Alastair D. Robertson

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure

We and others have previously shown that carvedilol improves left ventricular (LV) function and symptoms in chronic heart failure. This improvement in LV function has also been shown to be associated with an improvement in survival. This study evaluates the effect of carvedilol on LV mass, geometry, and degree of mitral regurgitation (MR). In 59 patients with symptomatic heart failure and LV ejection fraction <0.35, previously randomized to either treatment with carvedilol or placebo, we evaluated LV mass, geometry, and degree of MR over the time period of carvedilol treatment. LV mass decreased as early as 4 months into the treatment protocol and continued to decrease over a period of 1 year. LV geometry, defined by the length/diameter ratio, and severity of MR also improved with 4 months of therapy. Thus, compared with placebo treatment, carvedilol decreases LV mass while improving cardiac geometry and decreasing MR in patients with chronic heart failure. These changes occur in association with an improvement in LV systolic function. This process begins by 4 months of treatment and continues for 12 months.

Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure

BACKGROUND Human brain natriuretic peptide (hBNP) is a promising agent for the treatment of decompensated cardiac failure. However, the systemic hemodynamic, neurohormonal, and renal effects of hBNP have been incompletely studied in human heart failure. METHODS AND RESULTS The effects of a continuous 4-hour infusion of hBNP were determined in 16 decompensated heart failure patients in an invasive, randomized, double-blind, placebo-controlled study. Patients were evaluated during three 4-hour study periods: baseline, treatment (placebo [n = 4] versus hBNP 0.025 or 0.05 microgram/kg/min [n = 12]), and post-treatment. Urinary volume losses were replaced hourly to separate the vasodilatory and diuretic effects of hBNP. Two patients in the hBNP group were excluded from the analysis because of adverse events. hBNP significantly (P < .001) reduced right atrial pressure and pulmonary capillary wedge pressure by approximately 30% and 40%, respectively. hBNP also significantly lowered systemic vascular resistance from 1722 +/- 139 to 1101 +/- 83 dynes.s.cm-5 (P < .05). These unloading effects of hBNP produced a 28% increase in cardiac index (P < .05) with no change in heart rate. Compared to placebo, hBNP decreased plasma norepinephrine and aldosterone. Renal hemodynamics were unaffected by hBNP; however, most patients were resistant to its natriuretic effect. CONCLUSIONS 1) The predominant hemodynamic effects of hBNP were a decrease in cardiac preload and systemic vascular resistance. 2) hBNP also improved cardiac output without increasing heart rate. 3) Plasma norepinephrine and aldosterone levels decreased during hBNP infusion. 4) hBNP is pharmacologically active and has potential in the therapy for decompensated heart failure.

Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: A randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol

OBJECTIVE We compared the hemodynamic effects of dobutamine and enoximone administration before and after long-term beta-blocker therapy with metoprolol or carvedilol in patients with chronic heart failure (HF). BACKGROUND Patients with HF on beta-blocker therapy may need hemodynamic support with inotropic agents, and the hemodynamic response may be influenced by both the inotropic agent and the beta-blocker used. METHODS The hemodynamic effects of dobutamine (5 to 20 microg/kg/min intravenously) and enoximone (0.5 to 2 mg/kg intravenously) were assessed by pulmonary artery catheterization in 29 patients with chronic HF before and after 9 to 12 months of treatment with metoprolol or carvedilol at standard target maintenance oral doses. Hemodynamic studies were performed after >/=12 h of wash-out from all cardiovascular medications, except the beta-blockers that were administered 3 h before the second study. RESULTS Compared with before beta-blocker therapy, metoprolol treatment decreased the magnitude of mean pulmonary artery pressure (PAP) and pulmonary wedge pressure (PWP) decline during dobutamine infusion and increased the cardiac index (CI) and stroke volume index (SVI) response to enoximone administration, without any effect on other hemodynamic parameters. Carvedilol treatment abolished the increase in heart rate, SVI, and CI and caused a rise, rather than a decline, in PAP, PWP, systemic vascular resistance, and pulmonary vascular resistance during dobutamine infusion. The hemodynamic response to enoximone, however, was maintained or enhanced in the presence of carvedilol. CONCLUSIONS In contrast with its effects on enoximone, carvedilol and, to a lesser extent, metoprolol treatment may significantly inhibit the favorable hemodynamic response to dobutamine. No such beta-blocker-related attenuation of hemodynamic effects occurs with enoximone.

Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure

OBJECTIVES We sought to assess the effects of combined oral positive inotropic and beta-blocker therapy in patients with severe heart failure. BACKGROUND Patients with severe, class IV heart failure who receive standard medical therapy exhibit a 1-year mortality rate >50%. Moreover, such patients generally do not tolerate beta-blockade, a promising new therapy for chronic heart failure. Positive inotropes, including phosphodiesterase inhibitors, are associated with increased mortality when administered over the long term in these patients. The addition of a beta-blocker to positive inotropic therapy might attenuate this adverse effect, although long-term oral inotropic therapy might serve as a bridge to beta-blockade. METHODS Thirty patients with severe heart failure (left ventricular ejection fraction [LVEF] 17.2+/-1.2%, cardiac index 1.6+/-0.1 liter/min per m2) were treated with the combination of oral enoximone (a phosphodiesterase inhibitor) and oral metoprolol at two institutions. Enoximone was given at a dose of < or = 1 mg/kg body weight three times a day. After clinical stabilization, metoprolol was initiated at 6.25 mg twice a day and slowly titrated up to a target dose of 100 to 200 mg/day. RESULTS Ninety-six percent of the patients tolerated enoximone, whereas 80% tolerated the addition of metoprolol. The mean duration of combination therapy was 9.4+/-1.8 months. The mean length of follow-up was 20.9+/-3.9 months. Of the 23 patients receiving the combination therapy, 48% were weaned off enoximone over the long term. The LVEF increased significantly, from 17.7+/-1.6% to 27.6+/-3.4% (p=0.01), whereas the New York Heart Association functional class improved from 4+/-0 to 2.8+/-0.1 (p=0.0001). The number of hospital admissions tended to decrease during therapy (p=0.06). The estimated probability of survival at 1 year was 81+/-9%. Heart transplantation was performed successfully in nine patients (30%). CONCLUSIONS Combination therapy with a positive inotrope and a beta-blocker appears to be useful in the treatment of severe, class IV heart failure. It may be used as a palliative measure when transplantation is not an option or as a bridge to heart transplantation. Further study of this form of combined therapy is warranted.

Assessment of the risk of bleeding from esophageal varices by continuous monitoring of portal pressure

Portal pressure was monitored by means of an indwelling hepatic vein balloon catheter in patients with alcoholic cirrhosis and bleeding varices to determine the safety and feasibility of the technique and its value in predicting recurrence of bleeding. Forty patients were enrolled. Central venous access could not be achieved in 4 patients (10%). Hepatic vein catheterization was accomplished in the remaining 36 patients. Fourteen patients were either later found to have nonalcoholic liver disease or had already received treatment that excluded them from the protocol. The remaining 22 patients, who were treated with blood and fluid replacement, were monitored for up to 72 hours. Portal pressure was greater than 11 mm Hg in all patients (normal, less than 5 mm Hg) and did not change significantly over the 3 days of study. Portal pressure was significantly higher in the 9 patients who continued to bleed or rebled compared with the 13 patients who remained stable. The lowest pressure associated with continued bleeding or rebleeding was 16 mm Hg. Continuous monitoring of portal pressure in patients with bleeding esophageal varices due to alcoholic cirrhosis is safe and feasible and permits rapid stratification of the risk of continued bleeding or early rebleeding.

An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure.

Background—Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional &agr;2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel &bgr;-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether &agr;2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results—In the &bgr;-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the &bgr;-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and &agr;2C-AR gene polymorphisms (&agr;2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were &agr;2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153±57 pg/mL, P=0.012 compared with placebo versus decrease of 50±13 pg/mL in &agr;2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). &agr;2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the &agr;2C-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025). Conclusions—In the &bgr;-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by &agr;2C receptor genotype.

An α2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the β-Blocker Bucindolol in Chronic Heart FailureCLINICAL PERSPECTIVE

Background—Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional &agr;2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel &bgr;-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether &agr;2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results—In the &bgr;-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the &bgr;-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and &agr;2C-AR gene polymorphisms (&agr;2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were &agr;2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153±57 pg/mL, P=0.012 compared with placebo versus decrease of 50±13 pg/mL in &agr;2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). &agr;2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the &agr;2C-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025). Conclusions—In the &bgr;-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by &agr;2C receptor genotype.

Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics.

Hypothesis/introduction A polymorphic marker within the angiotensin-converting enzyme (ACE) gene has been associated with circulating and tissue ACE activity and with a variety of forms of cardiovascular disease. Since angiotensin II (Ang II) causes pulmonary vasoconstriction and vascular and myocardial remodelling, we postulated a role for the renin-angiotensin system and the ACE DD genotype in the pathophysiology of primary pulmonary hypertension (PPH) and in the right ventricular response to pressure overload in these patients. Methods and results The incidence of the ACE DD genotype was evaluated in 60 patients with severe PPH compared with two normal control populations, a group of healthy population-based controls (n=158) and subjects found suitable for cardiac organ donation (n=79). Genomic DNA extracted from peripheral leukocytes was amplified using the polymerase chain reaction to detect polymorphic markers. Haemodynamics were determined by right heart catheterisation in a subset of the PPH patients. The frequency of the ACE DD genotype was 45% in the patients with PPH, compared with 24% in the organ donors, and 28% in populationbased healthy controls (p=0.01 for chi-square test). Of the 32 PPH patients with baseline haemodynamics, 12 exhibited the ACE DD genotype and 20 were non-DD. While the mean pulmonary artery pressure and the duration of symptoms attributable to pulmonary hypertension was not different between the DD and non-DD groups, cardiac output was significantly lower (3.29±0.27 vs. 5.07±0.37 L/minute, p=0.002) and the trouvemean right atrial pressure tended to be higher (8.85±1.29 vs. 4.92±1.27 mmHg, p=0.08) in the non-DD group. The reduction in cardiac output seen in the non-DD group was not due to a difference in heart rate, but to a significant reduction in stroke volume, consistent with a decreased contractile state. In addition, non-DD patients exhibited a significantly worse functional capacity (NYHA Class 3.14±0.12 vs. 2.40±0.28, p=0.02). Conclusions 1) The ACE DD genotype is significantly increased in patients with severe PPH compared with normal controls, suggesting that certain individuals may be genetically predisposed to developing pulmonary hypertension. 2) The ACE DD genotype is associated with preserved right ventricular function in PPH patients, supporting a compensatory myocardial or inotropic role for Ang II in the pressure overloaded right ventricle.

Differential Regulation of Cardiac Angiotensin Converting Enzyme Binding Sites and AT1 Receptor Density in the Failing Human Heart

BACKGROUND The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT1) receptor in the failing human heart are not understood. METHODS AND RESULTS Radioligand binding with 3H-ramiprilat was used to measure ACE protein in membrane preparations of hearts obtained from 36 subjects with idiopathic dilated cardiomyopathy (IDC), 8 subjects with primary pulmonary hypertension (PPH), and 32 organ donors with normal cardiac function (NF hearts). 125I-Ang II formation was measured in a subset of hearts. Saralasin (125I-(Sar1,Ile8)-Ang II) was used to measure total Ang II receptor density. AT1 and AT2 receptor binding were determined with the AT1 receptor antagonist losartan. Maximal ACE binding (Bmax) was 578+/-47 fmol/mg in IDC left ventricle (LV), 713+/-97 fmol/mg in PPH LV, and 325+/-27 fmol/mg in NF LV (P<0.001, IDC or PPH versus NF). In IDC, PPH, and NF right ventricles (RV), ACE Bmax was 737+/-78, 638+/-137, and 422+/-49 fmol/mg, respectively (P=0.02, IDC versus NF; P=0.08, PPH versus NF). 125I-Ang II formation correlated with ACE binding sites (r=0.60, P=0.00005). There was selective downregulation of the AT1 receptor subtype in failing PPH ventricles: 6.41+/-1.23 fmol/mg in PPH LV, 2.37+/-0.50 fmol/mg in PPH RV, 5.38+/-0.53 fmol/mg in NF LV, and 7.30+/-1.10 fmol/mg in NF RV (P=0.01, PPH RV versus PPH LV; P=0.0006, PPH RV versus NF RV). CONCLUSIONS ACE binding sites are increased in both failing IDC and nonfailing PPH ventricles. In PPH hearts, the AT1 receptor is downregulated only in the failing RV.