Roland R. Brandt

Endothelin in human congestive heart failure

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Atrial natriuretic peptide in heart failure

Atrial natriuretic peptide hormone of cardiac origin, which is released in response to atrial distension and serves to maintain sodium homeostasis and inhibit activation of the renin-angiotensin-aldosterone system. Congestive heart failure is a clinical syndrome characterized by increased cardiac volume and pressure overload with an inability to excrete a sodium load, which is associated with increased activity of systemic neurohumoral and local autocrine and paracrine mechanisms. Circulating atrial natriuretic peptide is greatly increased in congestive heart failure as a result of increased synthesis and release of this hormone. Atrial natriuretic peptide has emerged as an important diagnostic and prognostic serum marker in congestive heart failure. In early heart failure, it may play a key role in preserving the compensated state of asymptomatic left ventricular dysfunction. Despite increased circulating atrial natriuretic peptide in heart failure, the kidney retains sodium and is hyporesponsive to exogenous and endogenous atrial natriuretic peptide. The mechanism for the attenuated renal response is multifactorial and includes renal hypoperfusion, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. Therapeutic strategies to potentiate the biologic actions of atrial natriuretic peptide may prolong the asymptomatic phase and delay progression to overt congestive heart failure.

Endothelin at Pathophysiological Concentrations Mediates Coronary Vasoconstriction via the Endothelin-A Receptor

BACKGROUND Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at low concentrations of exogenous ET-1 designed to mimic pathophysiological states compared with pharmacological concentrations. METHODS AND RESULTS ET-1 (group 1, n = 5) or sarafotoxin, a specific ET-B receptor agonist (group 3, n = 6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 dogs (n = 5), the same dose of ET-1 was infused with 4 micrograms/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n = 5), the same dose of sarafotoxin was infused with 50 micrograms/kg per minute of the specific inhibitor of nitric oxide formation, NG-monomethyl-L-arginine (L-NMMA). No difference in hemodynamics, coronary blood flow (CBF), coronary vascular resistance (CVR), or coronary artery diameter (CAD) was observed at baseline between the groups. In group 1, intracoronary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group that received ET-1 and the ET-A receptor antagonist (group 2) was significantly less than that in the group that received ET-1 alone (group 1) (-12 +/- 3% versus -48 +/- 6% [P < .001] and -4.6 +/- 0.8 versus 1.0 +/- 0.3 [P < .05], respectively). The administration of the ET-A receptor antagonist (group 2) abolished the ET-mediated increase in CVR (7 +/- 5% versus 105 +/- 21%, P < .005). There was no significant effect on CBF, CVR, or CAD in the group receiving sarafotoxin alone (group 3). The administration of L-NMMA and sarafotoxin (group 3). The administration of L-NMMA and sarafotoxin (group 4) resulted in a significant percentage decrease in CBF compared with the group that received sarafotoxin alone (-28 +/- 7% versus -8 +/- 2% [P < .05]). CONCLUSIONS The present study demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction mediated predominantly via the ET-A receptor because such vasoconstriction is significantly attenuated by blockade with FR-139317. The ET-B receptor may have a dual vasoconstrictive and vasodilatory effect.

Prognostic value of N-terminal pro-B-type natriuretic peptide for conservatively and surgically treated patients with aortic valve stenosis

Objective: To evaluate the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with aortic stenosis being treated conservatively or undergoing aortic valve replacement (AVR). Methods: 159 patients were followed up for a median of 902 days. 102 patients underwent AVR and 57 were treated conservatively. NT-proBNP at baseline was raised in association with the degree of severity and of functional status. Results: During follow up 21 patients (13%) died of cardiac causes or required rehospitalisation for decompensated heart failure. NT-proBNP at baseline was higher in patients with an adverse outcome than in event-free survivors (median 623 (interquartile range 204–1854) pg/ml v 1054 (687–2960) pg/ml, p  =  0.028). This difference was even more obvious in conservatively treated patients (331 (129–881) pg/ml v 1102 (796–2960) pg/ml, p  =  0.002). Baseline NT-proBNP independently predicted an adverse outcome in the entire study group and in particular in conservatively treated patients (area under the curve (AUC)  =  0.65, p  =  0.028 and AUC  =  0.82, p  =  0.002, respectively) but not in patients undergoing AVR (AUC  =  0.544). At a cut-off value of 640 pg/ml, baseline NT-proBNP was discriminative for an adverse outcome. Conclusion: NT-proBNP concentration is related to severity of aortic stenosis and provides independent prognostic information for an adverse outcome. However, this predictive value is limited to conservatively treated patients. Thus, the data suggest that assessing NT-proBNP may have incremental value for selecting the optimal timing of valve replacement.

Impact of Volume Loading and Load Reduction on Ventricular Refractoriness and Conduction Properties in Canine Congestive Heart Failure

OBJECTIVES This investigations was undertaken to examine the alteration of electrophysiologic properties, including refractoriness, strength-interval relations and conduction, with the development of heart failure and to characterize the impact of volume loading on these indexes in the cardiomyopathic setting. METHODS Electrophysiologic properties in eight dogs with pacing-induced dilated cardiomyopathy were compared with those in six control dogs before and after rapid infusion of 800 ml of intravenous saline. RESULTS The right ventricular (RV) and left ventricular (LV) effective refractory period (ERP) and absolute refractory period (ARP) were significantly longer in dogs with pacing-induced cardiomyopathy than in control dogs: RV ERP 181 +/- 11 ms versus 138 +/- 7 ms (mean +/- SD) (p < 0.0001) and anterior LV ERP 177 +/- 13 ms versus 128 +/- 11 ms (p < 0.0001), respectively; ARP 159 +/- 14 ms versus 114 +/- 7 ms (p < 0.0001) at the RV site and 153 +/- 12 versus 117 +/- 5 ms (p < 0.0001) at the anterior LV site. After volume loading in cardiomyopathic animals, posterior and anterior LV ERPs became prolonged to 178 +/- 5 ms (p = 0.004) and 189 +/- 14 ms (p = 0.065), respectively, shifting the strength-interval relation in the direction of longer S1S2 coupling intervals. Anterior LV monophasic action potential durations at 90% repolarization also became prolonged from 192 +/- 10 ms to 222 +/- 23 ms (p < 0.012) with volume loading. These findings were not altered by subsequent sodium nitroprusside. Local conduction times parallel and perpendicular to fiber orientation were not altered by development of cardiomyopathy or volume alterations. CONCLUSIONS The development of dilated cardiomyopathy results in significant prolongation of refractoriness and repolarization that is increased further by volume augmentation but is not reversed by pharmacologic load reduction. Although these abnormalities may contribute to the environment needed for a non-reentrant, triggered or stretch-mediated arrhythmogenic process in cardiomyopathic states, additional studies will be required to demonstrate such a focal mechanism conclusively.

Bradycardia-Induced Polymorphic Ventricular Tachycardia After Atrioventricular Junction Ablation for Sinus Tachycardia-Induced Cardiomyopathy

Bradycardia‐Induced Polymorphic VT. In a patient with severe left ventricular dysfunction resulting from chronic nonparoxysmal sinus tachycardia, rate control and improvement in left ventricular function were achieved with atrioventricular junction ablation and ventricular pacemaker implantation. Within 12 hours after the ablation procedure, several episodes of polymorphic ventricular tachycardia that may have been triggered by the abruptly decreased heart rate occurred. Recurrence of polymorphic ventricular tachycardia was prevented by an increase in pacing rate.

Neutral Endopeptidase Regulates C-Type Natriuretic Peptide Metabolism But Does Not Potentiate Its Bioactivity In Vivo

C-type natriuretic peptide (CNP) is a newly described 22-amino acid peptide of endothelial and renal cell origin with selective cardiovascular actions. Recent in vitro studies have reported that CNP is the most susceptible of all natriuretic peptides to enzymatic degradation by neutral endopeptidase 24.11 (NEP). The present study was undertaken to define the role of NEP in total and regional CNP metabolism and the modulatory actions of NEP inhibition on the biological actions of CNP. CNP (10 ng x kg(-1) x min(-1)) followed by candoxatrilat (240 microg x kg(-1) bolus and 8 microg x kg(-1) x min(-1)), a potent and selective NEP inhibitor, was administered intravenously to a group of anesthetized mongrel dogs (group 1) to permit calculation of total metabolic clearance rate (MCR); results were compared with those in a group receiving vehicle infusion followed by candoxatrilat (group 2; both groups, n=7). NEP inhibition increased circulating CNP achieved by exogenous infusion and reduced total MCR in group 1. The regional CNP MCRs increased after CNP administration. While the pulmonary MCR did not change during concomitant candoxatrilat infusion, renal MCR was suppressed. Hemodynamic changes were not different between groups. A mild natriuretic and diuretic effect in association with an increase in circulating and urinary ANP levels was not different between groups. Urinary CNP excretion did not change with CNP infusion but markedly increased after NEP inhibition. We conclude that (1) circulating CNP achieved by exogenous CNP infusion is regulated by NEP in vivo, (2) regional MCRs are heterogeneous with NEP inhibition, (3) NEP inhibition does not potentiate acute cardiovascular actions of CNP, and (4) a mild natriuretic and diuretic effect observed with CNP and NEP inhibition may be ANP dependent.

Intraoperative characterization of interventricular mechanical dyssynchrony using electroanatomic mapping system—a feasibility study

BackgroundInterventricular mechanical dyssynchrony (VVMD) is a strong predictor of cardiac resynchronization therapy (CRT) response. However, no simple and reliable clinical method of measuring VVMD during CRT implant is currently available. We tested the hypothesis that the EnSite™ NavX™ system (St. Jude Medical, St. Paul, MN, USA) can be used intraoperatively to determine VVMD, thereby facilitating CRT optimization.MethodsDuring CRT implant, the leads in the right atrium (RA), right ventricle (RV), and left ventricle (LV) were connected to the EnSite™ NavX™ system to record the real-time 3D motion of the lead electrodes. The distances from RA to RV lead electrodes (RA–RV) and RA to LV lead electrodes (RA–LV) were computed over ten cardiac cycles during each of RV pacing and biventricular (BiV) pacing, respectively. The degree of synchrony was computed from the distance waveforms between RA–RV and RA–LV by a cross-covariance method to characterize VVMD. Septal-to-posterior wall motion delay (SPWMD) from M-mode echocardiography (echo) was measured for reference at each pacing intervention. VVMD was present in all five patients undergoing CRT implant.ResultsFour of the five patients demonstrated clear improvement in EnSite™ NavX™-derived VVMD during BiV versus RV pacing, which corresponded to the SPWMD results by echo.ConclusionsIt is feasible to characterize VVMD and resynchronization in CRT patients with the EnSite™ NavX™ system during implant, demonstrating its potential as a tool for intraoperative CRT optimization.

Cardiac angiosarcoma: case report and review of the literature.

Das Angiosarkom ist der häufigste primäre maligne Tumor des Herzens im Erwachsenenalter mit einer schlechten Prognose. Die Krankheitszeichen sind meist unspezifisch, so dass die Diagnose oft mit Verzögerung erfolgt. Die Symptome werden durch Größe und Lage des Tumors bestimmt. Die Echokardiographie ist aufgrund der Präzision, fehlenden Invasivität und Kosteneffektivität die primäre Untersuchungsmethode. Eine verbesserte Überlebensrate wird nur durch eine vollständige chirurgische Resektion erreicht. Der natürliche Krankheitsverlauf wird durch eine postoperative Chemotherapie nicht verändert. Im nachfolgenden Fallbeispiel wird ein großes Angiosarkom mit Infiltration der rechten Vorhof- und Ventrikelwand beschrieben und ein kritischer Überblick über die aktuelle Literatur geboten. Angiosarcoma of the heart, the most common primary malignant cardiac tumor in adults is known to carry a dismal prognosis. The diagnosis is often delayed because of the nonspecific clinical presentation. Symptoms are determined by the size and location of the tumor. Echocardiography has become the primary diagnostic technique because of its high degree of accuracy, noninvasiveness, and cost effectiveness. Complete surgical resection is required for improved survival. Conventional postoperative chemotherapy does not appear to modify the clinical course. We report a case of cardiac angiosarcoma with a large mural mass infiltrating the right atrial and ventricular walls and critically review the pertinent literature.

Intracardiac Extension of a Lung Tumor Causing Left Ventricular Inflow Obstruction

A patient with the diagnosis of small cell lung cancer had syncopal episodes. The tumor was found to invade the right upper pulmonary vein with extension into the left atrium. The mass was protruding across the mitral valve producing ball-valve blockade. In this report the echocardiographic signs of a primary lung tumor with intraatrial extension causing left ventricular inflow tract obstruction are described.