Myocardial abnormalities in hypertensive patients with normal and abnormal left ventricular filling: a study of ultrasound tissue characterization and strain

Abnormal left ventricular (LV) filling is common, but not universal, in hypertensive LV hypertrophy (LVH). We sought to elucidate the relative contributions of myocardial structural changes, loading and hypertrophy to LV dysfunction in 113 patients: 85 with hypertensive LVH and 28 controls without LVH and with normal filling. Patients with normal dobutamine stress echocardiography and no history of coronary artery disease were selected, in order to exclude a contribution from ischaemia or scar. Abnormal LV filling was identified in 65 LVH patients, based on Doppler measurement of transmitral filling and annular velocities. All patients underwent grey-scale and colour tissue Doppler imaging from three apical views, which were stored and analysed off line. Integrated backscatter (113) and strain rate imaging were used to detect changes in structure and function; average cyclic variation of 113, strain rate and peak systolic strain were calculated by averaging each segment. Calibrated 113 intensity, corrected for pericardial 113 intensity, was measured in the septum and posterior wall from the parasternal long-axis view. Patients with LVH differed significantly from controls with respect to all backscatter and strain parameters, irrespective of the presence or absence of abnormal LV filling. LVH patients with and without abnormal LV filling differed with regard to age, LV mass and incidence of diabetes mellitus, but also showed significant differences in cyclic variation (P < 0.01), calibrated 113 in the posterior wall (P < 0.05) and strain rate (P < 0.01), although blood pressure, heart rate and LV systolic function were similar. Multivariate logistic regression analysis demonstrated that age, LV mass index and calibrated IB in the posterior wall were independent determinants of abnormal LV filling in patients with LVH. Thus structural and functional abnormalities can be detected in hypertensive patients with LVH with and without abnormal LV filling. In addition to age and LVH, structural (not functional) abnormalities are likely to contribute to abnormal LV filling, and may be an early sign of LV damage. 113 is useful for the detection of myocardial abnormalities in patients with hypertensive LVH.

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy

OBJECTIVES We sought to determine if a hypertensive response to exercise (HRE) is associated with myocardial changes consistent with early hypertensive heart disease. BACKGROUND An HRE predicts the development of chronic hypertension (HT) and may reflect a preclinical stage of HT. METHODS Patients with a normal left ventricular (LV) ejection fraction and a negative stress test were recruited into three matched groups: 41 patients (age 56 +/- 10 years) with HRE (210/105 mm Hg in men; > 190/105 in women), comprising 22 patients with (HT+) and 19 without resting hypertension (HT-); and 17 matched control subjects without HRE. Long-axis function was determined by measurement of the strain rate (SR), peak systolic strain, and cyclic variation (CV) of integrated backscatter in three apical views. RESULTS An HRE was not associated with significant differences in LV mass index. Exercise performance and diastolic function were reduced in HRE(HT+) patients, but similar in HRE(HT-) patients and controls. Systolic dysfunction (peak systolic strain, SR, and CV) was significantly reduced in HRE patients (p < 0.001 for all). These reductions were equally apparent in patients with and without a history of resting HT (p = NS) and were independent of LV mass index and blood pressure (p < 0.01). CONCLUSIONS An HRE is associated with subtle systolic dysfunction, even in the absence of resting HT. These changes occur before the development of LV hypertrophy or detectable diastolic dysfunction and likely represent early hypertensive heart disease. (C) 2004 by the American College of Cardiology Foundation.

Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension

Pulmonary vascular remodeling is an important pathological feature of pulmonary hypertension, leading to increased pulmonary vascular resistance and reduced compliance. It involves thickening of all three layers of the blood vessel wall (due to hypertrophy and/or hyperplasia of the predominant cell type within each layer), as well as extracellular matrix deposition. Neomuscularisation of non-muscular arteries and formation of plexiform and neointimal lesions also occur. Stimuli responsible for remodeling involve transmural pressure, stretch, shear stress, hypoxia, various mediators [angiotensin II, endothelin (ET)-1, 5-hydroxytryptamine, growth factors, and inflammatory cytokines], increased serine elastase activity, and tenascin-C. In addition, there are reductions in the endothelium-derived antimitogenic substances, nitric oxide, and prostacyclin. Intracellular signalling mechanisms involved in pulmonary vascular remodeling include elevations in intracellular Ca2+ and activation of the phosphatidylinositol pathway, protein kinase C, and mitogen-activated protein kinase. In animal models of pulmonary hypertension, various drugs have been shown to attenuate pulmonary vascular remodeling. These include angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, ET receptor antagonists, ET-converting enzyme inhibitors, nitric oxide, phosphodiesterase 5 inhibitors, prostacyclin, Ca2+-channel antagonists, heparin, and serine elastase inhibitors. Inhibition of remodeling is generally accompanied by reductions in pulmonary artery pressure. The efficacy of some of the drugs varies, depending on the animal model of the disease. In view of the complexity of the remodeling process and the diverse aetiology of pulmonary hypertension in humans, it is to be anticipated that successful anti-remodeling therapy in the clinic will require a range of different drug options. (C) 2001 Elsevier Science Inc. All rights reserved.

Comparison of pulmonary vascular function and structure in early and established hypoxic pulmonary hypertension in rats

In pulmonary hypertension, changes in pulmonary vascular structure and function contribute to the elevation in pulmonary artery pressure. The time-courses for changes in function, unlike structure, are not well characterised. Medial hypertrophy and neomuscularisation and reactivity to vasoactive agents were examined in parallel in main and intralobar pulmonary arteries and salt-perfused lungs from rats exposed to hypoxia (10% O-2) for 1 and 4 weeks (early and established pulmonary hypertension, respectively). After 1 week of hypoxia, in isolated main and intralobar arteries, contractions to 5-hydroxytryptamine and U46619 (thromboxane-mimetic) were increased whereas contractions to angiotensins I and II and relaxations to acetylcholine were reduced. These alterations varied quantitatively between main and intralobar arteries and, in many instances, regressed between 1 and 4 weeks. The alterations in reactivity did not necessarily link chronologically with alterations in structure. In perfused lungs, constrictor responses to acute alveolar hypoxia were unchanged after 1 week but were increased after 4 weeks, in conjunction with the neomuscularisation of distal alveolar arteries. The data suggest that in hypoxic pulmonary hypertension, the contribution of altered pulmonary vascular reactivity to the increase in pulmonary artery pressure may be particularly important in the early stages of the disease.

Vascular endothelial growth factor-B-deficient mice show impaired development of hypoxic pulmonary hypertension

To test the hypothesis that Vegf-B contributes to the pulmonary vascular remodelling, and the associated pulmonary hypertension, induced by exposure of mice to chronic hypoxia. Methods: Right ventricular systolic pressure, the ratio of right ventricle/[left ventricle+septum] (RV/[LV+S]) and the thickness of the media (relative to vessel diameter) of intralobar pulmonary arteries (o.d. 50-150 and 151-420 mum) were determined in Vegfb knockout mice (Vegfb(-/-); n=17) and corresponding wild-type mice (Vegfb(+/+); n=17) exposed to chronic hypoxia (10% oxygen) or housed in room air (normoxia) for 4 weeks. Results: In Vegfb(+/+) mice hypoxia caused (i) pulmonary hypertension (a 70% increase in right ventricular systolic pressure compared with normoxic Vegfb(+/+) mice; P

Effects of antenatal corticosteroid treatment on pulmonary ventilation and circulation in neonatal lambs with hypoplastic lungs

Our aim was to determine whether antenatal corticosteroids improve perinatal adaptation of the pulmonary circulation in lambs with lung hypoplasia (LH). LH was induced in 12 ovine fetuses between 105 and 140 days gestation (term similar to 147 days); in 6 of these the ewe was given a single dose of betamethasone (11.4 mg im) 24 hr before delivery (LH + B). All lambs, including a control group (n = 6), were delivered at similar to 140 days and ventilated for 2 hr during which arterial pressures, pulmonary blood flow (PBF), and ventilating pressure and flow were recorded. During ventilation, respiratory system compliance was lower in both LH + B and LH groups than in controls. Pulmonary vascular resistance (PVR) was lower in LH + B lambs than in LH lambs and similar to controls; PBF was reduced in LH lambs but was restored to control levels by betamethasone. The mean density of small arteries of LH + B lambs was similar to that of LH lambs (P = 0.06) and lower than in controls; the thickness of the media of small pulmonary arteries from LH + B lambs was similar to that in LH lambs and thicker than in controls. VEGF mRNA levels were not different between groups. PDGF mRNA levels in LH + B lambs were higher than in LH lambs; a similar trend (P = 0.06) was seen for PECAM-1. SP-C mRNA levels were greater in both LH and LH + B lambs than in controls. Effects of betamethasone were greater on indices of pulmonary circulation than ventilation. We conclude that a single dose of maternal betamethasone 24 hr prior to birth has significant favorable effects on the postnatal adaptation of the pulmonary circulation in lambs with LH.

Pulmonary Vascular remodelling in hypoxic rats: effects of amlodipine, alone and with perindopril

This study investigated whether pulmonary Vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (IO mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 mum o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Taus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension. (C) 2001 Elsevier Science B.V. All rights reserved.

Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is an important cause of renal artery stenosis, particularly in young females. Polymorphisms of the renin-angiotensin (RA) system have been implicated in the pathogenesis of hypertension and atherosclerotic vascular disease, and may play a role in the development of FMD. Examination of polymorphisms by PCR for angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT(1)R) A1166C and angiotensinogen (AGT) M235T and T174M was undertaken in 43 patients with typical multifocal renal arterial FMD (MF-FMD) and in 89 controls. The age of NIF-FMD patients at the time of diagnosis of hypertension did not differ (38.6 + 11.1 years vs 35.5 +/- 10.3 years, P = 0.12) from controls and the proportion (95% vs 86%, P = 0.14) of females was similar. Allele frequencies did not differ significantly between groups, except that MF-FMD patients had a significantly higher frequency of the ACE I allele than control subjects (0.62 vs 0.47, P = 0.026). Since the ACE I allele is associated with lower circulating ACE levels and possibly lower tissue levels of angiotensin II (Ang II), and since Ang II modulates vascular smooth muscle cell growth and synthetic activity, the I allele might predispose to defective remodelling of the arterial media, and thus to the development of MF-FMD. This contrasts with atherosclerotic renal artery stenosis, coronary stent restenosis and carotid intimal thickening, which are diseases affecting the arterial intima, and which are associated with increased frequency of the D allele.

5-Hydroxytryptamine and platelets: uptake and aggregation in hypoxic pulmonary hypertensive rats

Pulmonary hypertension is associated with various alterations in 5-hydroxytryptamine (5-HT) physiology. In this study in platelets from hypoxic pulmonary hypertensive rats (10% O-2; 1 week) and normoxic rats (room air), (i) initial rates of specific [H-3]5-HT uptake were measured and (ii) potentiation of collagen- and ADP-induced aggregation by 5-HT was quantified. The platelet count was almost halved in hypoxic rats. In uptake experiments, there was a decrease in 5-HT uptake in platelets from hypoxic compared with normoxic rats, due to a 36% reduction in the maximal initial rate of uptake. The aggregation experiments showed that 5-HT (1-100 muM) increased the magnitude of responses to collagen and the duration of responses to ADP, but there was no difference between hypoxic and normoxic rats. Abnormalities in platelet function may conceivably lead to increases in plasma 5-HT levels in hypoxic pulmonary hypertension, but are unlikely to aggravate pulmonary thromboembolism. (C) 2002 Elsevier Science B.V. All rights reserved.

Potentiation of 5-hydroxytryptamine (5-HT) responses by a 5-HT uptake inhibitor in pulmonary and systemic vessels: effects of exposing rats to hypoxia

The aim was to determine whether uptake of 5-hydroxytryptamine (5-HT) by the 5-HT transporter (SERT) modulates contractile responses to 5-HT in rat pulmonary arteries and whether this modulation is altered by exposure of rats to chronic hypoxia (10% oxygen; 8 h/day; 5 days). The effects of the SERT inhibitor, citalopram (100 nM), on contractions to 5-HT were determined in isolated ring preparations of pulmonary artery (intralobar and main) and compared with data obtained in systemic arteries. In intralobar pulmonary arteries citalopram produced a potentiation (viz. an increase in potency, pEC(50)) of 5-HT. The potentiation was endothelium-dependent in preparations from normoxic rats but endothelium-independent in preparations from hypoxic rats. In main pulmonary artery endothelium-independent potentiation was seen in preparations from hypoxic rats but no potentiation occurred in preparations from normoxic rats. In systemic arteries, citalopram caused endothelium-independent potentiation in aorta but no potentiation in mesenteric arteries; there were no differences between hypoxic and normoxic rats. It is concluded that SERT can influence the concentration of 5-HT in the vicinity of the vasoconstrictor receptors in pulmonary arteries. The data suggest that in pulmonary arteries from hypoxic rats, unlike normoxic rats, the SERT responsible for this effect is not in the endothelium and, hence, is probably in the smooth muscle. The data are compatible with reports that, in the pulmonary circulation, hypoxia induces/up-regulates SERT, and hence increases 5-HT uptake, in vascular smooth muscle. The findings may have implications in relation to the suggested use of SERT inhibitors in the treatment of pulmonary hypertension.