Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure

Background—Right ventricular (RV) dysfunction frequently occurs and independently prognosticates in left-sided heart failure. It is not clear which RV afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role, and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure. Methods and Results—We reviewed 724 consecutive patients with heart failure who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated heart failure. PAC showed a strong inverse relation with PVR (r=−0.64) and wedge pressure (r=−0.73), and provides stronger prediction of significant RV failure than PVR (area under the curve ROC 0.74 versus 0.67, respectively, P=0.003). During a mean follow-up of 3.2±2.2 years, both lower PAC (P\u3c0.0001) and higher PVR (P\u3c0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio=0.92 [95% CI: 0.84–1.0, P=0.037]). Treatment of heart failure resulted in a decrease in PVR (270±165 to 211±88 dynes·s–1·cm–5, P=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 mL/mm Hg, P\u3c0.0001), leading to an increase in pulmonary arterial time constant (PVR×PAC) (0.29±0.12 to 0.37±0.15 second, P\u3c0.0001). Conclusions—PAC bundles the effects of PVR and left-sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy

Studies on the direct vascular actions of diuretics

Although thiazide diuretics have been a mainstay of the drug therapy for the treatment of hypertension for over 30 years, the exact mechanism by which they reduce blood pressure is not known. In this thesis, the direct vascular actions of a thiazide diuretic (hydrochlorothiazide) were compared with those of thiazide like diuretics (chlorthalidone and indapamide) and a loop diuretic (furosemide). The vascular actions of these four diuretics were studied in the presence and absence of plasma solutions on the following tissue preparations: rat aortic rings, rat pulmonary artery rings, human uterine artery rings, and the rat perfused mesenteric bed. Whole animal experiments were conducted in control and a hypertensive rat model (DOCA/salt treated). Acute hypotensive effects of the diuretics were measured in rats with ligated ureters to prevent any diuretic effect. Acute tissue blood flow effects were also measured using the reference sample method with radioactively-label led microspheres. Results: (1) Diuretics possess a direct vasorelaxant effect only in the presence of plasma on in vitro arterial preparations. (2) This in vitro relaxant effects is endothelium-independent. (3) Albumin was found to be the main plasma cofactor required by diuretics. (4) Preincubation with albumin enables tissues to retain their responsiveness to diuretics in Krebs solution alone. (5) Excess albumin appears to decrease the vasorelaxant action of diuretics, presumably due to binding of the diuretics to albumin. (6) Diuretics possess acute blood pressure lowering and vasodilating effects in hypertensive animals by a mechanism independent of diuresis. (7) These in vivo effects are due to decreased total peripheral resistance and increased blood flow to specific vascular beds (intestine and kidney). (8) The potency of the vasorelaxant actions of the four diuretics tested in the various preparations is reproducible (indapamide > hydrochiorothiazide > chiorthalidone > furosemide) and is consistent. with their clinical antihypertensive potency. (9) Hydrochlorothiazide and chiorthalidone in plasma directly relax vascular smooth muscle by acting on calcium-activated potassium channels whereas indapamide and furosemide act by a different mechanism which is not prostaglandin-dependent. These data suggest that diuretics possess a direct vasorelaxant action which may be important to the antihypertensive action of these drugs.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat

Studies on the stimulant action of human gamma-globulin on spontaneous contractility: interaction with K⁺-channel openers and postaglandin inhibitors

The aim of this thesis was to investigate the stimulatory action of human gamma-globulin on the spontaneous activity of the rat mesenteric portal vein. Previous studies in our laboratory have identified human gamma-globulin and IgG as stimulatory factors which may be responsible for the smooth muscle abnormality associated with the etiology of essential hypertension (Pillai, 1989). This thesis is comprised of three studies. The first study examined whether or not human gamma-globulin exerts its stimulatory action only on spontaneously-active smooth muscles. The second study was to determine if the stimulatory action of human gamma-globulin on the spontaneous activity of the rat mesenteric portal vein is due to decreased potassium conductance. The aim of the third study was to determine if prostaglandins play a role in the stimulatory effects of human gamma-globulin. Human gamma-globulin significantly increased the contractile activity of spontaneously-active muscles (rat mesenteric portal vein and guinea-pig taenia-caeci) with respect to frequency, force, and integrated response of contraction, whereas it had no significant effect on the contractile activity of quiescent muscles (rat aorta and guinea-pig trachea). At a concentration of 4.35 mg/ml human gamma-globulin caused a 63% increase above the maximum integrated response obtained with the time/volume/pH control in the rat mesenteric portal vein and a 23% increase in integrated response above that of the time/volume/pH control in guinea-pig taenia-caeci. Human gamma-globulin had no significant effect on the actions of noradrenaline on the rat mesenteric portal vein. Glibenclamide, a potassium channel antagonist, potentiated the action of human gamma-globulin on the portal vein by 45% and on its own had a biphasic (increase followed by a decrease) effect on the spontaneous activity of the portal vein . Glibenclamide and human gamma-globulin in combination increased the degree of contracture or baseline tone of the portal vein . Diazoxide, a potassium channel opener, noncompetitively inhibited the action of human gamma-globulin on the rat mesenteric portal vein by 63%. Both concentrations of pinacidil (0.5 and 5 μM), which is a potassium channel opener, non-competitively inhibited the action of human gamma-globulin by 61% and 78%, respectively. Lemakalim, a potassium channel opener, decreased the spontaneous activity of the portal vein in a concentration-dependent manner. Lemakalim non-competitively antagonized the actions of both noradrenaline and glibenclamide on the rat mesenteric portal vein. Lemakalim potentiated the stimulatory action of human gamma-globulin on the integrated force of the spontaneous contractions of the rat mesenteric portal vein by 40% and 49% at concentrations of 0.5 and 5 μM, respectively. It did so in a manner similar to glibenclamide by interacting with human gamma-globulin to increase the contracture or baseline tone of the portal vein. Indomethacin, meclofenamic acid, corticosterone, phenylbutazone, aspirin, ibuprofen, and piroxicam all inhibited the stimulatory action of human gamma-globulin on the rat mesenteric portal vein, but only indomethacin, meclofenamic acid, and corticosterone did so to a significant level . Indomethacin was the most potent inhibitor of human gamma-globulin, decreasing the maximum integrated response of the rat mesenteric portal vein to human gamma-globulin by 40% and 60% at concentrations of 1x10⁻¹⁰ M and 1x10⁻⁶ M . Meclofenamic acid was the second most potent inhibitor of human gamma-globulin, decreasing the maximum integrated response of the rat mesenteric portal vein to human gamma-globulin by 15% and 52% at concentrations of 1x10⁻¹⁰ M and 1x10⁻⁶ M. Corticosterone decreased the maximum integrated response to human gamma-globulin in the rat mesenteric portal vein by 22% at a concentration of 1x10⁻⁵ M . The order of potency for the remaining NSAIDs was found to be phenylbutazone > aspirin > ibuprofen > piroxicam. In the ex vivo experiment, 10 mg/kg of indomethacin caused a statistically significant decrease in the response of the rat mesenteric portal vein to human gamma-globulin. It is concluded from these studies that human gamma-globulin exerts its stimulatory effects only on spontaneously active smooth muscle preparations. Findings from these studies may be taken to suggest that human gamma-globulin, which is a protein, may act by directly modulating a potassium channel such as the maxi-K⁺ channel. It also appears that prostaglandins play a role in the stimulatory action of human gamma-globulin on the rat mesenteric portal vein.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat

Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure

Background—Right ventricular (RV) dysfunction frequently occurs and independently prognosticates in left-sided heart failure. It is not clear which RV afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role, and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure. Methods and Results—We reviewed 724 consecutive patients with heart failure who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated heart failure. PAC showed a strong inverse relation with PVR (r=−0.64) and wedge pressure (r=−0.73), and provides stronger prediction of significant RV failure than PVR (area under the curve ROC 0.74 versus 0.67, respectively, P=0.003). During a mean follow-up of 3.2±2.2 years, both lower PAC (P\u3c0.0001) and higher PVR (P\u3c0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio=0.92 [95% CI: 0.84–1.0, P=0.037]). Treatment of heart failure resulted in a decrease in PVR (270±165 to 211±88 dynes·s–1·cm–5, P=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 mL/mm Hg, P\u3c0.0001), leading to an increase in pulmonary arterial time constant (PVR×PAC) (0.29±0.12 to 0.37±0.15 second, P\u3c0.0001). Conclusions—PAC bundles the effects of PVR and left-sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy

Sodium Nitroprusside for Advanced Low-Output Heart Failure

ObjectivesThis study was designed to examine the safety and efficacy of sodium nitroprusside (SNP) for patients with acute decompensated heart failure (ADHF) and low-output states.BackgroundInotropic therapy has been predominantly used in the management of patients with ADHF presenting with low cardiac output.MethodsWe reviewed all consecutive patients with ADHF admitted between 2000 and 2005 with a cardiac index ≤2 l/min/m2 for intensive medical therapy including vasoactive drugs. Administration of SNP was chosen by the attending clinician, nonrandomized, and titrated to a target mean arterial pressure of 65 to 70 mm Hg.ResultsCompared with control patients (n = 97), cases treated with SNP (n = 78) had significantly higher mean central venous pressure (15 vs. 13 mm Hg; p = 0.001), pulmonary capillary wedge pressure (29 vs. 24 mm Hg; p = 0.001), but similar demographics, medications, and renal function at baseline. Use of SNP was not associated with higher rates of inotropic support or worsening renal function during hospitalization. Patients treated with SNP achieved greater improvement in hemodynamic measurements during hospitalization, had higher rates of oral vasodilator prescription at discharge, and had lower rates of all-cause mortality (29% vs. 44%; odds ratio: 0.48; p = 0.005; 95% confidence interval: 0.29 to 0.80) without increase in rehospitalization rates (58% vs. 56%; p = NS).ConclusionsIn patients with advanced, low-output heart failure, vasodilator therapy used in conjunction with optimal current medical therapy during hospitalization might be associated with favorable long-term clinical outcomes irrespective of inotropic support or renal dysfunction and remains an excellent therapeutic choice in hospitalized ADHF patients