Hypertensive Heart Failure With Preserved Ejection Fraction Research Articles

PS-B10-4: AFFERENT RENAL NERVOUS SIGNALS CONTRIBUTE TO THE DEVELOPMENT OF HFPEF WITH SYMPATHOEXCITATION IN DAHL SALT-SENSITIVE HYPERTENSIVE RATS

Objective: Sympathetic activation is involved in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Renal nerves contain sympathetic efferent and sensory afferent fibers. Excitation of the renal efferent nerves increases renal renin release and sodium/water retention. On the other hand, the renal afferent nerves are activated by the renal injury associated with hypertension, and acute stimulation of the afferent nerves increases sympathetic output from the brain. In this study, we investigated whether the signals from the renal afferent nerves contribute to the development of hypertensive HFpEF using a novel method of selective afferent renal nerve denervation (ARDN) in Dahl salt-sensitive rats, a widely used animal model of HFpEF. Design and method: Male Dahl salt-sensitive rats were fed 0.3% low-salt diet (LS) or 8% high-salt diet (HS) from 7 weeks of age. At 9 weeks, LS-fed rats received sham operation (LS-Sham), and HS-fed rats were randomly divided into ARDN (HS-ARDN) or sham operation (HS-Sham). At 19 weeks, blood pressure, echocardiographic parameters, organ weights, and plasma norepinephrine levels were measured, and the histological and biochemical analysis of the heart were performed. Results: Systolic blood pressure was significantly increased in HS-Sham compared to LS-Sham, and this increase was not affected in HS-ARDN. By echocardiography, left ventricular (LV) fractional shortening did not differ between the three groups; however, E/e’ ratio was significantly increased in HS-Sham compared to LS-Sham and was attenuated in HS-ARDN. LV weight / body weight ratio and lung weight / body weigh ratio were significantly increased in HS-Sham compared to LS-Sham, and were decreased in HS-ARDN. Plasma norepinephrine levels were significantly higher in HS-Sham than LS-Sham, and this increase tended to be inhibited in HS-ARDN. LV fibrosis evaluated by Masson trichrome staining was significantly increased in HS-Sham compared to LS-Sham and was attenuated in HS-ARDN. ANP mRNA expression in LV tissue was extremely increased in HS-Sham compared to LS-Sham and was significantly attenuated in HS-ARDN. Conclusion: The signals from afferent renal nerves contribute to the development of HFpEF with sympathoexcitation in Dahl salt-sensitive hypertensive rats.

Abstract 13055: Endotrophin is Significantly Associated With Risk of Mortality in HFpEF Patients Irrespective of Underlying Atrial Fibrillation

Introduction: The global burden of heart failure with preserved ejection fraction (HFpEF) is increasing. HFpEF is projected to become the dominant type of HF, and atrial fibrillation (AF) is known to contribute to pathogenesis by aggravating fibrosis. Endotrophin is a bioactive molecule released from collagen type VI during its maturation, and it is a marker of fibroblast activity. The aim of this post-hoc analysis was to confirm the previously observed prognostic potential of endotrophin (measured by PRO-C6) for adverse outcome in HFpEF and to investigate the potential influence in risk stratification by AF. Methods: 166 patients with hypertensive HFpEF were included for analysis. 48.2% were NYHA Class II, 49.4% NYHA Class III and 1.2% NYHA Class IV. 50.6% of patients had a previous history of AF. Cardiac function was assessed by echocardiography and standard clinical measures. Circulating endotrophin was quantified at baseline in serum by means of an enzyme-linked immunosorbent assay, PRO-C6. Results: PRO-C6 levels increased significantly with disease severity in HFpEF patients (NYHA Class III vs II, p=0.0003), and in HFpEF patients with AF (p=0.023). PRO-C6 was able to discriminate between patients at risk of all-cause mortality (AUC=0.73, p<0.001), but no improvement in this association was observed when factoring in AF (AUC=0.72, p=0.001). When looking at patients stratified in PRO-C6 tertiles, patients in the upper tertile had a significantly higher risk of mortality (p<0.0001, hazard ratios 3 vs 1=4.1, 3 vs 2=3.5, respectively) and HF hospitalization (p<0.0001, hazard ratio 3 vs 1=4.4, 3 vs 2=1.6, respectively) compared to tertiles 1 and 2. Conclusions: In this population of hypertensive HFpEF patients, circulating endotrophin, measured by PRO-C6, was increased with increasing disease severity, and associated with a higher risk of adverse outcome in HFpEF, regardless of underlying AF. The data presented here suggest a potential role of endotrophin in HFpEF pathophysiology, associated to disease progression in HFpEF patients with or without AF. These data confirm previous observations, and strengthen the usefulness of endotrophin, measured by the PRO-C6 biomarker, as a prognostic tool aiding in assessment of HFpEF patients.

Left ventricular geometry transition in hypertensive patients with heart failure with preserved ejection fraction.

AimsHeart failure with preserved ejection fraction (HFpEF) develops in response to hypertensive left ventricular (LV) hypertrophy and is associated with increased cardiovascular events. Although the progression to systolic heart failure is a known consequence of LV hypertrophy and HFpEF, few data are available on the LV geometry change and frequency of deterioration to systolic dysfunction in this population.Methods and resultsWe evaluated the baseline and follow‐up characteristics in 680 patients with LV hypertrophy and HFpEF in this prospective cohort study. The primary endpoint was 5 year all‐cause mortality. The changes of LV geometry and heart failure transition were analysed. Systolic dysfunction [left ventricular ejection fraction (LVEF) < 50%] occurred in 182 patients (26.8%) during a 5 year follow‐up. Patients with LVEF deterioration were associated with a lower survival rate. Beta‐blocker prescription was a protective factor for preserved LVEF. And concentric LV geometry shifted to eccentric hypertrophy was uncommon (10.6%) during a 5 year follow‐up.ConclusionsA quarter of patients with hypertensive LV hypertrophy and HFpEF progresses to systolic dysfunction during a 5 year follow‐up, which was accompanied by poor clinical outcomes. And beta‐blocker therapy might play a protective role for preserved LVEF in this population.

Comprehensive Echocardiographic and Cardiac Magnetic Resonance Evaluation Differentiates Among Heart Failure With Preserved Ejection Fraction Patients, Hypertensive Patients, and Healthy Control Subjects

ObjectivesThe aim of this study was to investigate the utility of a comprehensive imaging protocol including echocardiography and cardiac magnetic resonance in the diagnosis and differentiation of hypertensive heart disease and heart failure with preserved ejection fraction (HFpEF). BackgroundHypertension is present in up to 90% of patients with HFpEF and is a major etiological component. Despite current recommendations and diagnostic criteria for HFpEF, no noninvasive imaging technique has as yet shown the ability to identify any structural differences between patients with hypertensive heart disease and HFpEF. MethodsWe conducted a prospective cross-sectional study of 112 well-characterized patients (62 with HFpEF, 22 with hypertension, and 28 healthy control subjects). All patients underwent cardiopulmonary exercise and biomarker testing and an imaging protocol including echocardiography with speckle-tracking analysis and cardiac magnetic resonance including T1 mapping pre- and post-contrast. ResultsEchocardiographic global longitudinal strain (GLS) and extracellular volume (ECV) measured by cardiac magnetic resonance were the only variables able to independently stratify among the 3 groups of patients. ECV was the best technique for differentiation between hypertensive heart disease and HFpEF (ECV area under the curve: 0.88; GLS area under the curve: 0.78; p < 0.001 for both). Using ECV, an optimal cutoff of 31.2% gave 100% sensitivity and 75% specificity. ECV was significantly higher and GLS was significantly reduced in subjects with reduced exercise capacity (lower peak oxygen consumption and higher minute ventilation–carbon dioxide production) (p < 0.001 for both ECV and GLS). ConclusionsBoth GLS and ECV are able to independently discriminate between hypertensive heart disease and HFpEF and identify patients with prognostically significant functional limitation. ECV is the best diagnostic discriminatory marker of HFpEF and could be used as a surrogate endpoint for therapeutic studies.

007 Comprehensive echocardiographic and cardiovascular magnetic resonance evaluation differentiates between patients with heart failure with preserved ejection fraction, hypertensive patients and healthy controls and identifies those with reduced exercise capacity on cardiopulmonary exercise testing

Objectives The aim of this study was to investigate the utility of a comprehensive imaging protocol including echocardiography and cardiovascular magnetic resonance (CMR) in the diagnosis and differentiation of hypertensive heart disease and heart failure with preserved ejection fraction (HFpEF). Background Hypertension is present in up to 90% of patients with HFpEF and is a major aetiological component. Despite current recommendations and diagnostic criteria for HFpEF, no non-invasive imaging technique has as yet shown the ability to identify any structural differences between patients with hypertensive heart disease and HFpEF. Methods We conducted a prospective cross-sectional study of 112 well-characterised patients (62 with HFpEF, 22 with hypertension and 28 healthy controls). All patients underwent cardiopulmonary exercise and biomarker testing and an imaging protocol including echocardiography with speckle tracking analysis and CMR including T1 mapping pre- and post-contrast. Results Echocardiographic global longitudinal strain (GLS) and extracellular volume (ECV) measured by CMR were the only variables able to independently stratify between the three groups of patients. ECV was the best technique for differentiation between hypertensive heart disease and HFPEF (AUC 0.88; GLS AUC 0.78, p Conclusions Both GLS and ECV are able to independently discriminate between hypertensive heart disease and HFpEF and identify patients with prognostically significant functional limitation. ECV is the best diagnostic discriminatory marker of HFpEF and could be used as a surrogate end-point for therapeutic studies.

Left Atrial Remodeling and Atrioventricular Coupling in a Canine Model of Early Heart Failure With Preserved Ejection Fraction

Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13-24]% versus 12 [10-14]%, P=0.008; end-systolic pressure-volume relationship slope 2.4 [1.9-3.2]mm Hg/mL HFpEF versus 1.5 [1.2-2.2]mm Hg/mL controls, P=0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [βLA] 0.16 [0.11-0.18]mm Hg/mL versus 0.06 [0.04-0.10]mm Hg/mL controls; P=0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with βLA. LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with βLA. In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

Heart failure with preserved ejection fraction in hypertension.

Hypertension is the most prevalent risk factor in heart failure with preserved ejection fraction (HFpEF) and plays a key role in the disease. The continued lack of effective therapies to improve outcomes in HFpEF underscores the knowledge gaps regarding the pathophysiology of HFpEF. This review builds on fundamental concepts in pressure overload-induced left ventricular modeling, and summarizes recent knowledge gained regarding the mechanisms underlying the transition from hypertensive heart disease to HFpEF. The pathophysiology of hypertensive HFpEF extends beyond the development of left ventricular hypertrophy and diastolic dysfunction to myocardial contractile dysfunction, beyond left atrial structural dilatation to left atrial functional decline, beyond macrovascular stiffening to microvascular dysfunction, beyond central cardiac triggers to systemic endothelial inflammation, beyond fibrosis to titin changes, and beyond collagen deposition to qualitative changes in collagen. The central paradigm involves a systemic proinflammatory state triggering a downstream cascade of cardiac microvascular endothelial activation, oxidative stress, and abnormal myocardial cyclic guanosine monophosphate signaling, leading to microvascular rarefaction, chronic ischemia, fibrosis and progression to HFpEF. Recent advances have provided insights into the pathophysiology of HFpEF in hypertension. Such knowledge provides novel opportunities for therapeutic strategies in the treatment of hypertensive HFpEF.

SODIUM-RESTRICTED DIETARY APPROACHES TO STOP HYPERTENSION DIET INCREASES EARLY MARKERS OF RENAL TUBULAR INJURY IN HYPERTENSIVE HEART FAILURE WITH PRESERVED EJECTION FRACTION

The sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) lowers systemic blood pressure and favorably affects cardiac and vascular function in hypertensive heart failure with preserved ejection fraction (HFPEF). Dietary sodium restriction reduces renal damage in HFPEF animal

Low-Sodium DASH Diet Improves Diastolic Function and Ventricular–Arterial Coupling in Hypertensive Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted dietary approaches to stop hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular-arterial coupling in hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium, 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central blood pressure (via radial arterial tonometry) and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the parametrized diastolic filling formalism that yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through the analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees) and ventricular-arterial coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs signed-rank tests were used for pre-post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155 ± 35 to 138 ± 30 and 130 ± 16 to 123 ± 18 mm Hg; both P=0.02), and central end-systolic pressure trended lower (116 ± 18 to 111 ± 16 mm Hg; P=0.12). In conjunction, diastolic function improved (c=24.3 ± 5.3 to 22.7 ± 8.1 g/s; P=0.03; k=252 ± 115 to 170 ± 37 g/s(2); P=0.03), Ea decreased (2.0 ± 0.4 to 1.7 ± 0.4 mm Hg/mL; P=0.007), and ventricular-arterial coupling improved (Ees:Ea=1.5 ± 0.3 to 1.7 ± 0.4; P=0.04). In patients with hypertensive HFPEF, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and ventricular-arterial coupling. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00939640.

Left Ventricular Stiffening as Therapeutic Target for Heart Failure With Preserved Ejection Fraction

The high prevalence of patients with heart failure (HF) with preserved ejection fraction (HFpEF) has highlighted the pivotal role of diastolic function in the development of HF. Abnormalities of diastolic function induce elevated left ventricular (LV) end-diastolic pressure, which leads to pulmonary edema and the symptoms of HF because the LV, left atrium and the pulmonary veins form 1 chamber while the mitral valve is opening. Thus, LV diastolic dysfunction results in the development of HF, in particular, HFpEF. LV stiffness mainly contributes to the transition to HFpEF, but noninvasive assessment and the therapeutic strategy for LV stiffness have not been fully established. This review will focus on the contribution of LV passive stiffness to the development of HFpEF and on the evaluation and treatment of LV stiffening based on insights gained from a hypertensive HFpEF animal model we have developed.

Low-Sodium Dietary Approaches to Stop Hypertension Diet Reduces Blood Pressure, Arterial Stiffness, and Oxidative Stress in Hypertensive Heart Failure With Preserved Ejection Fraction

Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In salt-sensitive HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155–138 mm Hg; P =0.02) and diastolic blood pressure (79–72 mm Hg; P =0.04), 24-hour ambulatory systolic (130–123 mm Hg; P =0.02) and diastolic blood pressure (67–62 mm Hg; P =0.02), and carotid-femoral pulse wave velocity (12.4–11.0 m/s; P =0.03). Urinary F2-isoprostanes decreased by 31% (209–144 pmol/mmol Cr; P =0.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of salt-sensitive hypertension, a phenotype present in many HFPEF animal models and suggest shared pathophysiological mechanisms linking these 2 conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.

L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease

Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis. Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients. L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.

Abstract 8244: Inhibition of Ca2+ Entry Mode of Na+/Ca2+ Exchanger Improves Survival Rate of Rat Model for Heart Failure with Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFPEF) has a poor prognosis as well as heart failure with reduced ejection fraction and its therapeutic strategy has not been established. Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of HFPEF. Plasma level of digitalis-like factors (DLFs) is increased in about a half of patients with hypertension, a principal underlying cardiovascular disease of HFPEF. DLFs inhibit ion-pumping function of Na+/K+-ATPase and activate the Ca2+ entry mode of Na+/Ca2+ exchanger (NCX). It is also known that DLFs promote collagen production in fibroblasts. Objective: The objective of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in preventing LV fibrosis and the development of HFPEF. Methods and Results: (1) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24-hour urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (2) Continuous administration of ouabain for 14 weeks developed LV fibrosis without the changes in blood pressure in Sprague-Dawley rats irrespective of NaCl loading. (3) Ouabain elevated intracellular Ca2+ concentration through the entry of extracellular Ca2+, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced 3H-proline incorporation in cardiac fibroblast, and SEA0400, the inhibitor of the NCX entry mode, suppressed these in vitro effects of ouabain. (4) In the HFPEF model, chronic administration of SEA0400 at subdepressor dose prevented the elevation of LV filling pressure and improved the survival rate in association with the attenuation of LV fibrosis and stiffening. Conclusion: DLFs and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

Abstract 8573: L-carnitine Prevents Heart Failure with Preserved Ejection Fraction in Associated with Attenuation of Cardiac Fibrosis

Backgrounds: Prognosis of heart failure with preserved ejection fraction (HFpEF) has not been improved because of unknown pathophysiology and unestablished therapeutic strategy. Cardiac fibrosis is known to play a crucial role in the development of HFpEF. Methods and Results: The comprehensive and quantitative analysis of metabolites with capillary electrophoresis time-of-flight mass spectrometry was conducted to find a substance which may be related to the development of HFpEF, and revealed decreased plasma free-carnitine levels in Dahl salt-sensitive rats (DSR) fed high-salt diet, a model of hypertensive HFpEF. We confirmed this result with enzymatic cycling method by showing decreased plasma and left ventricular (LV) free-carnitine levels with increased urinary free-carnitine excretion in HFpEF rats compared to control DSR fed normal chow. We also found that blood free-carnitine levels were decreased in HFpEF patients compared to age-matched normal volunteers. Expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was decreased in the LV and kidney of HFpEF rats. L-carnitine administration to HFpEF rats increased plasma and LV levels of free-carnitine, and prevented HFpEF with decreased myocardial stiffness constant and decreased area of LV fibrosis. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced increase in 3 H-proline incorporation. L-carnitine increased prostacyclin production and expression of fatty acid desaturase 1/2, rate-limiting enzymes in forming arachidonic acid, in the LV of DSR and cultured cardiac fibroblasts. LV arachidonic acid levels were increased in HFpEF rats by L-carnitine administration. Conclusions: L-carnitine may be effective in the prevention of HFpEF through enhanced production of prostacyclin and prevention of LV fibrosis and stiffening. L-carnitine supplementation may become a therapeutic option for HFpEF.

Ca2+ entry mode of Na+/Ca2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction

Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na(+)/K(+)-ATPase and activate the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. (i) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in Sprague-Dawley rats. (iii) Ouabain elevated intracellular Ca(2+) concentration through the entry of extracellular Ca(2+), increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced (3)H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening. Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

Quantitative left ventricular contractility analysis under stress: a new practical approach in follow-up of hypertensive patients

Excessive sympathetic activity and stress-induced left ventricular (LV) hypercontractility have been described in hypertensive LV hypertrophy. Recent quantitative data have shown that hypertensive LV hypertrophy is associated with preserved global LV function. However, progression of uncontrolled hypertension have detrimental effects on both the ejection fraction (EF) and LV contractile response to stress. Hypertensive LV hypertrophy has some common characteristics, including preserved global LV systolic function and LV volume with heart failure with preserved EF (HFPEF), which makes it difficult to differentiate between the two conditions at rest. Studies suggest that adopting an efficient antihypertensive therapy regimen may positively effect on the LV contractile capability in patients with long-standing hypertension. Evaluation of quantitative LV contractility under stress may be beneficial to differentiate between the hypertensive LV hypertrophy and HFPEF. It may also assist in developing a more effective modality in medical management of patients with hypertensive heart disease.

Noninvasive Assessment of Wall Distensibility With the Evaluation of Diastolic Epicardial Movement

Background Left ventricular (LV) wall stiffening plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Based on the linear elastic theory, we hypothesized that the evaluation of epicardial movement during diastole is helpful for the noninvasive assessment of LV wall distensibility. Methods and Results Based on the linear elastic theory, the epicardial movement index (EMI) was calculated on the echocardiogram as: endocardial movement during diastole − epicardial movement during diastole wall thickness at the beginning of diastole * epicardial movement during diastole We calculated diastolic wall strain (DWS) as follows to examine whether DWS substitutes for EMI: LV posterior wall thickness at end-systole − LV posterior wall thickness at end-diastole LV posterior wall thickness at end-systole The animal study using hypertensive Dahl salt-sensitive rats, HFpEF model, and normotensive Dahl rats showed the significant and inverse correlation of EMI or DWS with myocardial stiffness constant. Preload alteration did not affect EMI or DWS. In the clinical study, the HFpEF patients had lower EMI and DWS than the normal volunteers and the asymptomatic patients with LV hypertrophy. Conclusions The evaluation of epicardial movement may be useful in noninvasively assessing wall distensibility in the absence of LV systolic dysfunction.