Development Of Hypertensive Heart Failure Research Articles

S-51-3: EMPAGLIFLOZIN AMELIORATES CARDIAC HYPERTROPHY AND RENAL INJURY WITH SYMPATHOINHIBITION IN A RAT MODEL OF HYPERTENSIVE HEART FAILURE

Objective: SGLT2 inhibitors have been reported to have cardio- and reno-protective effects; however, its mechanisms are not fully understood. Sympathetic activation is critically involved in cardiac and renal damage during the development of hypertensive heart failure. In this study, we examined whether empagliflozin inhibits cardiac and renal damage with sympathoinhibition in the phase of cardiac hypertrophy using a rat model of hypertensive heart failure. Design and method: Male Dahl salt-sensitive rats were fed 0.3% low-salt (LS, n = 6) or 8% high-salt diet from 6 weeks of age and the high-salt-fed rats were assigned to the vehicle (HS-VEH, n = 6) or empagliflozin (HS-EMPA, n = 6) treatment groups at 8 weeks. Systolic blood pressure was measured by tail-cuff method at 6, 8, and 12 weeks. At 12 weeks, organ weight, plasma creatinine, and plasma norepinephrine were measured. Renal fibrosis was evaluated by Sirius red staining. The expression of c-Fos, a marker of neuronal activity, in the hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM), in which the presympathetic neurons are located, was evaluated by immunostaining. Results: Systolic blood pressure was elevated in HS-VEH and HS-EMPA compared to LS, whereas there was no significant difference between HS-VEH and HS-EMPA (at 12 weeks, LS 127.1 ± 5.3 mmHg, HS-VEH 224.5 ± 20.1 mmHg, HS-EMPA 223.8 ± 24.4 mmHg; p < 0.05 vs LS). Left ventricular weight was increased in HS-VEH compared to LS (1.13 ± 0.02 vs 0.90 ± 0.02 g, p < 0.05), and the increase was attenuated in HS-EMPA (1.06 ± 0.04 g, p < 0.05 vs HS-VEH). Kidney weight was similarly increased both in HS-VEH and HS-EMPA compared to LS; however, empagliflozin significantly attenuated the high salt-induced increases in renal fibrosis and plasma creatinine (LS 0.20 ± 0.02 mg/dL, HS-VEH 0.34 ± 0.06 mg/dL, HS-EMPA 0.20 ± 0.04 mg/dL; p < 0.05 for HS-VEH vs LS and HS-EMPA vs HS-VEH). Plasma norepinephrine was increased in HS-VEH compared to LS (1304 ± 627 vs 268 ± 54.5 pg/mL, p < 0.05) and was suppressed in HS-EMPA (648 ± 419 pg/mL, p = 0.05 vs VEH), which was consistent with the finding that the increase in c-Fos positive neurons within the PVN and RVLM in HS-VEH was significantly attenuated in HS-EMPA. Conclusions: In Dahl salt-sensitive hypertensive heart failure model, empagliflozin inhibits sympathetic activation and ameliorates cardiac hypertrophy and renal injury without lowering blood pressure in the pre-heart failure phase.

An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats.

Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis. Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5′-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.

Endogenous CCN5 Participates in Angiotensin II/TGF-β1 Networking of Cardiac Fibrosis in High Angiotensin II-Induced Hypertensive Heart Failure

Aberrant activation of angiotensin II (Ang II) accelerates hypertensive heart failure (HF); this has drawn worldwide attention. The complex Ang II/transforming growth factor (TGF)-β1 networking consists of central mechanisms underlying pro-fibrotic effects; however, this networking still remains unclear. Cellular communication network 5 (CCN5), known as secreted matricellular protein, mediates anti-fibrotic activity by inhibiting fibroblast-to-myofibroblast transition and the TGF-β1 signaling pathway. We hypothesized that endogenous CCN5 plays an essential role in TGF-β1/Ang II networking-induced cardiac fibrosis (CF), which accelerates the development of hypertensive HF. This study aimed to investigate the potential role of CCN5 in TGF-β1/Ang II networking-induced CF. Our clinical retrospective study demonstrated that serum CCN5 decreased in hypertensive patients, but significantly increased in hypertensive patients taking oral angiotensin-converting enzyme inhibitor (ACEI). A negative association was observed between CCN5 and Ang II in grade 2and 3 hypertensive patients receiving ACEI treatment. We further created an experimental model of high Ang II-induced hypertensive HF. CCN5 was downregulated in the spontaneously hypertensive rats (SHRs) and increased via the inhibition of Ang II production by ACEI. This CCN5 downregulation may activate the TGF-β1 signaling pathway, which promotes direct deposition of the extracellular matrix (ECM) and fibroblast-to-myofibroblast transition via activated Smad-3. Double immunofluorescence staining of CCN5 and cell markers of cardiac tissue cell types suggested that CCN5 was mainly expressed in the cardiac fibroblasts. Isolated cardiac fibroblasts were exposed to Ang II and transfected with small interfering RNA targeting CCN5. The expression of TGF-β1 together with Col Ia and Col IIIa was further promoted, and alpha-smooth muscle actin (α-SMA) was strongly expressed in the cardiac fibroblasts stimulated with Ang II and siRNA. In our study, we confirmed the anti-fibrotic ability of endogenous CCN5 in high Ang II-induced hypertensive HF. Elevated Ang II levels may decrease CCN5 expression, which subsequently activates TGF-β1 and finally promotes the direct deposition of the ECM and fibroblast-to-myofibroblast transition via Smad-3 activation. CCN5 may serve as a potential biomarker for estimating CF in hypertensive patients. A novel therapeutic target should be developed for stimulating endogenous CCN5 production.

Teneligliptin Prevents Cardiomyocyte Hypertrophy, Fibrosis, and Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats

BackgroundWe investigated the effects of the dipeptidyl peptidase 4 inhibitor teneligliptin on cardiac function and hemodynamics during heart failure in hypertensive model rats. Methods and ResultsFifty-five male Dahl salt-sensitive rats were divided into 4 groups: control group (0.3% NaCl chow; n = 13), hypertension (HT) group (8% NaCl chow; n = 20), HT–early TNL group (8% NaCl chow and teneligliptin from 6 weeks; n = 10), and HT–late TNL group (8% NaCl chow and teneligliptin from 10 weeks; n = 12). Hemodynamic measurement and tissue analyses were performed at 18 weeks. In all of the HT groups, systolic blood pressures were similarly elevated (P = .66) and heart weights similarly increased (P = .36) with and without TNL administration. LV end-diastolic dimension was significantly enlarged only in the HT–early TNL group compared with the control group (P = .025). Histologic analysis showed less fibrosis (P = .008) and cardiomyocyte widths (P = .009) in the HT–early TNL group compared with the HT group. On hemodynamic analysis, only the HT group showed significant LV end-diastolic pressure elevation (P = .049) and lung congestion (P < .001) compared with the control group. ConclusionsThese results suggest that teneligliptin prevents concentric LV hypertrophy, fibrosis, and development of congestive heart failure in Dahl salt-sensitive rats. Teneligliptin may inhibit pressure-overload hypertrophic adaption and result in LV eccentric hypertrophy with reduced LV ejection fraction.

GW26-e4505 Type 2 Ryanodine Receptor Hyperphosphorylation Plays a Role in the Development of Hypertensive Heart Failure

GW26-e4505 Type 2 Ryanodine Receptor Hyperphosphorylation Plays a Role in the Development of Hypertensive Heart Failure

Nicorandil Prevents Gαq-Induced Progressive Heart Failure and Ventricular Arrhythmias in Transgenic Mice

BackgroundBeneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gαq) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Gαq (Gαq-TG).Methodology/Principal FindingsNicorandil (6 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 8 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic nicorandil administration prevented the severe reduction of left ventricular fractional shortening and inhibited ventricular interstitial fibrosis in Gαq-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated Gαq-TG but not in nicorandil-treated Gαq-TG. eNOS gene expression was also increased in nicorandil-treated Gαq-TG compared with vehicle-treated Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated Gαq-TG but in none of 10 nicorandil-treated Gαq-TG. The QT interval was significantly shorter in nicorandil-treated Gαq-TG than vehicle-treated Gαq-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused Gαq-TG mouse hearts. Moreover, HMR1098, a blocker of cardiac sarcolemmal KATP channels, significantly attenuated the shortening of MAP duration induced by nicorandil in the Gαq-TG heart.Conclusions/SignificanceThese findings suggest that nicorandil can prevent the development of HF and ventricular arrhythmia caused by the activation of GPCR signaling through the shortening of the QT interval, action potential duration, the normalization of SERCA2 gene expression. Nicorandil may also improve the impaired coronary circulation during HF.

Abstract P170: Nicorandil Inhibits Gáq-Induced Chronic Heart Failure in Transgenic Mice

Introduction: Beneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gαq) -coupled receptor (GPCR) signaling pathway still remains unknown. We examined effects of chronic and acute administration of nicorandil on the development of HF and ventricular action potential (VAP) in transgenic mice with transient cardiac expression of activated Gαq (Gαq-TG), respectively. Method and Results: Nicorandil (6 mg/kg/day) or vehicle was chronically administered in Gαq-TG mice for 24 weeks from 8 weeks of age, and then ventricular function, and electrical and structural changes were investigated in the hearts. Chronic nicorandil administration improved the reduction of left ventricular fractional shortening (p &lt; 0.001) in Gαq-TG hearts. During 10 min of electrocardiogram recording, premature ventricular contractions (more than 20 beats/min) were observed in 7 of 10 vehicle-treated Gαq-TG but in none of 10 nicorandil-treated Gαq-TG hearts (p &lt; 0.01). QT interval was significantly shorter in nicorandil-treated Gαq-TG than in vehicle-treated Gαq-TG hearts (p &lt; 0.05). Chronic nicorandil administration improved the increased ventricular interstitial fibrosis (p &lt; 0.05) but not cardiac hypertrophy in Gαq-TG left ventricles. Real time RT-PCR revealed that mRNA expression levels of s sulfonylurea receptor 2B (SUR-2B) were decreased in vehicle-treatd Gαq-TG but not in nicorandil-treated Gαq-TG. In addition, chronic nicorandil increased endotherial nitric oxide syntheses gene expression in Gαq-TG hearts (p &lt; 0.05). Acute nicorandil administration (1 microM) significantly shortened the prolonged VAP duration and reduced the number of PVCs in vehicle treated Gαq-TG hearts. Conclusions: These findings suggest that nicorandil inhibits ventricular electrical and structural remodeling and arrhythmias through the shortening of VAP duration and the increased expression of SUR-2B and eNOS in a mouse model of HF.

Superoxide-Dependent Cathepsin Activation Is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotensin II Type 1 Receptor Blocker Treatment

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.

Abstract 2523: Azelnidipine Enhances Beneficial Effects of Olmesartan on Left Ventricular Remodeling During the Development of Hypertension-induced Heart Failure

Objective: This work was undertaken to investigate the comparative effect of angiotensin II type 1 receptor blocker (ARB) and a combination of ARB and calcium channel blocker (CCB) on left ventricular (LV) remodeling during the development of hypertensive heart failure (H-HF). Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n = 10 for each group) with vehicle, hydralazine (5 mg/kg/d), olmesartan (OLM, 5 mg/kg/d), or combined OLM and azelnidipine (AZE, 2mg/kg/d) for 8 weeks. The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins were localized in cardiac myocytes (CMCs), and Cat-dependent activities were increased by 4.1-fold in the LV of H-HF rats (n = 8, P&lt; 0.001) and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of H-HF rats (H-HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n = 6, P&lt; 0.0±1; control 22±2.1%). OLM suppressed not only macrophage infiltration but also levels of NADPH oxidase components (p22 phox , gp91 phox , and p47 phox ) concomitant with decreased NADPH activity and O2- production in LV tissues of H-HF rats. Along with its comparable anti-inflammatory effect, add-on AZE further improved all of these parameter changes by OLM. Furthermore, combination therapy significantly enhanced the improvement of LV fibrosis, hypertrophy, stiffness, and dysfunction by OLM. In vitro, H 2 O 2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with the antioxidants such as MnTmPyp (50 μmol/L) and N-acetylcysteine (5 mmol/L) as well as a NADPH oxidase inhibitor apocynin (100 μmol/L) in culture CMCs, SMCs, and macrophages (n = 6, P&lt; 0.01). Conclusions: OLM and a combination of OLM and AZE exerted cardioprotective effects in hypertensive HF, via elastolytic Cat activation inhibition by the reduction of NADPH oxidase-dependent superoxide anion production. AZE enhanced the cardioprotective effects of OLM. Thus, the combination of ARB with CBB is a promising potential therapeutic strategy for H-HF.

The Antagonism of Aldosterone Receptor Prevents the Development of Hypertensive Heart Failure Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats

Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 +/- 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 +/- 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%) and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.

Saturated glucose uptake capacity and impaired fatty acid oxidation in hypertensive hearts before development of heart failure.

Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using (131)I- or (125)I-labeled 9-methylpentadecanoic acid ((131)I- or (125)I-9MPA), and [(14)C]deoxyglucose ([(14)C]DG), fatty acid beta-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaCl, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [(14)C]DG increased markedly with age in the DS rats, whereas (131)I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of (125)I-9MPA beta-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [(14)C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats

Objectives. – The aim of the present study was to determine whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have preventive effects on the development of cardiac hypertrophy and heart failure. Background. – Statins have been reported to have various pleiotropic effects, such as inhibition of inflammation and cell proliferation. Methods. – Dahl rats were divided into three groups: LS, the rats fed the low-salt diet (0.3% NaCl); HS, the rats fed the high-salt diet (8% NaCl) from the age of 6 weeks; and CERI, the rats fed the high-salt diet with cerivastatin 1 mg/kg/d by gavage from the age of 6 weeks Results. – In HS rats, cardiac function was markedly impaired and all rats showed the signs of heart failure within 17 weeks of age. In CERI rats, cardiac function was better than that of HS and no rats were dead up to 17 weeks of age. The development of cardiac hypertrophy and fibrosis was attenuated, and the number of apoptotic cells and expression of proinflammatory cytokine interleukin (IL)-1β gene were less as compared with HS rats. Pretreatment of cerivastatin suppressed the adriamycin-induced apoptosis of cultured cardiomyocytes of neonatal rats. Conclusions. – These results suggest that statins have a protective effect on cardiac myocytes and may be useful to prevent the development of hypertensive heart failure.

Dual-tracer assessment of coupling between cardiac sympathetic neuronal function and downregulation of beta-receptors during development of hypertensive heart failure of rats.

Heart failure is associated with activation of the sympathetic nervous system and downregulation of beta-receptors. However, the coupling between cardiac sympathetic neuronal function and the beta-receptor during the development of hypertensive heart failure is not clear. We determined cardiac neuronal function and beta-receptors with a dual-tracer method of [131I]metaiodobenzylguanidine (MIBG) and 125I-cyanopindolol (ICYP) in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The rats were fed an 8% NaCl diet after the age of 6 weeks. Blood pressure was raised to >200 mm Hg at 12 weeks in DS rats and remained elevated until 18 weeks, but only slightly in DR rats. Left ventricular (LV) function of DS rats was preserved at 12 weeks but deteriorated at 18 weeks. Despite a 56% reduction of cardiac norepinephrine (NE) content at 12 weeks in DS rats, neither MIBG nor ICYP uptake in DS rats was different from that of DR rats. At 18 weeks, both MIBG and ICYP uptakes decreased, by 52% and 39%, respectively, in association with 71% reduction of cardiac NE, in DS rats. MIBG uptake of the LV was homogeneous at 6 weeks but was lower in the LV endocardial regions at 18 weeks in DS rats. The present results indicate that cardiac sympathetic neuronal function is relatively preserved at the compensated, hypertrophic stage of DS rats but deteriorates in association with beta-receptor downregulation at the failing stage. The cardiac neuronal dysfunction occurs heterogeneously. A combination of scintigraphic portrayal of beta-receptors with MIBG should provide valuable information regarding sympathetic nerve signaling in living hearts.

Pathophysiology and clinical aspects of hypertensive hypertrophy.

Individuals with hypertension and electrocardiographic (ECG) evidence of left ventricular hypertrophy (LVH) have a 10-fold greater risk of developing cardiac failure than hypertensives without ECG evidence of LVH. LVH in hypertension is characterized by myocardial fibrosis and structural changes to the small intramural arteries. Hypertensives with or without LVH have reduced coronary vasodilator reserve due to hypertensive disease of small coronary arteries. Prognosis of arterial hypertension is largely determined by cardiac complications. The aim of treatment of hypertensive heart disease is to reverse myocardial hypertrophy in order to prevent progression to hypertensive heart failure, as well as reversal of the hypertensive disease of small coronary arteries in order to improve coronary reserve. On the development of hypertensive heart failure, administration of digitalis, diuretics and angiotensin converting enzyme (ACE) inhibitors should be initiated. Although regression of LVH can be induced by dihydropyridine calcium channel blockers, ACE inhibitors and sympatholytic substances, clinical evidence of the reversal of hypertensive disease of small coronary arteries has still to be established.

Radionuclide measurements of diastolic function for assessing early left ventricular abnormalities in the hypertensive patient.

Three measurements of diastolic filling were compared in 29 patients with essential hypertension and 27 age matched normotensive controls. Systolic function was normal in all but one of the patients. The mean (1SD) first one third filling fraction (a measurement of early diastolic filling) was significantly lower in the hypertensive groups (0.27 (0.24] than in the control group (0.45 (0.16)). The hypertensive group was subdivided into those with electrocardiographic abnormalities and those without. In the subgroup with a normal electrocardiogram the mean (1SD) first one third filling fraction measurement (0.28 (0.16)) was significantly lower than in the control group. In the subgroup with an abnormal electrocardiogram, the first one third filling fraction was even lower (0.24 (0.9)). In addition, the time to peak filling rate (213 (56) ms) was significantly longer in the subgroup with the abnormal electrocardiogram than in the control group (164 (45) ms). However, the interobserver reproducibility of the time to peak filling measurement was poor. The peak filling rate was low in the subgroup with an abnormal electrocardiogram, but not significantly different from the normal controls. The discriminatory value of the three diastolic measurements did not improve with exercise. These results showed an early diastolic filling abnormality in essential hypertension that did not appear to be caused by disease of the large coronary vessels as it was present in patients with normal wall motion and a normal exercise electrocardiogram. The occurrence of diastolic abnormalities when systolic function is still normal may mark an early stage in the development of hypertensive heart failure, at a time when the process is still potentially reversible.

Hypothalamic pressor responses and salt-induced hypertension in Dahl rats.

Hypothalamic pressor responses and salt-induced hypertension in Dahl rats.