Heng-Jie Cheng

Angiotensin II Type 1 Receptor Blockade Prevents Alcoholic Cardiomyopathy

Background— Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT1) blockade on the development of alcoholic cardiomyopathy. Methods and Results— We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg · kg−1 · d−1 PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT1 receptor expression. The RAS activation was followed by a progressive fall in LV contractility (EES, alcohol-fed dogs 3.9±0.8 versus control dogs 8.1±1.0 mm Hg/mL); reductions in the peak velocity of myocyte shortening (78.9±5.1 versus 153.9±6.2 &mgr;m/s) and relengthening; and decreased peak systolic Ca2+ transient ([Ca2+]iT) and L-type Ca2+ current (ICa,L; P<0.05). Irbesartan prevented the alcohol-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and ICa,L. With alcohol plus irbesartan, plasma Ang II, cardiac angiotensin-converting enzyme activity, and AT1 remained close to control values. Conclusions— Chronic alcohol consumption produces RAS activation followed by progressive cardiac dysfunction. The cardiac dysfunction is prevented by AT1 receptor blockade.

Restrictive Left Ventricular Filling Pattern Does Not Result From Increased Left Atrial Pressure Alone

Background— The restrictive filling pattern seen with severe heart failure (HF) may be due to diastolic dysfunction with elevated left ventricular (LV) diastolic pressure or may be merely a manifestation of an overfilled LV as a result of increased left atrial (LA) pressure. We investigated whether the LV restrictive filling pattern is due to elevated LA pressure alone. Methods and Results— We studied conscious dogs instrumented to measure LA pressure, LV pressure, and 3 LV diameters. LV filling dynamics were evaluated in 2 situations with similar elevations of LA pressure: in normal animals after rapid volume loading with dextran 500 mL and in animals with pacing-induced HF with restrictive filling. With HF, there was increased LV chamber stiffness and slow relaxation. Volume loading and HF had similar heart rates (129±19 versus 131±15 bpm) and LA pressure (22.1±5.8 versus 22.6±3.3 mm Hg). The peak early filling rate (E) was increased with both HF and volume loading. However, in HF, the peak mitral annular velocity (E′) was decreased and delayed, and the E deceleration time was shorter. In contrast, with volume loading, E′ was increased and not delayed. Conclusion— The restrictive filling pattern is distinguished from overfilling of a normal ventricle by a reduced and delayed E′ and a shortened E deceleration time that reflect slow relaxation and increased LV stiffness.

Orally Available Levosimendan Dose-Related Positive Inotropic and Lusitropic Effect in Conscious Chronically Instrumented Normal and Heart Failure Dogs

Levosimendan (LS), a Ca2+ sensitizer, is presently limited to i.v. administration. The dose-related pharmacodynamic effects of newly developed oral LS remain undetermined. We assessed the dose-response relationship of oral LS in nine normal and seven pacing-induced heart failure (HF), conscious, chronically instrumented mongrel dogs. Animals received a placebo capsule on day 1, and then LS was administered at single oral doses of 0.025 (day 2), 0.05 (day 4), and 0.1 (day 8) mg/kg. We serially measured plasma LS concentrations, hemodynamic, and left ventricular (LV) systolic and diastolic functional responses periodically until 12 h after oral LS. In both normal and HF, after three incremental dosages of oral LS, the peak plasma LS concentrations (34.6, 66.8, and 123.2 ng/ml in normal and 38.3, 71.5, and 137.4 ng/ml in HF) were achieved within 2 h in proportion to the dose, parallel to an increased LV contractility (normal, from 5.7 mm Hg/ml placebo to 8.2, 10.5, and 12.6 mm Hg/ml; HF, from 3.7 mm Hg/ml placebo to 5.7, 7.1, and 8.7 mm Hg/ml), and decreased time constant of LV relaxation (τ) (normal, from 28.8 ms of placebo to 25.6, 24.7, and 23.5 mm Hg/ml; HF, from 44.7 ms of placebo to 38.9, 36.4, and 34.6 ms). Compared with placebo, total systemic vascular resistance and mean left atrial pressure were significantly reduced after LS. In HF, oral LS caused a dose-dependent increase of LV-arterial coupling and mechanical efficiency. Heart rate increased only after 0.1 mg/kg LS in normal dogs. In conclusion, oral LS produces vasodilatation and dose-dependent augmentation in LV contractility and relaxation both in normal and HF.

β3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of β3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. β3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac β3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 μg/kg iv), a selective β3-adrenergic receptor antagonist (β3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after β3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, β3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.

Response to Letter Regarding Article, “Restrictive Left Ventricular Filling Pattern Does Not Result From Increased Left Atrial Pressure Alone”

We are grateful for the interest in our article1 expressed by Razzolini and Tarantini. They agree that we have demonstrated that the restrictive filling is not due to an overfilled ventricle. However, they are concerned that this pattern is not due to diastolic dysfunction but instead results from systolic dysfunction. Although restrictive filling is most common in patients with heart failure associated with a …

870-1 Chronic beta3-adrenergic receptor blockade causes regression of cardiac dysfunction in a rat model of progressive heart failure

Introduction: The role of proB-type natriuretic peptide (proBNP) for the diagnosis of congestive heart failure (CHF) among patients presenting to the Emergency Department (ED) with dyspnea remains undefined. Accordingly, in the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study, we are systematically assessing the value of proBNP (Elecsys® proBNP Immunoassay, Roche Diagnostics Corporation) for the urgent evaluation of dyspneic patients with suspected acute CHF. Methods/Results: Enrollment for the PRIDE study has closed, and clinical follow up is to complete in October, 2003. The PRIDE study is a single-center, prospective, blinded trial of 600 patients, age >21 years, presenting with a complaint of dyspnea to an urban ED. Exclusion criteria include severe renal insufficiency (serum creatinine >2.5 mg/dl), ST segment depression or elevation on ECG, dyspnea following trauma, and >2 hours following urgent administration of intravenous loop diuretic. Following informed consent, information regarding demographics, past medical history, current medications, and presentation of each patient was gathered. A specimen of blood was collected for blinded proBNP measurement. At the end of standard clinical assessment (history, physical exam, ECG, chest x-ray), the treating ED physician provided a clinical estimate of the presence of CHF as the cause of dyspnea. The primary endpoint of the study will be a comparison of the predictive value of proBNP measurement versus clinical judgment for the presence of CHF at the time of clinical evaluation in the ED. Other endpoints will include correlation of proBNP levels with the diagnosis of CHF from presentation to 60 days of follow-up, as well as correlations with hospital length of stay. Conclusion: The PRIDE study is the first large-scale assessment of proBNP for the evaluation of patients with suspected acute CHF in the ED, and will establish a role for this biomarker in the urgent setting.