The pressure-overloaded right ventricle in pulmonary hypertension.
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Animals↗
Biomedical subjects
B D Lowes
Publications and source records attributed to B D Lowes.
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.
Atrial Natriuretic Factor↗
Second- and third-generation beta-blocking drugs in chronic heart failure.
The left-ventricular (LV) functional, hemodynamic, and antiadrenergic effects of metoprolol, bucindolol, and carvedilol have been compared in three concurrent placebo-controlled clinical trials in patients with symptomatic idiopathic dilated cardiomyopathy. All three drugs were well tolerated, all produced at least moderate degrees of beta-blockade as assessed by reduction in exercise heart rate, and all increased the left-ventricular ejection fraction. Compared with the beta 1-selective, second-generation compound metoprolol, the third-generation compounds bucindolol and carvedilol lowered indices of adrenergic activity and tended to improve LV function to a greater extent. In patients with chronic heart failure there may be important therapeutic response differences between second- and third-generation beta-blocking agents.
Adrenergic beta-Antagonists↗
Importance of angiotensin-converting enzyme in pulmonary hypertension.
Angiotensin II causes pulmonary vasoconstriction in man and in animals, and angiotensin-converting enzyme (ACE) inhibitors have prevented the development of chronic pulmonary hypertension in animals models. Angiotensin II may contribute to lung vascular remodeling in pulmonary hypertensive disease, since cilazapril, an inhibitor of ACE, reduces pulmonary vascular medical thickening in chronically hypoxic rats with established pulmonary hypertension. Furthermore, the ACE DD genotype, which has been associated with increased circulating and tissue ACE activity, has been associated with left ventricular hypertrophy in human hypertensive disorders. The ACE DD genotype may also 'permit' a greater hypertrophic adaptation of the pressure-over-loaded right ventricle. In fact, we have shown that pulmonary hypertension patients with maintained cardiac output and less right-heart failure fall into the group with the DD genotype and that patients with a low cardiac output and more severe right-heart failure fall into the group with the non-DD genotype, supporting the hypothesis. We assessed cardiopulmonary hemodynamics in patients with primary (unexplained) pulmonary hypertension and segregated the patients based on their ACE genotype. For similar mean pulmonary artery pressures in the DD and non-DD groups, the cardiac output was substantially lower in the patients with the non-DD genotype, whereas the values for mean right atrial pressure and pulmonary vascular resistance were double when compared with the DD group. Our data show that the ACE DD genotype is prevalent in patients with severe pulmonary hypertension and is a marker of maintained right ventricular function.
Animals↗
Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.
It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE.
Angiotensin I↗
Comparative hemodynamic effects of OPC-18790 and dobutamine in patients with advanced heart failure.
OPC-18790 (Otsuka America Pharmaceutical, Rockville, MD), a novel positive inotropic agent, produces titratable hemodynamic benefits in patients with advanced heart failure. In such patients, OPC-18790 has been shown to acutely increase the cardiac index, while reducing systemic vascular resistance and left ventricular filling pressure, without an associated increase in heart rate. This study was performed to compare the acute hemodynamic effects of OPC-18790 and the beta-adrenergic receptor agonist, dobutamine, in patients with advanced heart failure. OPC-18790 and dobutamine were compared on successive days in 13 patients with worsening New York Heart Association class III or IV heart failure. The mean (+/- SEM) left ventricular ejection fraction was 15 +/- 2% (range, 6-29%). Pretreatment hemodynamics were: heart rate, 96 +/- 2 beats/min; mean arterial pressure, 77 +/- 3 mmHg; cardiac index, 1.80 +/- 0.10 L/min/m2; pulmonary capillary wedge pressure, 27 +/- 1 mmHg; mean pulmonary arterial pressure, 41 +/- 2 mmHg; and systemic vascular resistance, 1,732 +/- 152 dynes.s/cm5. At infusion rates yielding comparable increases in the cardiac index (5 micrograms/kg/min for 2 hours for each drug), OPC-18790 produced significantly more favorable effects on heart rate (-2 +/- 3% vs 11 +/- 4%; P = .01), pulmonary capillary wedge pressure (-32 +/- 4% vs -17 +/- 8%; P = .04), mean pulmonary arterial pressure (-14 +/- 3% vs 6 +/- 11%; P = .06), stroke volume index (48 +/- 8% vs 29 +/- 7%; P = .02), stroke work index (70 +/- 11 vs 42% +/- 12%; P = .03), and rate pressure product (2 +/- 4% vs 14 +/- 4%; P = .05). The hemodynamic profile for OPC-18790 differs from dobutamine, with OPC-18790 exhibiting no increase in heart rate, greater preload reduction, and an increase in cardiac performance at a lower estimated metabolic cost.
Adrenergic beta-Antagonists↗
Low-dose inotropic therapy for ambulatory heart failure.
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Cardiotonic Agents↗
Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy.
Polymorphism in the angiotensin-converting enzyme (ACE) gene has been shown to correlate with circulating ACE concentrations, and also to be an independent risk factor for the development of myocardial infarction, particularly in men thought to be at low risk by standard criteria. We determined the genotypes of individuals with end-stage heart failure due to either ischaemic dilated cardiomyopathy (102) or idiopathic dilated cardiomyopathy (112) and compared these to organ donors with normally functioning hearts (79). Genotypes were determined by the polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene to amplify template DNA isolated from patients. Compared with the DD frequency in the control population, the frequency of the ACE DD genotype was 48% higher in individuals with idiopathic dilated cardiomyopathy (p = 0.008) and 63% higher in subjects with ischaemic cardiomyopathy (p = 0.008), suggesting that an ACE gene variant may contribute to the pathogenesis of both types of cardiomyopathy.
Adolescent↗