Left Ventricular End-diastolic Pressure-volume Relation Research Articles

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Acute vasopressin neutralization improves cardiac function in rats with chronic heart failure

Vasopressin is one of the leading pathophysiological drivers of chronic heart failure (CHF) acting via V1a-, V1b- and V2 receptors. Selective V2 and dual V1a-V2 receptor antagonists increases plasma sodium levels, but failed to reduce mortality in clinical studies. Vasopressin neutralization is an original alternative to receptor blockers but its effect in CHF is unknown. For this purpose, we investigated the short-term cardiac and vascular effects of the vasopressin neutralizing aptamer NOX-F37. Left ventricular (LV) function (hemodynamic by LV catheterization) and LV tissue perfusion (MRI) as well as mesenteric artery endothelial function (flow-mediated dilation by arteriography) were determined 2 hours after NOX-F37 administration (80 nM/kg; IP) to rats with CHF induced by left coronary artery ligation. Two hours after administration, NOX-F37 improved LV systolic function, illustrated by the increase in LV end-systolic pressure volume relationship (CHF: 20.2 ± 0.0.7; CHF + NOX: 23.3 ± 1.0 mmHg/RVU; P < 0.05) and diastolic function, illustrated by the decrease in LV end-diastolic pressure volume relationship (CHF: 4.03 ± 0.48; CHF + NOX: 2.06 ± 0.21 mmHg/RVU; P < 0.01), together with an increase in LV tissue perfusion (CHF: 6.12 ± 0.24; CHF + NOX: 10.10 ± 0.26 ml/min/g LV tissue; P < 0.001). However, mesenteric artery flow-induced dilatation was not improved (% dilatation at 150 μL/min; CHF: 10 ± 7; CHF + NOX: 9 ± 8). These results illustrate the immediate beneficial effects of vasopressin neutralization on cardiac function in CHF, confirming the existence of a deleterious vasopressinergic tone in this pathophysiological context. Investigations still needed to evaluate the persistence of effects of vasopressin neutralization over time during chronic and could contribute to the resolution of acute heart failure.

Impairment of left ventricular diastolic function and exercise capacity after yoyo dieting in female mice with or without ovariectomy-induced post-menopausal condition

Follow-up studies show that weight gain in women proportionally increases the risk of coronary heart disease and that weight cycling is associated with adverse cardiometabolic markers. Moreover, women after menopause are prone to weight gain. To work out a protocol responsible for weight fluctuation and to measure the cardiac functional consequences after a final weight loss, in mice having undergone or not an ovariectomy (OVX). Five-month-old female underwent OVX or not. Starting 5 days after surgery, mice were subjected to Yoyo dieting with successive periods (I, II, III) of a biphasic alternation of a high fat diet (HFD) (4-week constant phase of HFD60%) followed by standard diet (SD) (phase of 4, 6, 10 weeks for period I, II, III, respectively). Non-OVX control (CTL) mice were maintained on SD. At the end of the last SD phase, the global metabolism was evaluated by an insulin tolerance test and echo-MRI, the blood pressure was measured by plethysmography, the exercise capacity was evaluated on treadmill, then the left ventricular (LV) function was assessed by ultrasound and invasive hemodynamics. Body weight in Yoyo and OVX-Yoyo mice was higher to that of CTL mice at the end of period III. Moreover, the first phase of HFD resulted in a higher weight gain in OVX-yoyo mice, which kept bigger than Yoyo mice until the end of the protocol, however without difference in body composition. There was decreased insulin sensitivity in both Yoyo and Yoyo-OVX mice compared to CTL. There was no difference in blood pressure nor in LV fractional shortening between groups. Invasive hemodynamics showed no difference in LV-end diastolic pressure (LVEDP) but an increased LV end-diastolic pressure volume relation (LVEDPVR) in OVX-Yoyo mice, indicating decreased compliance. LV weight was increased in Yoyo mice only. Treadmill stress test showed decreased running duration for OVX-Yoyo mice only ( Fig. 1 ). In female mice subjected to the same Yoyo diet protocol, those in post-menopausal condition after OVX show an increased risk of developing heart failure with preserved ejection fraction and reduced exercise capacity.

Abstract 12140: SCN1B Expression Modulates Sodium Influx in Cardiomyocytes and Diastolic Function in the Adult Heart

Voltage-gated sodium channels (VGSCs) are macromolecular complexes composed of a number of proteins regulating channel biophysical properties. VGSCs generate Na + current (I Na ) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of I Na . Variants in the gene SCN1B , encoding the VGSC β1 and β1B subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of β1/β1B subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knock-out, cKO) were studied. Myocytes from cKO mice had decreased levels of Scn1b transcripts (-85%) and increased densities of fast- (+20%) and slow-inactivating (+140%) components of I Na , with respect to cells from corresponding control (Ctrl) animals. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were preserved in both male and female cKO mice, with respect to sex- and age-matched Ctrl animals. However, by transmitral flow Doppler echocardiography, cKO mice presented reduced velocity of the passive filling wave (-~20%), attenuated ratio of the passive-to-active filling velocity waves (-~20%), and prolonged isovolumic relaxation time (+~16%). Moreover, by pressure-volume (PV) loop assessment, cKO mice had steeper slope of the LV end diastolic PV relation and prolonged LV relaxation tau, suggesting impairment of diastolic function. Importantly, inhibition of late I Na with GS967 (0.5 mg/kg body weight) normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice, but had no consequences in Ctrl animals. At the cellular level, cKO myocytes presented delayed kinetics of Ca 2+ transients decay and cell shortening with respect to Ctrl myocytes. These defects were partly corrected by inhibition of the late I Na . Collectively, these results document that VGSC β1/β1B subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na + influx in cardiomyocytes.

One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction.

Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V-V0)}-1], where "P" is transmural pressure (pulmonary capillary wedge pressure - right atrial pressure), "S" is the pressure asymptote of the curve, "V" is the LV end-diastolic volume index, "V0" is equilibrium volume, and "a" is the constant that characterizes LV myocardial stiffness. Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min-1·kg-1, P<0.0001, interaction P=0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min-1·kg-1, P=0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P=0.001). In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03476785.

386-P: Chronic Treatment with the Direct AMPK Activator PXL770 Improves Cardiac, Vascular, and Renal Function in Rodents with Diabetes-Related Cardiorenal Disease

Introduction: PXL770 is a direct AMP kinase activator. In models of T2DM and NASH, PXL770 improves hyperglycemia and dyslipidemia and reduces: steatosis, inflammation, fibrogenesis. Whether these beneficial effects are associated with an improvement in diabetes-related cardiac, vascular and renal dysfunctions is unknown. Methods: Diabetic ZSF-1 rats were treated for 90 days with PXL770 (150 mg/kg BID), then cardiac function (left ventricular (LV) hemodynamics), in vitro flow-mediated dilation (FMD; arteriograph) of mesenteric artery, renal histology and function (transcutaneous GFR) were assessed. Results: Untreated ZSF-1 rats exhibited LV diastolic dysfunction, i.e., increases in LV End-Diastolic Pressure (LVEDP; 8.3±1.0 vs. 5.6±0.6 mm Hg in lean, p&amp;lt;.05) and LV End-Diastolic Pressure Volume Relation (LVEDPVR; 5.4±0.6 vs. 1.1±0.2 mm Hg/RVU in lean, p&amp;lt;.05). Myocardial tissue perfusion was reduced (4.0±0.2 vs. 7.4±0.9 ml/min/g in lean, p&amp;lt;.05). Untreated rats exhibited impaired mesenteric FMD (% of preconstriction; 37±11 vs. 70±7% in lean, p&amp;lt;.05) and renal function and structure as shown by a reduction in GFR (4.4±0.5 vs. 5.6±0.5 ml/min in lean, p&amp;lt;.05) and increase in glomerular score (2.3±0.2 vs. 0.6±0.1 AU in lean, p&amp;lt;.05). Compared to untreated ZSF-1 rats, 90-day PXL770 reduced glycaemia (-31 %, p&amp;lt;.05) and plasma triglycerides (-44 %, p&amp;lt;.05). PXL770 decreased LVEDP (-28 %) and LVEDPVR (2.7±0.2 mm Hg/RVU, p&amp;lt;.05) and increased LV tissue perfusion (+30 %, p&amp;lt;.05). PXL770 improved mesenteric FMD (64±3%, p&amp;lt;.05) and increased GFR (6.0±0.1 ml/min, p&amp;lt;.05) and reduced glomerular score (1.6±0.2, p&amp;lt;.05). Conclusion: In ZSF-1 rats, improvement of metabolic status induced by long-term treatment with the AMP kinase activator PXL770 is associated with an improved LV diastolic, vascular and renal function/structure. PXL770 could have therapeutic utility for the treatment of metabolic diseases and related co-morbid conditions. Disclosure Y. Stephan: None. M. Soulié: None. L. Nicol: None. P. Gluais-dagorn: Employee; Self; Poxel SA. S. Hallakou-bozec: None. P. Mulder: None. Funding Poxel SA

Left-ventricular hypertrophy in 18-month-old donor rat hearts was not associated with graft dysfunction in the early phase of reperfusion after cardiac transplantation\u2013gene expression profiling

The use of hearts with left-ventricular (LV) hypertrophy (LVH) could offer an opportunity to extend the donor pool for cardiac transplantation. We assessed the effects of LVH in 18-month-old spontaneously hypertensive stroke-prone (SHRSP) donor rats and following transplantation. In donors, cardiac function and structural alterations were assessed. Then, the hearts were transplanted into young normotensive-rats. We evaluated LV graft function 1 h after transplantation. The myocardial expression of 92 genes involved in apoptosis, inflammation, and oxidative-stress was profiled using PCR-array. Compared to controls, SHRSP-rats developed LVH, had increased LV systolic performance (slope of the end-diastolic pressure-volume (PV) relationship: 1.6±0.2 vs 0.8±0.1mmHg/μl, p<0.05) accompanied by diastolic dysfunction [prolonged time constant of LV pressure decay (Tau: 15.8±0.6 vs 12.3±0.5ms) and augmented diastolic stiffness (LV end-diastolic PV relationship: 0.103±0.012 vs 0.045±0.006mmHg/ml), p<0.05]. They presented ECG changes, myocardial fibrosis, and increased nitrotyrosine immunoreactivity and plasma troponin-T and creatine kinase-CM levels. After transplantation, even though the graft contractility was better in SHRSP rats compared to controls, the adverse impact of ischemia/reperfusion-injury on contractility was not altered (Ees ratio after versus before transplantation: 32% vs 29%, p>0.05). Whereas nitrotyrosine immunoreactivity was higher, myeloperoxidase-positive cell infiltration was decreased in the SHRSP+transplanted compared to control+transplanted. Among the tested genes, LVH was associated with altered expression of 38 genes in donors, while transplantation of these hearts resulted in the change of four genes. Alterations in 18-month-old donor hearts, as a consequence of hypertension and LVH, were not associated with graft dysfunction in the early phase of reperfusion after transplantation.

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice.

AimsIn post‐menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non‐steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders.Methods and resultsOvariectomy was performed in 4‐month‐old mice, treated or not at 7 months old for 1 month with finerenone (Fine) 1 mg/kg/day. Left ventricular (LV) cardiac and coronary endothelial functions were assessed by echocardiography, catheterization, and myography. Blood pressure was measured by plethysmography. Insulin and glucose tolerance tests were performed. Exercise capacity and spontaneous activity were measured on treadmill and in combined indirect calorimetric cages equipped with voluntary running wheel. OVX mice presented LV diastolic dysfunction without modification of ejection fraction compared with controls (CTL), whereas finerenone improved LV filling pressure (LV end‐diastolic pressure, mmHg: CTL 3.48 ± 0.41, OVX 6.17 ± 0.30**, OVX + Fine 3.65 ± 0.55†, **P < 0.01 vs. CTL, † P < 0.05 vs. OVX) and compliance (LV end‐diastolic pressure–volume relation, mmHg/RVU: CTL 1.65 ± 0.42, OVX 4.77 ± 0.37***, OVX + Fine 2.87 ± 0.26††, ***P < 0.001 vs. CTL, †† P < 0.01 vs. OVX). Acetylcholine‐induced endothelial‐dependent relaxation of coronary arteries was impaired in ovariectomized mice and improved by finerenone (relaxation, %: CTL 86 ± 8, OVX 38 ± 3**, OVX + Fine 83 ± 7††, **P < 0.01 vs. CTL, †† P < 0.01 vs. OVX). Finerenone improved decreased ATP production by subsarcolemmal mitochondria after ovariectomy. Weight gain, increased blood pressure, and decreased insulin and glucose tolerance in OVX mice were improved by finerenone. The exercise capacity at race was diminished in untreated OVX mice only. Spontaneous activity measurements in ovariectomized mice showed decreased horizontal movements, reduced time spent in a running wheel, and reduced VO2 and VCO2, all parameters improved by finerenone.ConclusionsFinerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy‐induced LV diastolic dysfunction with preserved ejection fraction.

Impaired left ventricular global longitudinal strain is associated with elevated left ventricular filling pressure after myocardial infarction.

Left ventricular (LV) global longitudinal strain (GLS) has emerged as a significant prognostic marker in patients after myocardial infarction (MI). Although elevated LV filling pressure after MI might alter GLS, direct evidence for this is lacking. This study aimed to clarify the association between GLS and LV filling pressure in a large animal MI model. A total of 104 Yorkshire pigs underwent both echocardiographic and hemodynamic assessments 1-4 wk after induction of large anterior MI. GLS was measured in the apical four-chamber view using a semiautomated speckle-tracking software. LV pressure-volume relationship was invasively measured using a high-fidelity pressure-volume catheter. GLS >-14% was considered impaired. Compared with pigs with LV ejection fraction (LVEF) >40% and preserved GLS (n = 29), those with LVEF >40% and impaired GLS (n = 37) and those with LVEF ≤40% (n = 38) had significantly higher LV end-diastolic pressure (15.5 ± 5.5 vs. 19.7 ± 5.8 and 19.6 ± 6.6 mmHg; P = 0.008 and P = 0.026, respectively) and higher LV mean diastolic pressure (7.1 ± 2.9 vs. 10.4 ± 4.5 and 11.1 ± 5.4 mmHg; P = 0.013 and P = 0.002, respectively). GLS was modestly correlated with τ (r = 0.21, P = 0.039) and slope of LV end-diastolic pressure-volume relationship (r = 0.43, P < 0.001). Impaired GLS was associated with higher LV end-diastolic and mean-diastolic pressures after adjusting for LVEF and baseline characteristics (P = 0.026 and P = 0.001, respectively). Impaired GLS assessed by speckle-tracking echocardiography was associated with elevated LV filling pressure after MI. GLS has an incremental diagnostic value for detecting elevated LV filling pressure and may be particularly useful for evaluating post-MI patients with preserved LVEF.NEW & NOTEWORTHY Strain analysis was performed in 104 pigs after MI, and its relationship to invasive hemodynamic measurements was studied. Impaired longitudinal strain was associated with high ventricular filling pressure independent of LVEF in post-MI setting. Global longitudinal strain is a potential prognostic marker after MI.

1963-P: Short- and Long-Term Empagliflozin Treatment Improves Cardiac Function in Rats with Chronic Heart Failure

Introduction: The SGLT2 inhibitor empagliflozin (EMPA) exerts beneficial cardiovascular effects in type-2 diabetes, but whether this occurs in chronic heart failure (CHF) is unknown. Thus we investigated, using a rat model whether EMPA exhibits protective effect in chronic heart failure (CHF). Methods: Rats with CHF were treated with EMPA (30 mg/kg PO for 7 days starting 83 days after coronary artery ligation or 90 days starting 7 days after coronary artery ligation) to assess effects on left ventricular (LV) function and hemodynamics (echocardiography, LV catheterization). Results: After 90 days untreated CHF rats presented LV systolic and diastolic dysfunction, illustrated by the decreases in LV end-systolic pressure (LV ESP) and in LV end-systolic pressure volume-relation (LV ESPVR) as well as the increases in LV end-diastolic pressure (LV EDP) and LV end-diastolic pressure volume-relation (LV EDPVR). Seven- and ninety-day EMPA treatment improved systolic and diastolic LV function, illustrated by the increases in LV ESP and in LV ESPVR as well as the reductions in LV EDP and in LV EDPVR. Conclusion: Short- and long-term EMPA treatment prevents LV dysfunction in rats with CHF. These results suggest that EMPA may exert protective effects in humans with CHF. Disclosure M. Soulié: None. Y. Stephan: None. L. Nicol: None. J. Henry: None. V. Richard: None. M. Pieper: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. P. Mulder: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA. Funding Boehringer Ingelheim

Short-and long-term administration of imeglimin counters cardiorenal dysfunction in a rat model of metabolic syndrome.

IntroductionImeglimin, a glucose‐lowering agent targeting mitochondrial bioenergetics, decreases reactive oxygen species (ROS) overproduction and improves glucose homeostasis. We investigated whether this is associated with protective effects on metabolic syndrome‐related left ventricular (LV) and vascular dysfunctions.MethodsWe used Zucker fa/fa rats to assess the effects on LV function, LV tissue perfusion, LV oxidative stress and vascular function induced by imeglimin administered orally for 9 or 90 days at a dose of 150 mg/kg twice daily.ResultsCompared to untreated animals, 9‐ and 90‐day imeglimin treatment decreased LV end‐diastolic pressure and LV end‐diastolic pressure‐volume relation, increased LV tissue perfusion and decreased LV ROS production. Simultaneously, imeglimin restored acetylcholine‐mediated coronary relaxation and mesenteric flow‐mediated dilation. One hour after imeglimin administration, when glucose plasma levels were not yet modified, imeglimin reduced LV mitochondrial ROS production and improved LV function. Ninety‐day imeglimin treatment reduced related LV and kidney fibrosis and improved kidney function.ConclusionIn a rat model, mimicking Human metabolic syndrome, imeglimin immediately countered metabolic syndrome‐related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion and after 90‐day treatment myocardial and kidney structure, effects that are, at least in part, independent from glucose control.

Lack of Cardiac Improvement After Cardiosphere-Derived Cell Transplantation in Aging Mouse Hearts.

Aging is one of the most significant risk factors for cardiovascular diseases, and the incidence of myocardial ischemia increases dramatically with age. Some studies have reported that cardiosphere-derived cells (CDCs) could benefit the injured heart. Nevertheless, the convincing evidence on CDC-induced improvement of aging heart is still limited. In this study, we tested whether the CDCs isolated from neonatal mice could benefit cardiac function in aging mice. We evaluated cardiac function of PBS- (n=15) and CDC-injected (n=19) aging mice. Echocardiography indicated that left ventricular (LV) ejection fraction (57.46%±3.57% versus 57.86%±2.44%) and LV fraction shortening (30.67%±2.41% versus 30.51%±1.78%) showed similar values in PBS- and CDC-injected mice. The diastolic wall thickness of LV was significantly increased after CDC injection, resulting in reduced diastolic LV volume. The pulse-wave Doppler and tissue Doppler imaging indicated that aging mice receiving PBS or CDC injection presented similar values of the peak early transmitral flow velocity, the peak late transmitral flow velocity, the ratio of the peak early transmitral flow velocity to the peak late transmitral flow velocity, and the ratio of the peak early transmitral flow velocity to the peak early diastolic mitral annular velocity, respectively. Pressure-volume loop experiment indicated that the LV end-diastolic pressure-volume relationship and end-systolic pressure-volume relationship were comparable in both PBS- and CDC-injected mice. Postmortem analysis of aging mouse hearts showed similar fibrotic degree in the 2 groups. In addition, the aging markers showed comparable expression levels in both PBS- and CDC-injected mice. The systemic aging performance measures, including exercise capacity, hair regrowth capacity, and inflammation, showed no significant improvement in CDC-injected mice. Finally, the telomere length was comparable between PBS- and CDC-injected mice. Together, these results indicate that CDCs do not improve heart function and systemic performances in aging mice.

Short- and long-term administration of the non-steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction.

To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage. In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods). Long-term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously, long-term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased. In rats with metabolic syndrome, the non-steroidal MR antagonist finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long-term effects, such as modifications in the myocardial structure.

Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg·kg-1·min-1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

Detrimental Effects of Aging, Ovariectomy and Weight Gain on Left Ventricular Structure and Function: A Potential Preclinical Model of Early Stage HFpEF

The incidence of heart failure with preserved ejection fraction (HFpEF) continues to increase and little is known about its pathophysiology. Two‐thirds of HFpEF patients are senile women and risk factors include hypertension and metabolic syndrome. Currently, no drugs are effective for HFpEF treatment and the development of animal models would assist in novel therapy evaluation. We implemented a rodent female animal model of aging, estrogen depletion and weight gain to evaluate the role of these factors in altering cardiac structure/function. Female, 18 month old, Fischer F344 rats were allocated into an aging (A) group, aging + ovariectomy (O) and aging + ovariectomy and 10% fructose (OF) in drinking water (n=8–13/group). For comparison purposes a young (3 month old, n=8) cohort of female rats was included. Left ventricular (LV) structure/function was monitored monthly by echocardiography. At 22 months of age, animals were anesthetized and LV function evaluated using a Millar conductance catheter. Histological measures of chamber morphometry, inflammation and collagen density (fibrosis) were also obtained. OF animals significantly increased body weight vs. A and O. While echocardiography did not detect major alterations in cardiac endpoints, intraventricular pressure‐volume loop analysis evidenced significant (p&lt;0.05) decreases in stroke volume (19% O and 27% for OF vs. A), stroke work (27 O and 31% OF vs. A), cardiac output (43 O and 44% OF vs. A) and increases in Tau (30–35% in A, O and OF vs. young) and LV end‐diastolic pressure volume relationship slope (i.e. stiffness) with ovariectomy in the presence of preserved ejection fraction for all groups. Histomorphometry did not detect changes in chamber dimensions. However, histological analysis indicated progressively increasing levels of inflammatory infiltration, perivascular and interstitial fibrosis with ovariectomy and with fructose supplementation in particular, in the subendocardium (see figure). In conclusion, in the setting of aging, ovariectomy (which depletes estrogens), further deteriorates myocardial microstructure which may facilitate the loss of diastolic and global functional indices in the apparent presence of preserved ejection fraction. This model may serve to understand the role that estrogen depletion and weight gain may have in the development of HFpEF.Support or Funding InformationDoD 150090 to FVThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Protein tyrosine phosphatase 1B inactivation limits aging-associated heart failure in mice

We have previously shown that protein tyrosine phosphatase 1B (PTP1B) inactivation in mice [PTP1B-deficient (PTP1B-/-) mice] improves left ventricular (LV) angiogenesis, perfusion, remodeling, and function and limits endothelial dysfunction after myocardial infarction. However, whether PTP1B inactivation slows aging-associated cardiovascular dysfunction remains unknown. Wild-type (WT) and PTP1B-/- mice were allowed to age until 18 mo. Compared with old WT mice, in which aging increased the LV mRNA expression of PTP1B, old PTP1B-/- mice had 1) reduced cardiac hypertrophy with decreased LV mRNA levels of hypertrophic markers and atrial and brain natriuretic peptides, 2) lower LV fibrosis (collagen: 16 ± 3% in WT mice and 5 ± 3% in PTP1B-/- mice, P < 0.001) with decreased mRNA levels of transforming growth-factor-β1 and matrix metalloproteinase-2, and 3) higher LV capillary density and lower LV mRNA level of hypoxic inducible factor-1α, which was associated over time with a higher rate of proangiogenic M2 type macrophages and a stable LV mRNA level of VEGF receptor-2. Echocardiography revealed an age-dependent LV increase in end-diastolic volume in WT mice together with alterations of fractional shortening and diastole (transmitral Doppler E-to-A wave ratio). Invasive hemodynamics showed better LV systolic contractility and better diastolic compliance in old PTP1B-/- mice (LV end-systolic pressure-volume relation: 13.9 ± 0.9 in WT mice and 18.4 ± 1.6 in PTP1B-/- mice; LV end-diastolic pressure-volume relation: 5.1 ± 0.8 mmHg/relative volume unit in WT mice and 1.2 ± 0.3 mmHg/relative volume unit in PTP1B-/- mice, P < 0.05). In addition, old PTP1B-/- mice displayed a reduced amount of LV reactive oxygen species. Finally, in isolated resistance mesenteric arteries, PTP1B inactivation reduced aging-associated endothelial dysfunction (flow-mediated dilatation: -0.4 ± 2.1% in WT mice and 8.2 ± 2.8% in PTP1B-/- mice, P < 0.05). We conclude that PTP1B inactivation slows aging-associated LV remodeling and dysfunction and reduces endothelial dysfunction in mesenteric arteries. NEW & NOTEWORTHY The present study shows that protein tyrosine phosphatase 1B inactivation in aged mice improves left ventricular systolic and diastolic function associated with reduced adverse cardiac remodeling (hypertrophy, fibrosis, and capillary rarefaction) and limits vascular endothelial dysfunction. This suggests that protein tyrosine phosphatase 1B inhibition could be an interesting treatment approach in age-related cardiovascular dysfunction.

Reversing the Cardiac Effects of Sedentary Aging in Middle Age-A Randomized Controlled Trial: Implications For Heart Failure Prevention.

Poor fitness in middle age is a risk factor for heart failure, particularly heart failure with a preserved ejection fraction. The development of heart failure with a preserved ejection fraction is likely mediated through increased left ventricular (LV) stiffness, a consequence of sedentary aging. In a prospective, parallel group, randomized controlled trial, we examined the effect of 2 years of supervised high-intensity exercise training on LV stiffness. Sixty-one (48% male) healthy, sedentary, middle-aged participants (53±5 years) were randomly assigned to either 2 years of exercise training (n=34) or attention control (control; n=27). Right heart catheterization and 3-dimensional echocardiography were performed with preload manipulations to define LV end-diastolic pressure-volume relationships and Frank-Starling curves. LV stiffness was calculated by curve fit of the diastolic pressure-volume curve. Maximal oxygen uptake (Vo2max) was measured to quantify changes in fitness. Fifty-three participants completed the study. Adherence to prescribed exercise sessions was 88±11%. Vo2max increased by 18% (exercise training: pre 29.0±4.8 to post 34.4±6.4; control: pre 29.5±5.3 to post 28.7±5.4, group×time P<0.001) and LV stiffness was reduced (right/downward shift in the end-diastolic pressure-volume relationships; preexercise training stiffness constant 0.072±0.037 to postexercise training 0.051±0.0268, P=0.0018), whereas there was no change in controls (group×time P<0.001; pre stiffness constant 0.0635±0.026 to post 0.062±0.031, P=0.83). Exercise increased LV end-diastolic volume (group×time P<0.001), whereas pulmonary capillary wedge pressure was unchanged, providing greater stroke volume for any given filling pressure (loading×group×time P=0.007). In previously sedentary healthy middle-aged adults, 2 years of exercise training improved maximal oxygen uptake and decreased cardiac stiffness. Regular exercise training may provide protection against the future risk of heart failure with a preserved ejection fraction by preventing the increase in cardiac stiffness attributable to sedentary aging. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02039154.

Sex-Specific Effects of Adrenergic-Induced Left Ventricular Remodeling in Spontaneously Hypertensive Rats

ObjectiveThe aim of this work was to determine whether adrenergic-induced left ventricular (LV) dilation and eccentric remodeling in pressure-overload hypertrophy is sex specific. Methods and ResultsChronic β-adrenoreceptor activation was produced in male and female spontaneously hypertensive rats (SHRs) by means of daily administration of isoproterenol (ISO; 0.04 mg/kg daily) from 9 to 15 months of age. LV chamber dimensions were determined in vivo by means of echocardiography and ex vivo in isolated perfused heart preparations. The acute hemodynamic response to ISO, the degree of myocardial necrosis and apoptosis, and collagen distribution were also assessed. Female SHRs demonstrated inotropic and chronotropic responses to ISO similarly to male SHRs. Compared with control subjects (saline solution vehicle), following chronic ISO administration, LV end-diastolic diameter (mm) was increased in male (ISO 7.8 ± 0.3 vs control 6.6 ± 0.2; P < .001) but not in female (ISO 6.3 ± 0.2 vs control 6.2 ± 0.2; P = .23) SHRs. Similarly, compared with control, ISO administration increased the volume intercept of the LV end-diastolic pressure-volume relation (mL) in male (ISO 0.31 ± 0.02 vs control 0.22 ± 0.01; P < .0001) but not in female (ISO 0.17 ± 0.01 vs control 0.17 ± 0.01; P = 1.00) SHRs. Relative wall thickness was also decreased in male SHRs receiving ISO but not in female SHRs receiving ISO. Chronic ISO administration increased the percentage of area covered by interstitial collagen in male but not in female SHRs. Finally, chronic adrenergic stimulation failed to influence LV chamber or myocardial systolic function in either male or female SHRs. ConclusionsMale SHRs are more susceptible to adrenergic-induced LV dilation and eccentric LV remodeling than female SHRs. These effects are associated with increased collagen deposition. In pressure-overload hypertrophy, LV dilation and eccentric LV remodeling occur before LV dysfunction in male rats.

Risk factors for heart failure are associated with alterations of the LV end-diastolic pressure-volume relationship in non-heart failure individuals: data from a large-scale, population-based cohort.

Left-ventricular (LV) remodelling impacts on the LV end-diastolic pressure-volume relationship (EDPVR), which is different in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a large-scale, population-based cohort (Gutenberg Health Study), we aimed to investigate alterations of the EDPVR in HF patients and their association to risk factors and all-cause mortality in non-HF individuals. Based on clinical and echocardiographic data, participants were divided into 'No HF' (n = 14487), HFrEF (n = 215), and HFpEF (n = 79). We estimated the position of the EDPVR and its stiffness-coefficient β from echocardiographic data using a single-beat method. The EDPVR was shifted rightward in HFrEF and leftward in HFpEF compared with 'No HF', while the stiffness-coefficient β was increased in both HFrEF and HFpEF. In 'No HF', a higher stiffness-coefficient β was associated with age, female gender, hypertension, diabetes, and obesity, while age and female gender were associated with a leftward shift of the EDPVR, whereas dyslipidaemia, obesity, smoking, and impaired renal function were associated with a rightward shift of the EDPVR. Both changes of the EDPVR were associated with increased all-cause mortality. In a large-scale, population-based cohort, we show distinct alterations of the EDPVR in HFrEF and HFpEF. Already in non-HF individuals, the presence of risk factors for HF is linked alterations of the EDPVR, which are associated with increased mortality.

Selective Heart Rate Reduction Improves Metabolic Syndrome-related Left Ventricular Diastolic Dysfunction.

Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown. We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1)). Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified. In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.