Shaohua Wang

In Vivo Gene Transfer of the O2-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

Background—Alveolar hypoxia acutely elicits pulmonary vasoconstriction (HPV). Chronic hypoxia (CH), despite attenuating HPV, causes pulmonary hypertension (CH-PHT). HPV results, in part, from inhibition of O2-sensitive, voltage-gated potassium channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). CH decreases Kv channel current/expression and depolarizes and causes Ca2+ overload in PASMCs. We hypothesize that Kv gene transfer would normalize the pulmonary circulation (restore HPV and reduce CH-PHT), despite ongoing hypoxia. Methods and Results—Adult male Sprague-Dawley rats were exposed to normoxia or CH for 3 to 4 weeks and then nebulized orotracheally with saline or adenovirus (Ad5) carrying genes for the reporter, green fluorescent protein reporter±human Kv1.5 (cloned from normal PA). HPV was assessed in isolated lungs. Hemodynamics, including Fick and thermodilution cardiac output, were measured in vivo 3 and 14 days after gene therapy by use of micromanometer-tipped catheters. Transgene expression, measured by quantitative RT-PCR, was confined to the lung, persisted for 2 to 3 weeks, and did not alter endogenous Kv1.5 levels. Ad5-Kv1.5 caused no mortality or morbidity, except for sporadic, mild elevation of liver transaminases. Ad5-Kv1.5 restored the O2-sensitive K+ current of PASMCs, normalized HPV, and reduced pulmonary vascular resistance. Pulmonary vascular resistance decreased at day 2 because of increased cardiac output, and remained reduced at day 14, at which time there was concomitant regression of right ventricular hypertrophy and PA medial hypertrophy. Conclusions—Kv1.5 is an important O2-sensitive channel and potential therapeutic target in PHT. Kv1.5 gene therapy restores HPV and improves PHT. This is, to the best of our knowledge, the first example of K+ channel gene therapy for a vascular disease.

Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk for stroke, heart failure and cardiovascular‐related mortality. Candidate targets for anti‐AF drugs include a potassium channel Kv1.5, and the ionic currents IKACh and late INa, along with increased oxidative stress and activation of NFAT‐mediated gene transcription. As pharmacological management of AF is currently suboptimal, we have designed and characterized a multifunctional small molecule, compound 1 (C1), to target these ion channels and pathways.

Comparative study on tube-load modeling of arterial hemodynamics in humans.

In this paper, we assess the validity of two alternative tube-load models for describing the relationship between central aortic and peripheral arterial blood pressure (BP) waveforms in humans. In particular, a single-tube (1-TL) model and a serially connected two-tube (2-TL) model, both terminated with a Windkessel load, are considered as candidate representations of central aortic-peripheral arterial path. Using the central aortic, radial and femoral BP waveform data collected from eight human subjects undergoing coronary artery bypass graft with cardiopulmonary bypass procedure, the fidelity of the tube-load models was quantified and compared with each other. Both models could fit the central aortic-radial and central aortic-femoral BP waveform pairs effectively. Specifically, the models could estimate pulse travel time (PTT) accurately, and the model-derived frequency response was also close to the empirical transfer function estimate obtained directly from the central aortic and peripheral BP waveform data. However, 2-TL model was consistently superior to 1-TL model with statistical significance as far as the accuracy of the central aortic BP waveform was concerned. Indeed, the average waveform RMSE was 2.52 mmHg versus 3.24 mmHg for 2-TL and 1-TL models, respectively (p < 0.05); the r² value between measured and estimated central aortic BP waveforms was 0.96 and 0.93 for 2-TL and 1-TL models, respectively (p < 0.05). We concluded that the tube-load models considered in this paper are valid representations that can accurately reproduce central aortic-radial/femoral BP waveform relationships in humans, although the 2-TL model is preferred if an accurate central aortic BP waveform is highly desired.

Delayed cardiac tamponade after coronary artery laceration.

Delayed cardiac tamponade after laceration of a coronary artery is unusual and uncommonly reported in the literature. We describe a patient in whom this potentially fatal complication developed 8 days after a stab wound to his chest. In our review of the English language literature we identified only one other report of delayed tamponade after coronary artery laceration.

Modeling and System Identification of Arterial Hemodynamics in Humans

This paper seeks to determine the validity of two distinct tube-load models relating central aortic blood pressure to peripheral blood pressure in humans. Specifically a single-tube model (1-TL) and a serially connected two-tube (2-TL) model, both terminating in a Windkessel load, are considered as representations of the central aortic-peripheral arterial path. The validity and fidelity of the two models was assessed and compared quantitatively by fitting central aortic, radial and femoral blood pressures collected from 8 patients. Both models fitted the BP waveform pairs effectively, and were capable of estimating pulse travel time (PTT) accurately; also the model derived frequency responses were close to the empiric transfer function estimates derived from central and peripheral BP measurements. The 2-TL model was consistently better than 1-TL with statistical significance in terms of accuracy of the central aortic BP waveform, the average waveform RMSE were 2.52 mmHg versus 3.24 mmHg respectively (p<0.05).Copyright

Left Ventricular Epicardial Lead Implantation via Left Minithoracotomy

OBJECTIVE The transvenous placement of left ventricular epicardial leads is limited by long procedure times, high procedural failure rates and limited sites for lead placement. Open surgical approaches are used primarily after failure of the transvenous approach but provide additional important benefits. This study assesses the surgical outcomes of left anterior minithoracotomy for the implantation of left ventricular epicardial pacing leads in cardiac resynchronization therapy. METHODS Eleven patients were referred for open left ventricular epicardial lead placement. Mean patient age was 66.2 (59-77) years. The patients had New York Heart Association class III (II-IV) heart failure, a mean left ventricular ejection fraction of 18 +/- 5 % and mean QRS duration of 177 +/- 29 milliseconds. RESULTS Left ventricular epicardial leads were successfully placed in all patients. Mean surgery time was 101 +/- 33 minutes and intraoperative lead parameters were: R wave 14.5 +/- 9.8 millivolts, lead threshold 1.4 +/- 0.9 volts at 0.5 milliseconds, impedance 1127 +/- 693 ohms. Impedance was statistically different at 40 +/- 25 weeks with 571 +/- 199 ohms ( P = 0.033). CONCLUSIONS Left ventricular epicardial lead implantation via left anterior minithoracotomy is safe and effective.

North American trial results at 1 year with the Sorin Freedom SOLO pericardial aortic valve

OBJECTIVES A North American prospective, 15-centre Food and Drug Administration (FDA) valve trial was designed to assess the safety and effectiveness of the Freedom SOLO stentless pericardial aortic valve in the treatment of surgical aortic valve disease. METHODS Beginning in 2010, 251 patients (mean: 74.7 ± 7.5 years), were recruited in the Freedom SOLO aortic valve trial. One hundred eighty-nine patients have been followed for at least 1 year and are the basis for this review. Preoperatively, 54% of patients had NYHA functional class III or IV symptoms, and the majority of patients had a normal ejection fraction (EF) (median EF = 61%). Concomitant procedures were performed in 61.9% of patients, with coronary artery bypass grafting (CABG) (48.7%) being the most common followed by a MAZE procedure (13.7%). Reoperations were performed in 8.5% of patients in the study. RESULTS The entire cohort of 251 patients enrolled had 7 deaths prior to 30 days, 2 of which were valve-related (aspiration pneumonia and sudden death) and 5 were not valve-related. There were 11 deaths after 30 days, 1 valve-related (unknown cardiac death) and 10 not valve-related. Five valves were explanted, 3 early (endocarditis, acute insufficiency and possible root dissection) and 2 late (endocarditis). Thirty-day adverse events include arrhythmias requiring permanent pacemaker (4.2%), thromboembolic events (3.7%) and thrombocytopenia (7.4%). One-year follow-up of all 189 patients demonstrated mean gradients for valve sizes 19, 21, 23, 25 and 27 mm of 11.7, 7.8, 6.3, 4.6 and 5.0 mmHg, respectively. Effective orifice areas for the same valve sizes were 1.2, 1.3, 1.6, 1.8 and 1.9 cm(2), respectively. Ninety-six percent of patients (181/189) were in NYHA class I or II at the 1-year follow-up. CONCLUSIONS The Freedom SOLO stentless pericardial aortic valve demonstrated excellent haemodynamics and a good safety profile out to the 1 year of follow-up.

Gene transfer in human pulmonary arteries using adenoviral vectors: increasing expression and activity of potassium channels

At the onset of CHF, the mean shortening fraction was 15% 6.5(6.5-26%). Cardiac cath in 17 pts showed a low cardiac index (mean 2.1 0.65) and increased PVR (mean 5.3 2.2). Mean SF at Htx listing was 15%; however, there was progression of AV valve regurgitation. One pt died of multiorgan failure; 17 pts were transplanted (1987-2000). One, 2 and 5 yr survivals were 100, 92 and 60%. Two pts were lost to followup. One pt was re-transplanted for graft vasculopathy (GCAD). There were 7 deaths, 4.8 yrs (1.2-7.1) post Htx due to rejection(3), pulmonary embolus(1), GCAD(1), and other(2). PTLD did not occur in this cohort; however, 1 pt had cancer recurrence 15 months post Htx. Conclusions: Cardiomyopathy leading to Htx can occur over a wide range of cumulative anthracycline doses. The time course from chemotherapy to ACM is highly variable. Therefore, routine and long-term cardiovascular monitoring of cancer survivors appears indicated. Outcomes post-Htx are acceptable as only one patient in this series developed recurrent cancer.