Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure.

BACKGROUND: Delivering therapeutic materials, like stem cells or gene vectors, to the myocardium is difficult in the setting of ischemic heart failure because of decreased coronary flow and impaired microvascular perfusion (MP). The aim of this study was to determine if mechanical left ventricular (LV) unloading with the Impella increases coronary flow and MP in a subacute myocardial infarction. METHODS AND RESULTS: Anterior transmural myocardial infarction (infarct size, 26.0±3.4%) was induced in Yorkshire pigs. At 2 weeks after myocardial infarction, 6 animals underwent mechanical LV unloading by Impella, whereas 4 animals underwent pharmacological LV unloading using sodium nitroprusside for 2 hours. LV unloading with Impella significantly reduced end-diastolic volume (-16±11mL, P=0.02) and end-diastolic pressure (EDP; -32±23 mm Hg, P=0.03), resulting in a significant decrease in LV end-diastolic wall stress (EDWS) (infarct: 71.6±14.7 to 43.3±10.8 kdynes/cm2 [P=0.02]; remote: 66.6±20.9 to 40.6±13.3 kdynes/cm2 [P=0.02]). Coronary flow increased immediately and remained elevated after 2 hours in Impella-treated pigs. Compared with the baseline, MP measured by fluorescent microspheres significantly increased within the infarct zone (109±81%, P=0.003), but not in the remote zone. Although sodium nitroprusside effectively reduced LV-EDWS, 2 (50%) of sodium nitroprusside-treated pigs developed profound systemic hypotension. A significant correlation was observed between the infarct MP and EDWS (r2=0.43, P=0.03), suggesting an important role of EDWS in regulating MP during LV unloading in the infarcted myocardium. CONCLUSIONS: LV unloading using an Impella decreased EDWS and increased infarct MP without hemodynamic decompensation. Mechanical LV unloading is a novel and efficient approach to increase infarct MP in patients with subacute myocardial infarction.

Echocardiographic and hemodynamic assessment for predicting early clinical events in severe acute mitral regurgitation.

The diagnostic role of echocardiographic and hemodynamic assessment in acute mitral regurgitation (AMR) remains unclear. The central question of this study was to determine if echocardiographic and hemodynamic parameters can predict early clinical events in AMR. AMR was induced by percutaneously severing the mitral valve chordae tendineae in 39 Yorkshire pigs. Immediately after AMR induction, echocardiographic and hemodynamic exams were performed, and compared between those who died and those who survived within 30-days of the procedure. Echocardiographic indices of MR severity as well as the left atrial pressure showed significant differences between survivors and non-survivors in univariate analysis. Multi-variate logistic regression analysis revealed that echocardiography-derived regurgitant fraction and vena contracta as well as mean left atrial pressure could be used to segment the cohort into survivors and non-survivors. Our study demonstrated, for the first time, that echocardiographic and hemodynamic assessment of AMR provides predictive information on early clinical events in a clinically relevant animal model of AMR.

Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure.

BACKGROUND: Increased protein phosphatase-1 in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting protein phosphatase-1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. OBJECTIVES: This study sought to determine the therapeutic efficacy of a re-engineered adenoassociated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy. METHODS: Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation. One month after mitral regurgitation induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naive pigs received different doses of BNP116.I-1c for safety evaluation. RESULTS: At 1 month after mitral regurgitation induction, pigs developed HF as evidenced by increased left ventricular end-diastolic pressure and left ventricular volume indexes. Treatment with BNP116.I-1c resulted in improved left ventricular ejection fraction (-5.9 ± 4.2% vs. 5.5 ± 4.0%; p < 0.001) and adjusted dP/dt maximum (-3.39 ± 2.44 s-1 vs. 1.30 ± 2.39 s-1; p = 0.007). Moreover, BNP116.I-1c-treated pigs also exhibited a significant increase in left atrial ejection fraction at 2 months after gene delivery (-4.3 ± 3.1% vs. 7.5 ± 3.1%; p = 0.02). In vitro I-1c gene transfer in isolated left atrial myocytes from both pigs and rats increased calcium transient amplitude, consistent with its positive impact on left atrial contraction. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs. CONCLUSIONS: Intracoronary delivery of BNP116.I-1c was safe and improved contractility of the left ventricle and atrium in a large animal model of nonischemic HF.

Cardiac Gene Delivery in Large Animal Models: Antegrade Techniques.

Percutaneous antegrade coronary injection is among the least invasive cardiac selective gene delivery methods. However, transduction efficiency is quite low with a simple bolus antegrade injection. In order to improve the transduction efficiency using antegrade delivery, several additional approaches have been proposed.In this chapter, we briefly discuss important elements associated with intracoronary delivery methods and present protocols for three different catheter-based antegrade delivery techniques in a preclinical large animal model. Despite the lower transduction efficacy relative to more invasive delivery techniques, antegrade techniques have the advantage of being clinically well established and having safer profiles which is important when treating patients with cardiac disease.

Inhaled Gene Transfer for Pulmonary Circulation.

Chronic pulmonary hypertension (PH) is associated with right ventricular failure and high mortality regardless of the underlying disease. Currently, therapies can improve clinical outcomes in specific subsets of patients, but have little impact on the progression of pulmonary vascular remodeling. Upon new advances in vector development and delivery techniques, gene therapy is a novel strategy in this field with the potential of overcoming the main limitations of approved drug therapies: modulation of novel anti-remodeling targets and selective pulmonary vasculature targeting with minimal systemic effects. In the recent years, several reports have shown that gene transfer to the pulmonary vascular system is feasible in rodent models of PH. Our group has focused on the translation of airway delivery of viral vectors in small and large animals. Here, we describe a procedure to achieve vector transduction at the distal vasculature in animal models of PH and the methods to evaluate the outcomes of this intervention as a promising new approach in pulmonary vascular diseases.

Increased stiffness is the major early abnormality in a pig model of severe aortic stenosis and predisposes to congestive heart failure in the absence of systolic dysfunction.

BACKGROUND: It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis. METHODS AND RESULTS: Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure-volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end-diastolic pressure-volume relationship ß: 0.053±0.017 versus 0.028±0.009 mm Hg/mL, P=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end-systolic pressure-volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca(2+)) ATPase protein levels in the left ventricle were similar. There were significant increases in 3-dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end-diastolic pressure in pigs with aortic banding in contrast to decreased end-diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis. CONCLUSION: Increased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis.