Neal Padmanabhan

Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease ☆

OBJECTIVES We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF). BACKGROUND Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF. METHODS Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat. RESULTS In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01). CONCLUSIONS Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.

Differences in arterial compliance, microvascular function and venous capacitance between patients with heart failure and either preserved or reduced left ventricular systolic function

Up to 50% of patients with the clinical syndrome of heart failure have preserved left ventricular systolic function (HF‐PSF). These patients may have abnormalities of ventriculo‐vascular coupling, due to increased vascular and ventricular stiffness.

Angiotensin-Converting Enzyme–Independent Contraction to Angiotensin I in Human Resistance Arteries

BACKGROUND In vitro studies of myocardial tissue suggest that angiotensin II (Ang II) may be generated by both ACE and chymase. A similar dual pathway may exist in the vasculature. We studied the effects of ACE and chymase inhibitors on the contractile response to angiotensin I (Ang I) in human resistance arteries to investigate ACE-independent generation of Ang II. METHODS AND RESULTS Subcutaneous resistance arteries (250 to 350 microm) were obtained from gluteal biopsies from volunteers and New Zealand White rabbits and mounted on a wire myograph. Contractile ability was tested with high-potassium depolarization and norepinephrine 10 micromol/L and endothelial integrity by relaxation to acetylcholine 3 micromol/L. Cumulative concentration-response curves were constructed for Ang I in the presence of enalaprilat 1 micromol/L, chymostatin 10 micromol/L, or both inhibitors together. In the rabbit, enalaprilat completely inhibited the Ang I response. In human vessels, enalaprilat or chymostatin alone had no effect, but the combination of enalaprilat and chymostatin almost completely inhibited the response to Ang I. CONCLUSIONS A dual pathway for Ang II generation exists in human resistance arteries, mediated by ACE and a chymostatin-sensitive enzyme, probably chymase. We confirm that a marked species difference exists in the mechanism of Ang II generation between the human and the rabbit. More efficacious suppression of the renin-angiotensin system may require development of novel enzyme inhibitors or combinations of currently available drugs.

Ten Years Experience of In-Center Thrice Weekly Long Overnight Hemodialysis

BACKGROUND AND OBJECTIVES Published studies suggest that longer hemodialysis (HD) sessions are associated with improved morbidity and mortality, but few centers offer long sessions. The Western Infirmary renal unit has offered long overnight hemodialysis (LOH) (6 to 7 h) thrice weekly since 1998. The aim of this study was to describe patients who chose LOH and compare outcomes with patients on conventional hours (4 to 5 h) HD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS Patients who ever had LOH for three or more consecutive sessions were identified (n = 146). Indices of urea reduction ratio (URR), anemia, hyperphosphatemia, and predialysis BP (BP) control in a subgroup of all patients on LOH for at least 1 yr since 2004 were compared with age, sex, and diabetes-matched controls undergoing conventional duration HD. RESULTS The mean age at the time of starting LOH was 51.8 yr and 74.7% started with a functioning arteriovenous fistula. Median duration of continuous LOH was 1.6 yr. Of those no longer on LOH, only 33.3% reverted to conventional hours HD (mean duration LOH 2.2 yr). When comparing LOH and conventional HD cohorts, there was increased URR and mean hemoglobin with a trend toward lower mean erythropoietin index. There was a trend toward fewer phosphate binder tablets but no difference in mean serum phosphate, BP, or number of prescribed antihypertensive medicines. CONCLUSIONS LOH is a well tolerated hemodialysis option, associated with improved URR and better control of anemia.

A guide to wire myography.

Wire myography is an in vitro technique that allows us to examine functional responses and vascular reactivity of isolated small resistance arteries. Vessels from various species, including transgenic models, and vascular beds can be examined in a variety of pathological disease states. Vessels are dissected, cleaned, and then mounted onto a four-channel myograph under isometric techniques. Each vessel is then normalized to determine maximum active tension development. This allows the standardization of initial experimental conditions, an important consideration when examining pharmacological differences between vessels.

Haemoglobin Mass and Running Time Trial Performance after Recombinant Human Erythropoietin Administration in Trained Men

Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake ( O2 max). Purpose This study defined the time course of changes in Hbmass, O2 max as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field. Methods 19 trained men received rHuEpo injections of 50 IU•kg−1 body mass every two days for 4 weeks. Hbmass was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. O2 max and 3,000 m time trial performance were measured pre, post administration and at the end of the study. Results Relative to baseline, running performance significantly improved by ∼6% after administration (10∶30±1∶07 min:sec vs. 11∶08±1∶15 min:sec, p<0.001) and remained significantly enhanced by ∼3% 4 weeks after administration (10∶46±1∶13 min:sec, p<0.001), while O2 max was also significantly increased post administration (60.7±5.8 mL•min−1•kg−1 vs. 56.0±6.2 mL•min−1•kg−1, p<0.001) and remained significantly increased 4 weeks after rHuEpo (58.0±5.6 mL•min−1•kg−1, p = 0.021). Hbmass was significantly increased at the end of administration compared to baseline (15.2±1.5 g•kg−1 vs. 12.7±1.2 g•kg−1, p<0.001). The rate of decrease in Hbmass toward baseline values post rHuEpo was similar to that of the increase during administration (−0.53 g•kg−1•wk−1, 95% confidence interval (CI) (−0.68, −0.38) vs. 0.54 g•kg−1•wk−1, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration compared to baseline (13.7±1.1 g•kg−1, p<0.001). Conclusion Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated O2 max and Hbmass.

The Emerging Potential of the Apelin-APJ System in Heart Failure

The apelin-APJ system is a novel neurohormonal pathway, with studies to date suggesting that it may be of pathophysiologic relevance in heart failure and may indeed be a viable therapeutic target in this syndrome. This interest is driven primarily by the demonstration of its vasodilator, inotropic, and aquaretic actions as well as its apparent antagonistic relationship with the renin-angiotensin system. However, its promise is heightened further by the observation that, unlike other and more established cardioprotective pathways, it appears to be down-regulated in heart failure, suggesting that augmentation of this axis may have a powerful effect on the heart failure syndrome. We review the literature regarding the apelin-APJ system in heart failure and suggest areas requiring further research.

Genetic basis of cardiovascular disease — the renin-angiotensin-aldosterone system as a paradigm

human, hypertension, aldosterone, cytochrome P-450 CYP11B2, angiotensin I, angiotensin II, renin, renin-angiotensin system, myocardial infarction, hypertrophy, arteries, heart, endothelium

Aortic Stiffness and Diastolic Flow Abnormalities in End-Stage Renal Disease Assessed by Magnetic Resonance Imaging

Background: Arterial stiffness is associated with adverse cardiovascular outcomes, particularly in end-stage renal disease (ESRD). One mechanism linking arterial stiffness with cardiovascular events may be the changes in pressure wave reflection on ventricular ejection and coronary perfusion during diastole. We illustrate this using MRI to describe aortic elastic properties and alterations of diastolic flow in comparison to derived central pressure characteristics. Methods: Ten patients with ESRD and ten control subjects were studied. Transverse images of the ascending aorta were obtained by cardiac MRI. Aortic distensibility was calculated using brachial pulse pressure. MRI flow maps were obtained from the ascending aorta and aortic pressure was calculated using SphygmoCor™. Results: ESRD patients had reduced aortic distensibility compared to the controls (median 0.00464 mm Hg–1 vs. 0.00152 mm Hg–1, p = 0.0057). Furthermore, in diastole, normal subjects show net reversal of blood flow in the ascending aorta, with a mean of –19.6 versus +7.6 ml/min in the ESRD group; p = 0.045. Conclusions: Using non-invasive methods we have demonstrated a marked reduction in aortic distensibility along with disturbances in aortic flow, providing insight into the pathophysiology of ventricular–vascular interaction. The normal group showed reversal of diastolic blood flow, which may have a direct relationship with coronary perfusion parameters, which was absent in the ESRD group.

Severe left ventricular systolic dysfunction in a patient with a typical haemolytic-uraemic syndrome treated with rituximab - coincidence or cause?

A 26-year-old female with haemolytic–uraemic syndrome (HUS) refractory to daily plasma exchange was successfully treated with rituximab. Subsequent testing confirmed the presence of mutations in genes encoding complement factor I and CD46. On Day 32 she developed pulmonary oedema, and echocardiography demonstrated severe left ventricular systolic dysfunction. There was no evidence of recent myocardial infarction. Cardiac involvement has been reported, not only in thrombotic thrombocytopaenic purpura (TTP) but also with rituximab therapy. However, it is unclear if atypical HUS is also associated with cardiac disease. We recommend echocardiography in all patients with TTP–HUS and in any patients commencing treatment with rituximab.