Teresa DeMarco

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness

CONTEXT Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. OBJECTIVE To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. DESIGN, SETTING, AND PARTICIPANTS The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. MAIN OUTCOME MEASURES The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. RESULTS Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. CONCLUSIONS Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony

OBJECTIVE To measure ventricular contractile synchrony in patients with dilated cardiomyopathy (DCM) and to evaluate the effects of biventricular pacing on contractile synchrony and ejection fraction. BACKGROUND Dilated cardiomyopathy is characterized by abnormal ventricular activation and contraction. Biventricular pacing may promote a more coordinated ventricular contraction pattern in these patients. We hypothesized that biventricular pacing would improve synchrony of right ventricular and left ventricular (RV/LV) contraction, resulting in improved ventricular ejection fraction. METHODS Thirteen patients with DCM and intraventricular conduction delay underwent multiple gated equilibrium blood pool scintigraphy. Phase image analysis was applied to the scintigraphic data and mean phase angles computed for the RV and LV. Phase measures of interventricular (RV/LV) synchrony were computed in sinus rhythm and during atrial sensed biventricular pacing (BiV). RESULTS The degree of interventricular dyssynchrony present in normal sinus rhythm correlated with LV ejection fraction (r = -0.69, p < 0.01). During BiV, interventricular contractile synchrony improved overall from 27.5 +/- 23.1 degrees to 14.1 +/- 13 degrees (p = 0.01). The degree of interventricular dyssynchrony present in sinus rhythm correlated with the magnitude of improvement in synchrony during BiV (r = 0.83, p < 0.001). Left ventricular ejection fraction increased in all thirteen patients during BiV, from 17.2 +/- 7.9% to 22.5 +/- 8.3% (p < 0.0001) and correlated significantly with improvement in RV/LV synchrony during BiV (r = 0.86, p < 0.001). CONCLUSIONS Dilated cardiomyopathy with intraventricular conduction delay is associated with significant interventricular dyssynchrony. Improvements in interventricular synchrony during biventricular pacing correlate with acute improvements in LV ejection fraction.

Effects of Cardiac Resynchronization Therapy With or Without a Defibrillator on Survival and Hospitalizations in Patients With New York Heart Association Class IV Heart Failure

Background— Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial to assess the potential benefits of CRT and CRT-D. Methods and Results— The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical therapy, CRT, or CRT-D. In the class IV patients (n=217), the primary end point of time to death or hospitalization for any cause was significantly improved by both CRT (hazard ratio [HR], 0.64; 95% CI, 0.43 to 0.94; P=0.02) and CRT-D (HR, 0.62; 95% CI, 0.42 to 0.90; P=0.01). Time to all-cause death and HF hospitalization was also significantly improved in both CRT (HR, 0.57; 95% CI, 0.37 to 0.87; P=0.01) and CRT-D (HR, 0.49; 95% CI, 0.32 to 0.75; P=0.001) Time to all-cause death trended to an improvement in both CRT (HR, 0.67; 95% CI, 0.41 to 1.10; P=0.11) and CRT-D (HR, 0.63; 95% CI, 0.39 to 1.03; P=0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group (HR, 0.27; 95% CI, 0.08 to 0.90; P=0.03). There was a nonsignificant reduction in time to HF deaths for both CRT (HR, 0.68; 95% CI, 0.34 to 1.37; P=0.28) and CRT-D (HR, 0.79; 95% CI, 0.41 to 1.52; P=0.48). Conclusions— CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF patients similar to those enrolled in COMPANION.

Poor Correlation Between Pulmonary Arterial Wedge Pressure and Left Ventricular End-diastolic Volume after Coronary Artery Bypass Graft Surgery

The authors studied 12 surgical patients in the intensive care unit post coronary artery bypass graft surgery and ten nonsurgical patients in the coronary care unit with chronic heart failure to determine the usefulness of the pulmonary arterial wedge pressure as an indicator of left ventricular preload. Left ventricular end diastolic volume was derived from concomitant determination of ejection fraction (gated blood pool scintigraphy) and stroke volume (determined from thermodilution cardiac output). In the nonsurgical patients, there was a significant correlation between changes in pulmonary arterial wedge pressure and left ventricular end-diastolic volume (P < 0.05, r = 0.57). In the 12 patients studied during the first few hours after surgery, there was a poor correlation between changes in pulmonary wedge pressure (range = 4–32 mmHg) and left ventricular end-diastolic volume (range = 25–119 ml/m2), and a poor correlation between pulmonary arterial wedge pressures and stroke work index. In contrast, there was a good correlation between left ventricular end-diastolic volume and stroke work index. The poor correlation between the pulmonary arterial wedge pressure and left ventricular end-diastolic volume was not explained by changes in systemic or pulmonary vascular resistance. The altered ventricular pressure–volume relationship may reflect acute changes in ventricular compliance in the first few hours following coronary artery bypass graft surgery. While measurement of pulmonary arterial wedge pressure remains valuable in clinical management to avoid pulmonary edema, it cannot reliably be used as an index of left ventricular preload while attempting to optimize stroke volume in patients immediately following coronary artery bypass graft surgery.

Magnetic resonance-based assessment of global coronary flow and flow reserve and its relation to left ventricular functional parameters: a comparison with positron emission tomography.

BACKGROUND Measurement of coronary sinus blood flow (CSF) by phase-contrast magnetic resonance (PC-MR) imaging at rest and during hyperemia may allow noninvasive assessment of global coronary hemodynamics. METHODS AND RESULTS Sixteen healthy volunteers (age, 22 to 32 years) were examined with MR and PET in random order within 1 to 2 days. At rest and during hyperemia (dipyridamole 0.56 mg/kg), CSF was measured by a cine PC-MR technique (temporal resolution, 40 ms; spatial resolution, 1.25x0.8 mm(2)), and myocardial blood flow (MBF) was measured by [(13)N]NH(3) PET. PET and MR agreed closely for coronary flow reserve (CFR; mean difference, 2.2+/-14.7%; Bland-Altman method). CSF divided by either total left ventricular mass or an estimate of drained myocardium (LVM(drain)) correlated highly with PET flow data (r=0.93 and 0.95, respectively) and with measures of oxygen demand, ie, heart rate, afterload-corrected fiber shortening, and peak systolic stress determined by MR (overall correlation coefficients, 0.81 and 0.87, respectively, multivariate analysis). CSF/LVM(drain) did not differ significantly from PET-derived MBF (difference, 3.6+/-16.6%). In orthotopic heart transplant recipients (n=9), CFR was reduced and blood supply-demand relationships at rest were shifted toward higher flows (P<0.0001). CONCLUSIONS This integrated MR approach allows comprehensive assessment of autoregulated and hyperemic coronary flow and is suitable for serial measurements in patients. In transplanted hearts, elevated resting flow is the major cause of reduced CFR.

Cyclosporine impairs release of endothelium-derived relaxing factors in epicardial and resistance coronary arteries.

BackgroundCyclosporin A is reported to impair endothelium-mediated vasorelaxation and induce endothelin release in some noncoronary vascular beds. We wished to determine whether acute cyclosporine administration induces endothelial dysfunction in coronary conductance or resistance arteries. Methods and ResultsWe examined the effect of intracoronary acetylcholine, N omega-nitro-L-arginine methyl ester (L- NAME), L-arginine, nitroglycerin, and adenosine before and after acute cyclosporine administration (3 mg/kg IV over 30 minutes) in anesthetized dogs. Flow velocity was measured with a 0.014-in Doppler wire to assess resistance vessel responses, and epicardial coronary lumen area was simultaneously measured with a 4.3F, 30-MHz imaging catheter inserted over the Doppler wire. In 6 dogs, acetylcholine-induced increase in flow velocity was attenuated by cyclosporine in vehicle (137% to 55% at 10−5 mol/L, P < .001), as was acetylcholine- induced epicardial vasodilation (14.1% to 6.7% at 10−5 mol/L, P < .001). Vasodilation in response to intracoronary nitroglycerin (200 μg) and adenosine (6 mg) were unchanged by cyclosporine. Epicardial vasoconstriction with L-NAME (10−4 mol/L) was reduced by cyclosporine (Pre, 7.4 ± 0.9%; Post, 2.6 ± 1.2%; P = .04), but L- arginine (10−4 mol/L) had no effect after cyclosporine. In another 5 dogs, pure cyclosporine impaired acetylcholine-induced vasodilatation to the same degree as cyclosporine in vehicle (Cremophor); vehicle infusion did not impair endothelial function. In 5 more dogs, cyclosporine did not increase either arterial or coronary sinus concentrations of endothelin-1. ConclusionsThe present study shows that cyclosporine acutely impairs release of endothelium-derived relaxing factor in canine conductance and resistance coronary arteries and provides evidence for decreased epicardial nitric oxide release after cyclosporine. The potential contribution of acute cyclosporine- induced coronary endothelial dysfunction to posttransplant vasculopathy needs further study.

Coronary vasodilator effects of BNP: mechanisms of action in coronary conductance and resistance arteries

Brain natriuretic peptide (BNP), a hormone secreted predominantly in ventricular myocytes, may influence coronary vascular tone. We studied the coronary vasodilatory response to BNP under physiological conditions and after preconstriction with endothelin-1 (ET-1) in anesthetized pigs. Average peak-flow velocity (APV) was measured using intracoronary Doppler, and cross-sectional area (CSA) was measured using intravascular ultrasound. Coronary blood flow (CBF) was calculated. Intracoronary BNP induced dose-dependent increases in CSA, APV, and CBF similar in magnitude to those induced by nitroglycerin (NTG). The magnitude of BNP-induced vasodilation was accentuated after preconstriction with ET-1. Pretreatment with either the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester or the cyclooxygenase inhibitor indomethacin attenuated the coronary vasodilator effect of BNP in resistance arteries without influencing epicardial vasodilation. Pretreatment with the ATP-sensitive potassium-channel blocker glibenclamide enhanced epicardial vasodilation in response to BNP. We conclude that BNP exerts coronary vasodilator effects, predominantly in epicardial conductance vessels. An accentuated vasodilatory response to BNP occurs in ET-1-preconstricted arteries. BNP-induced vasodilation in coronary resistance arteries may be partially mediated via nitric oxide and/or prostaglandin release.Brain natriuretic peptide (BNP), a hormone secreted predominantly in ventricular myocytes, may influence coronary vascular tone. We studied the coronary vasodilatory response to BNP under physiological conditions and after preconstriction with endothelin-1 (ET-1) in anesthetized pigs. Average peak-flow velocity (APV) was measured using intracoronary Doppler, and cross-sectional area (CSA) was measured using intravascular ultrasound. Coronary blood flow (CBF) was calculated. Intracoronary BNP induced dose-dependent increases in CSA, APV, and CBF similar in magnitude to those induced by nitroglycerin (NTG). The magnitude of BNP-induced vasodilation was accentuated after preconstriction with ET-1. Pretreatment with either the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester or the cyclooxygenase inhibitor indomethacin attenuated the coronary vasodilator effect of BNP in resistance arteries without influencing epicardial vasodilation. Pretreatment with the ATP-sensitive potassium-channel blocker glibenclamide enhanced epicardial vasodilation in response to BNP. We conclude that BNP exerts coronary vasodilator effects, predominantly in epicardial conductance vessels. An accentuated vasodilatory response to BNP occurs in ET-1-preconstricted arteries. BNP-induced vasodilation in coronary resistance arteries may be partially mediated via nitric oxide and/or prostaglandin release.

The Alpha-1D Is the Predominant Alpha-1-Adrenergic Receptor Subtype in Human Epicardial Coronary Arteries

OBJECTIVES The goal was to identify alpha-1-adrenergic receptor (AR) subtypes in human coronary arteries. BACKGROUND The alpha1-ARs regulate human coronary blood flow. The alpha1-ARs exist as 3 molecular subtypes, alpha1A, alpha1B, and alpha1D, and the alpha1D subtype mediates coronary vasoconstriction in the mouse. However, the alpha1A is thought to be the only subtype in human coronary arteries. METHODS We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19 to 70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed alpha1- and beta-AR subtype messenger ribonucleic acid (mRNA) by quantitative real-time reverse transcription polymerase chain reaction and subtype proteins by radioligand binding and extracellular signal-regulated kinase (ERK) activation. RESULTS The alpha1D subtype was 85% of total coronary alpha1-AR mRNA and 75% of total alpha1-AR protein, and alpha1D stimulation activated ERK. In contrast, the alpha1D was low in LV myocardium. Total coronary alpha1-AR levels were one-third of beta-ARs, which were 99% the beta2 subtype. CONCLUSIONS The alpha1D subtype is predominant and functional in human epicardial coronary arteries, whereas the alpha1A and alpha1B are present at very low levels. This distribution is similar to the mouse, where myocardial alpha1A- and alpha1B-ARs mediate beneficial functional responses and coronary alpha1Ds mediate vasoconstriction. Thus, alpha1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective alpha1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial alpha1A- and/or alpha1B-AR signaling without causing coronary vasoconstriction.

Evaluation of acute dual-chamber pacing with a range of atrioventricular delays on cardiac performance in refractory heart failure.

OBJECTIVES This study evaluated how variations in atrioventricular (AV) delay affect hemodynamic function in patients with refractory heart failure being supported with intravenous inotropic and intravenous or oral inodilating agents. BACKGROUND Although preliminary data have suggested that dual-chamber pacing with short AV delays may improve cardiac function in patients with heart failure, detailed Doppler and invasive hemodynamic assessment of patients with refractory New York Heart Association class IV heart failure has not been performed. METHODS Nine patients with functional class IV clinical heart failure had Doppler assessment of transvalvular flow and right heart catheterization performed during pacing at AV delays of 200, 150, 100 and 50 to 75 ms. RESULTS Systemic arterial, pulmonary artery, right atrial and pulmonary capillary wedge pressures, cardiac index, systemic and pulmonary vascular resistances, stroke volume index, left ventricular stroke work index (SWI) and arteriovenous oxygen content difference demonstrated no significant changes during dual-chamber pacing with AV delays of 200 to 50 to 75 ms. There were also no changes in the Doppler echocardiographic indexes of systolic or diastolic ventricular function. The study was designed with SWI as the outcome variable. Assuming a clinically significant change in the SWI of 5 g/min per m2, a type I error of 0.05 and the observed standard deviation from our study, the observed power of our study is 85% (type II error of 15%). CONCLUSIONS Changes in AV delay between 200 and 50 ms during dual-chamber pacing do not significantly affect acute central hemodynamic data, including cardiac output and systolic or diastolic ventricular function in patients with severe refractory heart failure due to dilated cardiomyopathy.

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

RATIONALE Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.