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Background Much in the diagnosis of diastolic ventricular dysfunction is dependent upon the filling pattern, and most patients diagnosed with diastolic heart failure are elderly. Data from healthy asymptomatic individuals across a range of ages are rare. We sought to find an age-related variation in normal diastolic physiology, specifically the filling pattern and segmental myocardial longitudinal velocities.Methods and Results To assess the effect of normal ageing on left ventricular longitudinal function, we studied myocardial shortening and lengthening velocities using the tissue Doppler technique in 60 healthy subjects who were randomly selected from the Umeå (Sweden) General Population Register, which represents a wide range of ages (23–88 years). Myocardial velocities were documented at four left ventricular sites (anterior, left, posterior and septal) and at three levels (basal, mid-cavity and apical). Transmitral, transtricuspid and pulmonary venous flow velocities were recorded using pulsed-wave Doppler. While systolic myocardial velocities were conserved across ages, there was a marked decrease in early diastolic velocities with age (from 16cm.s−1at 30 years to 9cm.s−1at 80 years at the basal segment) and a corresponding significant increase in late diastolic velocities (from 10 to 16cm.s−1). Although these findings were most marked at the basal level, they were also clearly manifested at the apical level. Myocardial lengthening velocities were related to transmitral flow velocities, showing a correlation of 0·64 (P<0·0001) in early diastole and 0·68 (P<0·0001) in late diastole. Finally, diastolic pulmonary venous flow velocity was found to correlate with early diastolic myocardial velocities (at the basal level, r=0·53, P<0·0001).Conclusions Normal ageing causes a decrease in early diastolic and a substantial increase in late diastolic myocardial lengthening velocities. These changes explain the known trends in the transmitral flow pattern with age. In contrast, systolic myocardial velocities do not change significantly with age. These findings should be considered when evaluating diastolic function, especially in the elderly. [ABSTRACT FROM PUBLISHER]

The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or β-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats ( n = 6); AS ( n = 6); AS ( n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP "area under the curve" was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine γ-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients.

Background: The objective of this study was to provide for the first time data on plasma catecholamines, cortisol, glutathione and malondialdehyde after long term dehydration (20 days) in the presence and absence of angiotensin II (Ang II) AT1 receptor blocker (losartan) versus levels in time-matched, non-dehydrated control camels and to record the responses of glutathione and malondialdehyde activity in liver and kidney homogenates in control, dehydrated-losartan treated and dehydrated camels. Eighteen male camels were studied, six hydrated (control group), six dehydrated and treated with losartan (treated group) and six dehydrated not treated (dehydrated)., Results: Plasma levels of norepinephrine and dopamine were significantly increased (P < 0.01) in both treated and dehydrated groups compared to time matched control, whereas Plasma epinephrine level showed significant decrease (P < 0.05) in both treated and dehydrated groups compared to control. Plasma cortisol also showed significant increase (P < 0.01) in both treated and dehydrated groups compared to control. Glutathione levels in plasma, liver and kidney homogenates for both treated and dehydrated groups reveled significant increase (P < 0.05) Likewise, malondialdehyde levels in plasma, liver and kidney homogenates were substantially and significantly increased in both treated and dehydrated groups., Conclusion: In conclusion, the results of this study demonstrated that dehydration substantially increased the circulating levels of norepinephrine, dopamine and cortisol but decreased plasma epinephrine. Similarly, losartan showed similar effects to that of dehydration. In addition, this investigation showed dehydration alone or in combination with losartan induced significant increments in glutathione and malondialdehyde activities in plasma, liver and kidney homogenates, presumably in order to counteract the potentially damaging effects of free radicals. Blockade of angiotensin II AT1 receptors did not alter significantly the response of dehydration in any of these indices.

The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

Systemic sclerosis (SSc) is frequently associated with interstitial lung disease (ILD) often leading to lung fibrosis. In this study we investigated whether matrix metalloproteinase 9 (MMP-9) and its natural inhibitor; the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), would be associated with remodelling in ILD in SSc. Levels of total MMP-9, pro-MMP-9 and TIMP-1 were measured in bronchoalveolar lavage (BAL) fluid from nine SSc patients with ILD, seven SSc patients without ILD and 16 age- and sex-matched healthy controls. Total MMP-9 and pro-MMP-9 levels were significantly elevated in SSc patients with ILD, compared to levels in SSc patients without ILD and healthy controls. In SSc patients with ILD calculated active MMP-9 levels were significantly higher than in SSc patients without ILD and tended to be higher than in healthy controls. TIMP-1 levels were elevated in both patient groups compared to healthy controls. Total-, pro- and active MMP-9 levels as well as pro-MMP-TIMP-1 and active MMP-9/TIMP-1 ratios were inversely associated with total lung capacity. The present study suggests that MMP-9 plays a pathophysiological role in the remodelling in ILD and lung fibrosis associated with SSc, and may represent a new therapeutic target in this condition.

Vitamin D deficiency is common in Arab countries particularly among women. This is the result of a low dietary intake of the vitamin, limited exposure to sunlight (a paradox in view of the high sunshine figures), skin colour, obesity and high parity. Apart from its adverse effects on bone in women and their offspring, vitamin D deficiency has the potential to cause or exacerbate heart failure through a number of mechanisms including activation of the renin-angiotensin system and increased arterial pressure. Accordingly, we propose that ensuring adequate vitamin D levels in Arab women will have a much greater impact on health than just the prevention of bone disease. In particular, we suggest that prevention and correction of vitamin D deficiency will reduce the incidence of heart failure and, for Arab women with established heart failure and vitamin D deficiency, improve cardiac function.

Objective: To investigate the relationship between endothelium-dependent and endothelium-independent functions and the stiffness of conduit arteries as well as levels of endothelial activation markers in patients with systemic sclerosis (SSc)., Methods: Endothelium-dependent (i.e., flow-mediated) and endothelium-independent (i.e., nitroglycerin-induced) dilation of the brachial artery was measured as the percentage of change from baseline (FMD% and NTG%, respectively) in 24 SSc patients and 24 age- and sex-matched healthy controls by high-resolution ultrasound imaging. The maximum increase in systolic pressure per unit of time (dP/dt(max)), as a measure of arterial wall stiffness, was assessed in the radial artery by pulse applanation tonometry. Plasma nitrate, the most important metabolite of nitric oxide, and 24-hour urinary excretion of nitrate were measured by gas chromatography mass spectrometry. Soluble E-selectin and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured by enzyme-linked immunosorbent assay., Results: Brachial artery FMD% and NTG% did not differ between SSc patients and controls. Radial artery dP/dt(max) was significantly increased in the patients and correlated significantly with elevated levels of plasma nitrate and sVCAM-1. Twenty-four-hour urinary nitrate excretion tended to be elevated. Brachial artery NTG% was significantly inversely correlated with levels of plasma nitrate and soluble endothelial adhesion molecules., Conclusion: The ability of the brachial arteries to dilate in response to hyperemia and nitroglycerin challenge is preserved in SSc. Stiffness of the radial artery is increased, however. Endothelial activation seems to determine the extent of the brachial artery NTG% and the radial artery dP/dt(max). The data are compatible with the hypothesis that nitrate tolerance is present in the vascular smooth muscle cells of the brachial artery wall in SSc.

Chronic heart failure (CHF) studies investigating the clinical, hemodynamic, and therapeutic importance of endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) are largely based on resting plasma levels, which may vary with prior exertion and postprandial status. This study investigated the importance of peak-exercise plasma levels of ET-1, ANP, and BNP in the assessment of left ventricular (LV) systolic function. Thirty-six male-patients ages 58 +/- 10 (mean +/- SD ) with NYHA class I-IV CHF due to coronary artery disease or idiopathic dilated cardiomyopathy were enrolled. LV systolic function was assessed by echocardiography and radionuclide ventriculography. Resting and peak cardiopulmonary exercise venous blood sampling and treadmill exercise testing were performed in the fasting state. Resting plasma levels of ET-1, ANP, and BNP were elevated compared with reference laboratory normal values. Exercise induced significant (p < 0.0001) increase in plasma levels of ET-1, ANP, and BNP. On univariate analysis peak-exercise plasma levels of ET-1, ANP, and BNP were more closely related to echocardiographically determined LV end-diastolic diameter and end-systolic diameter than their resting values. Multiple step-wise regression models identified resting and peak-exercise plasma levels of ET-1 and ANP but only the resting BNP as independent predictors of LV dimensions and systolic function. Peak exercise plasma levels of ANP and ET-1 are potentially more reliable and important than their resting levels as markers of LV systolic dysfunction and LV dimensions in patients with heart failure.

Objective: To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease., Methods: We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting., Results: Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate., Conclusion: NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.

We related atrial natriuretic peptide (ANP) among 30 consecutive patients with systemic sclerosis (SScl) and 48 gender- and age-matched controls to the measurements of left ventricular (LV) function as evaluated by echocardiography and external pulse curves to determine possible causative factors for an increased level of plasma ANP. The patients had a markedly elevated plasma ANP level (239.4 +/- 59 vs. 178.2 +/- 36 pmol/l, p < 0.0005), which was not related to LV systolic function, heart rate, or blood pressure. Patients had LV hypertrophy and plasma ANP correlated directly to interventricular septal thickness (r = 0.41, p < 0.005), LV posterior wall thickness (r = 0.32, p < 0.01), and wall thickness to cavity dimension (r = 0.44, p < 0.0005), LV mass index (r = 0.40, p < 0.005). LV early filling properties were impaired, with reduction of atrial emptying index (p < 0.0005) and increased contribution of atrial contraction to LV filling. Plasma ANP correlated to atrial emptying index (r = 0.41, p < 0.0005) and to apex-cardiographic a wave (r = 0.28, p < 0.05). Plasma ANP was also related to left atrial dimension index (r = 0.27, p < 0.05), and was still related to atrial emptying index, but not to left atrial dimension, when considering the degree of LV hypertrophy in multivariate analysis. We conclude that ANP is elevated in patients with SScl. Reduced LV compliance, probably due to increased fibrosis, may cause changes in atrial pressure sufficient to stimulate ANP production without systolic dysfunction as a prerequisite.