Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling.

BACKGROUND: Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (IKs), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of Iks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome. METHODS AND RESULTS: LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo telemetry demonstrated steepening of the QT/RR slope in LQT1 with TICM (LQT1-TICM; pre: 0.26±0.04, post: 0.52±0.01, P<0.05). In vivo electrophysiology showed that LQT1-TICM had higher incidence of VF than LMC-TICM (6 of 11 vs. 3 of 11, respectively). Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05). LQT1-TICM developed spatially discordant alternans (DA), which caused conduction block and higher-frequency VF (15±1 Hz in LQT1-TICM vs. 13±1 Hz in LMC-TICM, p<0.05). Ca2+ DA was highly dynamic and preceded voltage DA in LQT1-TICM. Ryanodine abolished DA in 5 out of 8 LQT1-TICM rabbits, demonstrating the importance of Ca2+ in complex DA formation. Computer simulations suggested that HF remodeling caused Ca2+-driven alternans, which was further potentiated in LQT1-TICM due to the lack of IKs. CONCLUSIONS: Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+. Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.

Initial risk assessment for pulmonary hypertension in patients with COPD.

BACKGROUND: Pulmonary hypertension (PH) is a comorbidity associated with increased mortality in chronic obstructive pulmonary disease (COPD) patients. It is not known which clinical markers are predictive of PH in COPD. The goal of this study was to develop a clinical tool to identify patients who should be sent for initial screening with echocardiography. METHODS: Of 127 patients screened, 94 primary-care patients with COPD were enrolled. All underwent full pulmonary function testing, 6-minute walk distance (6MWD), exercise oximetry, Saint George's Respiratory Questionnaire, and transthoracic echocardiography. Eighty-six patients had measurable pulmonary artery pressures (PAP) on echocardiography. Elevated PAP was defined as a systolic PAP > 35 mmHg. RESULTS: Pre- and post-bronchodilator FEV(1) (P = 0.04 and P = 0.03, respectively), exercise oxyhemoglobin desaturation (P = 0.003), and 6MWD (P = 0.004) were associated with elevated PAP on univariate analysis. Diffusion capacity was lower but did not reach statistical significance (P = 0.07). In multivariate analysis, statistically significant independent variables were >3% decrease in exercise oxyhemoglobin saturation and decline in prebronchodilator FEV(1) (P = 0.01 and P = 0.04, respectively). A composite prediction model was developed that assigned one point for each of the following: age > 55 years, oxyhemoglobin desaturation > 3%, prebronchodilator FEV(1) < 50% predicted, and 6MWD < 1175 ft. Prevalence rates of elevated PAP were 32% for a score of 0-1 (low risk), 68% for a score of 2 (moderate risk), and 78% for a score of 3-4 (high risk). The composite score exhibited a strong trend with elevated PAP prevalence (Cochrane-Armitage trend statistic P = 0.001). CONCLUSION: A simple prediction tool using routine office-based parameters can be used to identify COPD patients at high risk for elevated PAP and initiate the first step in screening for PH with echocardiography. It is important that right heart catheterization be performed to confirm the diagnosis and guide treatment decisions.