Desert Hedgehog-related endothelial dysfunction is sufficient to induce diastolic dysfunction

Heart Failure with preserved Ejection Fraction (HFpEF) is a clinical syndrome in which patients have symptoms of Heart Failure (HF), such as dyspnea and fatigue, a Left Ventricular Ejection Fraction (LVEF) ≥ 50% and evidence of cardiac dysfunction as a cause of symptoms, such as abnormal Left Ventricular (LV) diastolic dysfunction with elevated filling pressures. Besides LV diastolic dysfunction, recent investigations suggest a more complex and heterogeneous pathophysiology, including systolic reserve abnormalities, chronotropic incompetence, stiffening of ventricular tissue, atrial dysfunction, secondary Pulmonary Arterial Hypertension (PAH), impaired vasodilatation and endothelial dysfunction. Unlike Heart Failure with Reduced Ejection Fraction (HFrEF), clinical trials over the years have not yet identified effective treatments that reduce mortality in patients with HFpEF. A database on use of carvedilol in a private cardiologist's practice was begun in 1997 and concluded at the end of 2018. We used this database to test the hypothesis that combining pharmacological interventions to address diastolic dysfunction (carvedilol), volume overload (spironolactone/eplerenone) and endothelial dysfunction (statins) with weight loss may benefit patients with HFpEF. We report analysis of 335 patients with HFpEF comprised of 61% female (mean age 74 ± 8) and 39% males (mean age 72 ± 7). Initial EF ranged between 50 and 77% with mean EF of 57 ± 6%. Only 15 patients were changed to metoprolol succinate, verapamil or diltiazem because of adverse side effects. Two hundred and twenty of the patients were in normal sinus rhythm when started on carvedilol, spironolactone/eplerenone and statin therapy with weight loss counseling. After 5 years, 191 patients were still on combination therapy, and only 31 (17%) had developed Atrial Fibrillation (AF). Compared to previous HFpEF trials reporting a 32% risk of developing atrial fibrillation after 4 years, our combination therapy significantly (p < 0.05) reduced the risk of developing AF over 5 years. Thus, irrespective of age and sex with comorbidities of type 2 Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD), patients with HFpEF can be managed successfully with carvedilol, spironolactone/eplerenone and statins with a clinical benefit being a reduced risk of developing AF. We consider these data hypothesis-generating and hope these results will be tested further in database analyses and clinical trials.

Download Full-text

Abstract 10036: Olmesartan Improves Not Only Vascular Endothelial Dysfunction but Cardiac Diastolic Dysfunction in Hypertensive Heart Failure With Preserved Ejection Fraction - ORION Study

Circulation ◽

10.1161/circ.132.suppl_3.10036 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Eiichiro Yamamoto ◽

Keisuke Ohba ◽

Yoshihiro Hirata ◽

Takanori Tokitsu ◽

Koichi Sugamura ◽

...

Keyword(s):

Heart Failure ◽

Endothelial Dysfunction ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Reactive Hyperemia ◽

Renin Angiotensin System ◽

Anterior Wall ◽

Left Ventricular ◽

At1 Receptor ◽

Peripheral Arterial Tonometry

Introduction: The optimal treatment for heart failure (HF) with preserved left ventricular (LV) ejection fraction (EF) (HFpEF) has not been established. Using an experimental model of HFpEF, we previously reported a novel mechanism underlying reversal of endothelial dysfunction and HFpEF by AT1 receptor blocker (ARB). By performing this study (ORION: OlmesaRtan Improvement endothelial functiON with hypertension study), we examined the effects of ARB on hypertensive HFpEF patients, focusing on reactive oxygen species (ROS). Methods and Results: We examined prospectively 20 hypertensive HFpEF patients, taking any renin-angiotensin system inhibitors, switched to appreciable amounts of highly-selective ARB; olmesartan (average dosage amounts: 22.9 mg/day) for 3 months. Despite no additive hypotensive effects of olmesartan, endothelial dysfunction assessed by fingertrip digital reactive hyperemia (RH) peripheral arterial tonometry using Endo-PAT2000 was significantly reversed (RH-index; 1.57±0.34 to 1.87±0.50, P=0.034), accompanied by significant reduction of serum derivatives of reactive oxidative metabolites levels, novel biomarker of ROS (362.8±13.7 to 302.1±9.4 unit called the Carratelli unit [U.CARR], P=0.001). Olmesartan treatments significantly improved cardiac diastolic function evaluated by the ratio of early transmitral flow velocity to tissue doppler early diastolic mitral annular velocity (15.4 to 11.0, P<0.001) but not LVEF and LV anterior wall thickness in echocardiography, and decreased plasma B-type natriuretic peptide levels (214.9 to 191.4, P<0.05) in HFpEF patients. Additionaly, olmesartan significantly increased plasma superoxide dismutase activity (2.39±0.73 to 3.06±0.78 U/mL, P=0.02) and adiponectin levels (2.66±1.55 to 4.12±1.99 μg/mL, P<0.05), but not affect plasma nitrates and nitrites (NO3-/NO2-) levels (53.2±28.1 to 62.9±28.4 μmol/L). Conclusions: These data suggested that strong AT1 receptor blockade by olmesartan restored not only endothelial dysfunction but cardiac diastolic dysfunction in HFpEF beyond hypotensive effects. Increased in SOD activities and adiponectin levels, but not nitric oxide levels, might contribute to these beneficial effects of olmesartan.

Download Full-text

Increased left ventricular mass and diastolic dysfunction are associated with endothelial dysfunction in normotensive offspring of subjects with essential hypertension

Blood Pressure ◽

10.1080/08037050701189941 ◽

2007 ◽

Vol 16 (1) ◽

pp. 36-44 ◽

Cited By ~ 8

Author(s):

Bogomir Žižek ◽

Pavel Poredoš

Keyword(s):

Essential Hypertension ◽

Endothelial Dysfunction ◽

Diastolic Dysfunction ◽

Left Ventricular Mass ◽

Left Ventricular ◽

Ventricular Mass

Download Full-text

Investigation of endothelial dysfunction and arterial stiffness in children with type 1 diabetes mellitus and the association with diastolic dysfunction

Diabetes and Vascular Disease Research ◽

10.1177/1479164113508564 ◽

2013 ◽

Vol 11 (1) ◽

pp. 19-25 ◽

Cited By ~ 25

Author(s):

Murat Çiftel ◽

Halil Ertuğ ◽

Mesut Parlak ◽

Gayaz Akçurin ◽

Fırat Kardelen

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Endothelial Dysfunction ◽

Arterial Stiffness ◽

Diastolic Dysfunction ◽

Type 1 Diabetes Mellitus

Download Full-text

P5456The role of ST2 as an early marker of endothelial dysfunction in hypertensive patients

European Heart Journal ◽

10.1093/eurheartj/ehz746.0412 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A D Farcas ◽

M A Stoia ◽

M Mocan ◽

R M Chiorescu ◽

D L Mocan-Hognogi ◽

...

Keyword(s):

Regression Analysis ◽

Endothelial Dysfunction ◽

Diastolic Dysfunction ◽

Brachial Artery ◽

Predictive Marker ◽

Relative Increase ◽

Left Ventricular ◽

Hypertensive Patients ◽

Group A ◽

Group B

Abstract Background The association between endotelial dysfunction and progression of diastolic dysfunction suggests that endotelial and myocardial impairment might have similar pathogenic pathways. Moreover, in hypertensive diabetics the endotelial function is worse in those with impaired diastolic performance compared to normal diastolic performance. ST2 provides additional data to echocardiography in early detection of diastolic performance alteration in hypertension (HT) and is a prominent predictive marker of worse clinical outcome in hypertensive patients. There is scarce data on ST2 role in detection of early vascular involvement in hypertensive patients. Purpose The aim of the study is to evaluate whether ST2 levels correlate with impaired endotelial function in hypertensive patients. Methods Our prospective study included 84 hypertensive patients (mean age 52.9±14.4 yrs, 54.3% males and 45.7% females), after they signed an informed consent. All patients underwent clinical and laboratory (including ST2) evaluation. To investigate endothelial function, we performed ultrasound measurement of the brachial artery diameter both at rest and during reactive hyperemia in the muscle distal to the brachial artery (BA) which causes endothelium-dependent vasodilatation. The study methodology was approved by the Ethical Committee and statistical data processing was performed with SPSS. Results Patients were assigned to group A – those without left ventricular hypertrophy (LVH) and group B – those with LVH. There were no significant differences regarding gender, age and HT stage between groups A and B. Patients in group A had lower ST2 levels [18.83 (13.98 - 42.05) vs 55.63 (48.6 - 100.21) vs, p<0.001] and fewer risk factors (1.4 vs 2.6, p<0.01) compared to group B. We found significant differences regarding diastolic performance parameters between the groups. The relative increase in diameter (% FMD; DD = D 100) was significantly higher in group A than group B (6.67±0.43% vs 3.10±0.33%, p<0.01). ST2 levels were greater in group B and correlated with the degree of endotelial dysfunction evaluated by flow-mediated dilatation (FMD) (r=0.411, p<0.01). Multiple regression analysis showed that ST2 had a significant negative correlation with the relative increase in arterial diameter while multivariate Cox regression analysis showed ST2 was an independent predictor of endothelial dysfunction severity in hypertensive patients (hazard ratio: 4.012, 95% confidence interval: 1.207–31.24, P=0.031). Conclusions ST2 levels correlate with cardiovascular risk and are a significant predictive marker of endothelial dysfunction in hypertensive patients regardless of diastolic dysfunction.

Download Full-text

Abstract 19340: Advanced Peripheral Endothelial Dysfunction Correlates with Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Left Ventricular Ejection Fraction in Hypertensive Patients

Circulation ◽

10.1161/circ.130.suppl_2.19340 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Eiichi Akiyama ◽

Seigo Sugiyama ◽

Yasushi Matsuzawa ◽

Hiroyuki Suzuki ◽

Masaaki Konishi ◽

...

Keyword(s):

Heart Failure ◽

Endothelial Dysfunction ◽

Confidence Interval ◽

Ejection Fraction ◽

Endothelial Function ◽

Diastolic Dysfunction ◽

Odds Ratio ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Hypertensive Patients

Background: Left ventricular (LV) diastolic dysfunction (DD) and vascular functions including peripheral endothelial function play an important role in the pathogenesis of heart failure (HF) with preserved LV ejection fraction (EF) (HFPEF). Hypertension is the most important risk factor in HFPEF and the increased workload caused by hypertension results in LV pathological hypertrophy and LVDD. However, the importance of endothelial function in hypertensive patients with LVDD or HFPEF remains yet undetermined. We investigated the association between peripheral endothelial function, LVDD, and HFPEF in hypertensive patients. Methods and Results: We evaluated cardiac function by echocardiography measuring the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e’) and LVEF. We also noninvasively assessed peripheral endothelial function by reactive hyperemia-peripheral arterial tonometry (RH-PAT) as the RH-PAT index(RHI) in 405 hypertensive patients with preserved LVEF (LVEF>50%), comprising 180 HFPEF and 225 non-HF patients (LVDD; E/e’>15, non-HF with LVDD; n=98, non-HF without LVDD; n=127). RHI negatively correlated with E/e’ (r=-0.24, P<0.001) and B-type natriuretic peptide (r=-0.19, P<0.001). RHI was significantly lower in hypertensive patients with HFPEF than in non-HF hypertensive patients (0.49±0.17 vs. 0.62±0.20, P<0.001). Furthermore, RHI was significantly lower in non-HF hypertensive patients with LVDD than those without LVDD (0.58±0.19 vs. 0.65±0.21, P=0.01). Multivariate logistic regression analysis identified that lower RHI independently correlated with the presence of HFPEF in hypertensive patients with preserved LVEF (odds ratio: 0.65, 95% confidence interval: 0.55-0.77, P<0.001) and with the presence of LVDD in non-HF hypertensive patients (odds ratio: 0.65, 95% confidence interval: 0.71-0.95, P=0.01). Conclusions: RHI was independently associated with the presence of HFPEF and LVDD in hypertensive patients with preserved LVEF. Endothelial dysfunction in microcirculation could play a crucial role in the pathogenesis of LVDD and HFPEF in hypertensive patients.

Download Full-text