Marc Pritzker

Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices

OBJECTIVE Pulsatile and nonpulsatile left ventricular assist devices are effective in managing congestive heart failure. Despite early evidence for clinical efficacy, the long-term impact of nonpulsatile flow on end-organ function remains to be determined. Our goal was to compare rates of gastrointestinal bleeding in nonpulsatile and pulsatile device recipients. METHODS In a retrospective review of 101 left ventricular assist device recipients (55 nonpulsatile, 46 pulsatile) from October 31, 2003, to June 1, 2007, at a single center, gastrointestinal bleeding was defined as guaiac-positive stool with hemoglobin drop requiring transfusion of at least 2 units of packed red blood cells. To assess bleeding risk outside the initial postoperative course, any patients with a device in place for 15 days or less was excluded. RESULTS Twelve nonpulsatile and 3 pulsatile left ventricular assist device recipients had gastrointestinal bleeding 16 days or longer after device implantation. The event rates were 63 events/100 patient-years for nonpulsatile devices and 6.8 events/100 patient-years for pulsatile devices (P = .0004). This difference persisted for bleeding occurring 31 days or longer after device implantation, with 46.5 events/100 patient-years for nonpulsatile devices versus 4.7 events/100 patient-years for pulsatile devices (P = .0028). Mortalities were similar between groups (15% nonpulsatile vs 17% pulsatile, P = .6965). CONCLUSION Patients with nonpulsatile left ventricular assist devices appear to have a higher rate of gastrointestinal bleeding events than do pulsatile left ventricular assist device recipients. Further prospective evaluation is needed to determine potential etiologies and strategies for reducing gastrointestinal bleeding in this population.

Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart

Background— Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. Methods and Results— Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)–induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased ≈4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3′-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. Conclusions— Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.

Prevention of recurrent sudden cardiac arrest: role of provocative electropharmacologic testing

This study evaluates the usefulness of serial provocative electropharmacologic testing for predicting the efficacy of prophylactic antiarrhythmic treatment regimens in patients resuscitated from sudden cardiac arrest in the absence of acute myocardial infarction. Testing was carried out in 34 consecutive patients (28 men and 6 women) who required cardiopulmonary resuscitation and direct current countershock for treatment of primary ventricular fibrillation (28 patients), ventricular tachycardia (5 patients) or excessively rapid heart rate during atrial fibrillation with preexcitation (1 patient). In 8 (24%) of the 34 patients, drug testing either was not feasible because of absence of inducible arrhythmia or was incomplete because of patient withdrawal from study; and 3 of these 8 patients had recurrent sudden cardiac arrest within 10 to 19 months. In an additional five patients, treatment regimens failed to prevent initiation of sustained ventricular tachyarrhythmias in the catheterization laboratory, and two of these five patients had cardiac arrest recurrences within 2 weeks to 25 months of follow-up. In the remaining 21 (62%) of the 34 patients, including 3 patients with preexcitation syndrome, a drug regimen or surgical treatment, or both, was found that prevented inducible life-threatening tachyarrhythmias in the laboratory. Subsequently, only 1 (5%) of these 21 patients died suddenly within a 7 to 38 month (mean +/- standard deviation, 18 +/- 8.3) follow-up period. Thus, provocative electropharmacologic testing appears to be useful in predicting response to therapy in survivors of sudden cardiac arrest.

Effects of the HeartMate II continuous-flow left ventricular assist device on right ventricular function

BACKGROUND Continuous-flow devices have become the standard of care for mechanical circulatory support for end-stage heart failure patients because of improved survival and durability. The effects of these devices, such as the HeartMate II (HMII) left ventricular assist device (LVAD), on right ventricular (RV) function have not been evaluated in detail. This study evaluated the incidence of RV failure, alterations in RV function, severity of tricuspid regurgitation (TR), and cardiac hemodynamics after HMII implantation. METHODS Echocardiograms (n = 22) and right heart catheterizations (n = 40) were performed before and after 4 to 6 months of HMII support in 40 bridge-to-transplant patients. Right heart failure was defined as the requirement for inotropes and/or nitric oxide requirement after LVAD implantation for >14 days or the need for right-sided mechanical circulatory support. RESULTS Overall, RV failure after HMII implantation occurred in 2 of 40 patients (5%). Significant improvements occurred in cardiac index, with reductions in right atrial pressure, RV stroke work index, tricuspid annular motion, mean pulmonary artery pressure, and pulmonary vascular resistance after HMII support. There was a trend towards reduction in TR after LVAD support (p = 0.075). CONCLUSIONS The incidence of RV failure after support with continuous-flow devices such as the HMII is low. The favorable effects of the HMII on cardiac hemodynamics result in improved RV function, improved right- and left-sided hemodynamic profiles, and a reduction in TR severity. These findings may have important implications for LVAD patients needing longer-term support.

Electrophysiologic effects of theophylline in young patients with recurrent symptomatic bradyarrhythmias.

In this study, both acute electrophysiologic actions of intravenously administered theophylline and clinical effects of chronic oral theophylline therapy were assessed in 10 young patients (aged 9 to 41 years) without clinically significant cardiac disease, in whom recurrent symptoms of syncope and dizziness were attributed to transient bradyarrhythmias (sinus pauses, marked sinus bradycardia or paroxysmal atrioventricular [AV] block). Intravenous theophylline infusion (serum concentration range 9.5 to 12.0 mg/liter) shortened means sinus cycle length (control 973 +/- 285 ms versus theophylline 880 +/- 226 ms, p less than 0.005) and decreased both the estimated sinoatrial conduction time (control 169 +/- 56.0 ms versus theophylline 143 +/- 55.3 ms, p less than 0.05) and the maximum corrected sinus node recovery time (control 442 +/- 251.0 ms versus theophylline 255 +/- 146.2 ms, p less than 0.05). In addition, theophylline infusion shortened the minimum atrial paced cycle length with sustained 1:1 AV conduction (control 414 +/- 86 ms versus theophylline 379 +/- 97 ms, p less than 0.05) and consistently reduced AV node functional refractory periods. Subsequent chronic oral theophylline therapy (serum levels 9 to 12 mg/liter) was tolerated in 8 patients (80%). During a follow-up of 5 to 24 months, suppression of symptoms was achieved in 6 of the 8 patients. Thus, theophylline exhibits positive chronotropic and dromotropic effects in man at serum concentrations in the usual therapeutic range (10 to 15 mg/liter). Furthermore, suppression of symptoms during follow-up suggests that theophylline treatment may be a useful therapeutic consideration in some patients with recurrent symptomatic bradyarrhythmias.

Transesophageal Study of Infant Supraventricular Tachycardia: Electrophysiologic Characteristics

Programmed electrical stimulation of the heart to initiate and terminate tachycardia and analysis of the temporal relation between ventricular and atrial activation during tachycardia have been useful in the evaluation of supraventricular tachycardia (SVT). Such techniques have rarely been applied to evaluate infants with SVT. We used a silicone rubber-coated bipolar electrode catheter (15 or 22 mm interelectrode spacing), positioned in the esophagus, for electrical stimulation of the heart and recording of electrograms for the evaluation of 14 infants aged 1 to 84 days with SVT. Three infants had electrocardiographic features of Wolff-Parkinson-White syndrome, and no infant had other manifestations of congenital heart disease. Tachycardia cycle lengths ranged from 180 to 295 ms and ventriculoatrial intervals recorded from the esophagus were 80 to 220 ms. In 12 infants, transesophageal atrial stimulation was used to terminate and initiate SVT using stimuli of 9.9 ms and 10 to 20 mA. Initiation and termination of SVT by electrical stimulation suggest that SVT in infants is due to reentry, and the presence of ventriculoatrial intervals greater than 70 ms further suggests that accessory atrioventricular connections (usually concealed) constitute a portion of the reentry circuit.

Cardiac arrest in young, ostensibly healthy patients: Clinical, hemodynamic, and electrophysiologic findings

This study examines the clinical, hemodynamic, and electrophysiologic findings in a unique group of 11 young (aged 15 months to 29 years) survivors of a cardiac arrest. All patients were previously in good health, and cardiac arrest was the initial manifestation of cardiac disease in all. Overt clinical and hemodynamic abnormalities were not as common as previously reported, and in some instances apparent cardiac abnormalities failed to provide a link to cardiac arrest. No patient had congenital heart disease or hypertrophic cardiomyopathy. However, during multicatheter electrophysiologic study, sustained tachyarrhythmia was reproducibly initiated in 8 of 11 patients (73%). Young, ostensibly healthy patients who survive cardiac arrest form a diverse group. Diligent programmed intracardiac electrical stimulation may demonstrate life-threatening tachycardias in these patients. Treatment to prevent recurrence of cardiac arrest is difficult in this group of patients. However, the ability to initiate tachycardia in the electrophysiologic laboratory may be useful in the management of these patients.

Safety and Efficacy of Epoprostenol in Patients with Severe Congestive Heart Failure

Patients with advanced heart failure often remain severely symptomatic and have a high mortality rate despite currently available therapy. We studied the safety and efficacy of a new approach to the patient with refractory heart failure: continuous intravenous treatment via a portable infusion pump with epoprostenol (prostacyclin), a potent pulmonary and systemic vasodilator. A group of 33 patients with severe heart failure (64% New York Heart Association class IV and 36% class III) and profound ventricular dysfunction (median left ventricular ejection fraction, 0.15)--despite prior treatment with diuretics (100%), digitalis (91%), angiotensin-converting enzyme inhibitors (85%), and dobutamine (30%)--underwent a baseline 6-minute walk test prior to dose titration with epoprostenol during invasive hemodynamic monitoring. Subjects responding during the dose titration were randomized, on an open basis, to receive either continuous epoprostenol infusion via an indwelling central venous catheter plus conventional therapy or conventional therapy alone for 12 weeks. The initial dose-ranging study with epoprostenol produced a significant decline in systemic and pulmonary vascular resistance and a substantial increase in cardiac index despite a fall in pulmonary capillary wedge pressure. Symptoms related to vasodilation were noted within the first week after randomization to epoprostenol in 9 of 16 patients but resolved with adjustment of the infusion and concomitant medications in all but one subject. Dose adjustments during the chronic epoprostenol infusion were infrequent after the first week and complications related to the drug delivery system were rare. The change in distance walked from baseline to the last available 6-minute walk test was significantly greater in patients who received epoprostenol compared with patients assigned to standard therapy (72 +/- 40 vs -39 +/- 32 m, mean +/- SEM; p = 0.033). Our study suggests that long-term intravenous infusion of epoprostenol is feasible in patients with severe heart failure and our hemodynamic and functional results suggest clinical benefit as well. However, until recent results indicating an adverse effect of epoprostenol on survival are fully evaluated, the role of this drug in the treatment of advanced heart failure will remain uncertain.

Intravenous amiodarone for the rapid treatment of life-threatening ventricular arrhythmias in critically ill patients with coronary artery disease

This study examined the effectiveness of intravenous amiodarone for rapid control and prevention of recurrent life-threatening ventricular tachyarrhythmias associated with cardiovascular collapse. In 22 critically ill patients with coronary artery disease (mean ejection fraction 27 +/- 13%), recurrent ventricular tachyarrhythmias proved refractory to 3.7 +/- 1.1 (mean +/- standard deviation) conventional antiarrhythmic drugs. In the 24-hour period before intravenous amiodarone treatment, patients experienced 2.4 +/- 2.3 (range 1 to 9) episodes of life-threatening ventricular tachycardia, ventricular fibrillation or both, requiring 4.0 +/- 3.9 direct current cardioversions. Within the 24 hours after initiation of intravenous amiodarone therapy (900 to 1,600 mg/day), 20 of 22 patients remained alive and had 1.1 +/- 1.6 episodes of life-threatening ventricular arrhythmias, requiring 1.9 +/- 3.1 direct current cardioversions. In the second 24-hour period, there were 19 survivors and life-threatening arrhythmias were reduced to 0.4 +/- 0.7 episode/patient requiring 0.4 +/- 0.9 direct current cardioversion. Overall, arrhythmias were controlled in 11 of 22 (50%) patients within the first 24 hours, and in 14 of 22 (64%) in the second 24 hours. Intravenous amiodarone therapy was well tolerated. Twelve patients were discharged from the hospital and 8 remained alive at a mean follow-up of 22 +/- 14 months. Thus, in critically ill patients, intravenous amiodarone may be useful for rapid control of spontaneous, refractory, life-threatening ventricular tachyarrhythmias.

Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction.

Veno-occlusive disease is among the most serious complications following hematopoietic stem cell transplantation. While hepatic veno-occlusive disease occurs more commonly, the pulmonary variant remains quite rare and often goes unrecognized antemortem. Endothelial damage may represent the pathophysiologic foundation of these clinical syndromes. Recent advances in the treatment of hepatic veno-occlusive disease may have application to its pulmonary counterpart.