral/aortic valve disease; severe carotid stenosis; aortic abnormalities; ventricular paced rhythm; left bundle branch and anterior fascicular blocks; interventricular conduction delay; and atrial fibrillation. Invasive LVEDP and pressure waveforms at the iliac bifurcation were measured using transducer-tipped Millar catheters with simultaneous ECG. LVEDP range was 9.3-40.5 mmHg. LVEDP = 18 mmHg was used as cutoff. Random forest (RF) classifiers were trained using data from 36 patients and blindly tested on 10 patients.Main results.Our proposed ML classifier models accurately predict true LVEDP classes using appropriate physics-based features, where the most accurate demonstrates 100.0% (elevated) and 80.0% (normal) success in predicting true LVEDP classes on blind data.Significance.We demonstrated that physics-based ML models can instantaneously classify LVEDP using information from femoral waveforms and ECGs. Although an invasive validation, the required ML inputs can be potentially obtained non-invasively.

Association of body adiposity with left ventricular concentric remodeling and diastolic dysfunction.

BACKGROUND: Obesity is a significant risk factor for heart failure with preserved ejection fraction (HFpEF). In this study, we explore the relationships between body mass index (BMI) and adipose tissue compartments such as visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), with respect to left ventricular (LV) structure and function in subjects with preserved LV systolic function. METHODS: Between January and December 2020, this retrospective study included 749 participants who exhibited preserved LV systolic function and underwent transthoracic echocardiography along with abdominal computed tomography. LV structural and functional variables as well as EAT, VAT, and SAT thickness were evaluated using echocardiography and computed tomography. RESULTS: SAT decreased, while VAT and EAT progressively increased with age. There were significant correlations between BMI and various adipose tissues, with the strongest correlation observed with SAT (r = .491, p < .001) compared to VAT (r = .371, p < .001) or EAT (r = .135, p < .001). However, EAT demonstrated the most substantial association with decreased LV end-diastolic dimension, LV end-systolic dimension, and septal mitral annular velocity and increased relative wall thickness (all p < .05), while VAT and SAT did not show significant associations with LV remodeling and functional parameters after adjusting for clinical variables. CONCLUSION: EAT is the most critical adipose tissue influencing LV geometric and functional changes, compared with VAT or SAT. Thick EAT is associated small LV chamber size, concentric remodeling, and relaxation abnormalities.

Diastolic and systolic blood pressure and gout: a Mendelian randomization study.

Background: Although there is solid epidemiological evidence supporting the connection between hypertension and gout, little has been said about the relationship between diastolic and systolic blood pressure and gout, the causal relationship and direction associated are uncertain, so we aim to research the causal relationship between diastolic and systolic blood pressure and gout. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect between 2 blood pressure phenotypes (including diastolic blood pressure and systolic blood pressure) and 5 gout phenotypes (including gout, drug-induced gout, idiopathic gout, unspecified gout, and strictly defined gout) using genome-wide association study statistics. The inverse variance weighting method was used to generate the main results, while sensitivity analyses using MR-Egger, weighted median, Cochran's Q test, Egger intercept test, and leave-one-out analysis, were performed to assess the stability and reliability of the results. Results: After the screening, we found a causal relationship between diastolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout, and a causal relationship between systolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout. Conclusion: From a genetic predisposition, controlling blood pressure may reduce the risk of gout.

Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.

BACKGROUND: Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms. METHODS: Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy. RESULTS: In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P<0.001 versus con; HFpEF/Empa: 19.4±3.2; P<0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (Vmax complex IV: con: 0.18±0.07 mmol O2/s/mg; HFpEF: 0.13±0.05 mmol O2/s/mg; P<0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O2/s/mg; P=0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P=0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P=0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa. CONCLUSIONS: The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling.