Immunosuppression decreases inflammation and increases AAV6-hSERCA2a-mediated SERCA2a expression.

The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and normal canine models to study safety, efficacy, and the effects of immunosuppression. Tachycardic-paced dogs received left ventricle (LV) wall injection of AAV6-hSERCA2a or solvent. Pacing continued postinjection for 2 or 6 weeks, until euthanasia. Tissue/serum samples were analyzed for hSERCA2a expression (Western blot) and immune responses (histology and AAV6-neutralizing antibodies). Nonpaced dogs received AAV6-hSERCA2a and were analyzed at 12 weeks; a parallel cohort received AAV-hSERCA2a and immunosuppression. AAV-mediated cardiac expression of hSERCA2a peaked at 2 weeks and then declined (to ~50%; p<0.03, 6 vs. 2 weeks). LV end diastolic and end systolic diameters decreased in 6-week dogs treated with AAV6-hSERCA2a (p<0.05) whereas LV diameters increased in control dogs. Dogs receiving AAV6-hSERCA2a developed neutralizing antibodies (titer ≥1:120) and cardiac cellular infiltration. Immunosuppression dramatically reduced immune responses (reduced inflammation and neutralizing antibody titers <1:20), and maintained hSERCA2a expression. Thus cardiac injection of AAV6-hSERCA2a promotes local hSERCA2a expression and improves cardiac function. However, the hSERCA2a protein level is reduced by host immune responses. Immunosuppression alleviates immune responses and sustains transgene expression, and may be an important adjuvant for clinical gene therapy trials.

Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion.

Erythropoietin (Epo) has anti-apoptotic and pro-angiogenic effects in rodent models of myocardial infarction (MI). We tested the hypothesis that a long-acting Epo derivative (darbepoetin) has a beneficial effect on infarct size and peri-infarct remodeling in a clinically relevant large animal model of ischemia-reperfusion. A human acute MI scenario was simulated in 16 domestic pigs by inflating an angioplasty balloon in the proximal left circumflex (LCx) artery for 60 min. The animals were randomized to darbepoetin 30 microg/kg i.v. or placebo (saline) at the time of reperfusion. Treatment with darbepoetin did not lead to a reduction in the infarct size at 2 weeks as assessed by histology (30.3+/-1.8% of the volume at risk for placebo vs. 33.2+/-2.5% for darbepoetin). However, significant effects were seen in the peri-infarct region. Histological evaluation revealed decreased interstitial fibrosis (6.8+/-0.7% of myocardial sections area vs. 9.6+/-0.7%, p=0.02) and increased average capillary area (106+/-3% of the non-infarcted myocardium vs. 89+/-4%, p=0.003) in the treatment arm in the absence of significant cardiac hypertrophy. This resulted in preserved regional wall motion as assessed by tissue Doppler-derived radial strain (subepicardial radial strain 90.1+/-21.2% for darbepoetin vs. 20.3+/-10.1% for placebo, p<0.05). However, this did not translate to improved wall thickening (126.5+/-6.0% of diastolic thickness for darbepoetin vs. 119.8+/-5.4% for placebo, p=NS). Beneficial effects of darbepoetin to peri-infarct remodeling were observed in a clinically relevant model of ischemia-reperfusion. Although the infarct size was not reduced, there was a limited decrease in interstitial fibrosis, increased capillary area and regional functional improvement in darbepoetin-treated animals.

Feasibility study of the use of the TandemHeart percutaneous ventricular assist device for treatment of cardiogenic shock.

BACKGROUND: The mortality of cardiogenic shock (CGS) remains high despite currently available pharmacological and mechanical treatment options. The standard of care in medically refractory situations has been the insertion of an intra-aortic balloon pump. The purpose of this study was to investigate the feasibility, safety, and hemodynamic impact of the TandemHeart percutaneous left ventricular assist device (pVAD) in CGS. METHODS: Thirteen patients from five centers in the US with the diagnosis of CGS were enrolled in the study. Hemodynamic measurements, including cardiac index (CI), mean arterial pressure (MAP), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) were performed presupport, during support and after device removal. Patients were monitored for 6 months. RESULTS: The pVAD was successfully implanted in all 13 patients, with duration of support averaging 60 +/- 44 hr. During support, CI increased from 2.09 +/- 0.64 at baseline to 2.53 +/- 0.65 (P = 0.02), MAP increased from 70.6 +/- 11.1 to 81.7 +/- 14.6 (P = 0.01), PCWP decreased from 27.2 +/- 12.2 to 16.5 +/- 4.8 (P = 0.01), and CVP from 12.9 +/- 3.7 to 12.6 +/- 3.6 (P = NS). Ten patients survived to device explant, 6 of whom were bridged to another therapy. Seven patients survived to hospital discharge and were all alive at 6 months. The two most common adverse events were distal leg ischemia (n = 3) and bleeding from the cannulation site (n = 4). CONCLUSION: The TandemHeart PTVA System may be a useful complementary treatment for patients with CGS, especially as a bridge to another treatment. Further study is needed to definitively establish safety and efficacy.

Atypical echocardiographic findings of endocarditis in an immunocompromised patient.

Cardiovascular manifestations in patients infected with human immunodeficiency virus (HIV) have been altered by the introduction of highly active antiretroviral therapy regimens that allow more effective prophylactic treatment and an increased time of survival. Because of this, noninfectious cardiac conditions associated with HIV disease are being recognized with increasing frequency in these patients. Cardiac involvement in HIV-infected patients varies from clinically silent to overtly symptomatic disease. By some estimates a direct cardiac cause of mortality is between 1% and 6% of all cases. Pericardial effusion, pericarditis, myocarditis, cardiomyopathy, endocarditis, and pulmonary hypertension are well-recognized cardiac illnesses associated with HIV infection. Echocardiography has been crucial in evaluating HIV-infected patients to assess the extent of cardiac involvement. This case report illustrates atypical echocardiographic manifestations of endocarditis and paravalvular abscess in an immunocompromised patient.

Intermittent noninfarction Q waves: a finding suggestive of latent preexcitation.

OBJECTIVE: To describe 3 patients who presented with chest pain and intermittent Q waves on the electrocardiogram (ECG) and were subsequently found to have latent preexcitation. PATIENTS AND METHODS: During a span of 8 years, 3 patients were evaluated because of atypical chest pain and pathologic Q waves in the inferior leads; in all 3 patients, the Q waves were intermittent. No patient had a history of arrhythmia or had Wolff-Parkinson-White pattern on the ECG. Diagnostic and therapeutic interventions for suspected myocardial infarction included cardiac catheterization in 2 patients, intravenous thrombolytic therapy in 1 patient, and heparin in 2 patients. Ischemic heart disease was excluded in all. Patients underwent pharmacological testing and/or electrophysiologic study for suspected preexcitation. RESULTS: Despite the absence of ECG markers of preexcitation, the presence of a latent accessory atrioventricular connection was confirmed in each patient by pharmacological or electrophysiologic studies. CONCLUSION: In patients who present with intermittent noninfarction Q waves, the most likely diagnosis is latent preexcitation. Clinicians need to be educated about this clinical diagnosis and encouraged to pursue confirmatory testing. Such patients should be informed about the nature and importance of their electrocardiographic abnormality.