Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels.

Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K(Ca)3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K(Ca)3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K(Ca)3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K(Ca)3.1 functions potently inhibited fibroblast proliferation by G(0)/G(1) arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K(Ca)3.1 in affected kidneys. Mice lacking K(Ca)3.1 (K(Ca)3.1(-/-)) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and alphaSMA(+) cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K(Ca)3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K(Ca)3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K(Ca)3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

Characterization of left ventricular activation in patients with heart failure and left bundle-branch block.

BACKGROUND: Conventional activation mapping in the dilated human left ventricle (LV) with left bundle-branch block (LBBB) morphology is incomplete given the limited number of recording sites that may be collected in a reasonable time and given the lack of precision in marking specific anatomic locations. METHODS AND RESULTS: We studied LV activation sequences in 24 patients with heart failure and LBBB QRS morphology with simultaneous application of 3D contact and noncontact mapping during intrinsic rhythm and asynchronous pacing. Approximately one third of the patients with typical LBBB QRS morphology had normal transseptal activation time and a slightly prolonged or near-normal LV endocardial activation time. A "U-shaped" activation wave front was present in 23 patients because of a line of block that was located anteriorly (n=12), laterally (n=8), and inferiorly (n=3). Patients with a lateral line of block had significantly shorter QRS (P<0.003) and transseptal durations (P<0.001) and a longer distance from the LV breakthrough site to line of block (P<0.03). Functional behavior of the line of block was demonstrated by a change in its location during asynchronous ventricular pacing at different sites and cycle lengths. CONCLUSIONS: A U-shaped conduction pattern is imposed on the LV activation sequence by a transmural functional line of block located between the LV septum and the lateral wall with a prolonged activation time. Assessment of functional block is facilitated by noncontact mapping, which may be useful for identifying and targeting specific locations that are optimal for successful cardiac resynchronization therapy.

Cardiac resynchronization therapy.

Despite advances in medical therapy for patients with congestive heart failure, morbidity and mortality remain high. Conventional atrioventricular pacing with a short atrioventricular delay was first introduced as a nonpharmacologic treatment for patients with severe heart failure. Further development of this new therapeutic approach led to biventricular pacing, also known as cardiac resynchronization therapy. Many studies have been published and many are still ongoing. This review summarizes the results reported in randomized trials and focuses on questions that have not yet been answered.

Exercise performance following cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay.

Patients with heart failure (HF) frequently have an impaired heart rate response to exercise and reduced oxygen consumption (VO(2)). Cardiac resynchronization therapy (CRT) has been shown to increase functional capacity in patients with HF and conduction delay. However, detailed analysis of improvement in functional capacity after CRT is still lacking. This study aimed to provide a detailed analysis of the changes in metabolic, ventilation parameters, and heart rate profiles in patients with HF and ventricular conduction delay following implantation with resynchronization devices. We provided a retrospective review on 50 patients in New York Heart Association functional class >II, with left ventricular ejection fraction <35%, on optimal medical therapy, and whose functional capacity was evaluated by cardiopulmonary exercise testing before and after CRT. Detailed analysis of VO(2), carbon dioxide production (VCO(2)), heart rate, minute ventilation (V(E) [liters per minute]), tidal volume (V(T)), respiratory rate, and heart rate profile during exercise were performed. Following CRT, peak VO(2) increased significantly from 14 +/- 4 to 17 +/- 4 (p <0.0001), and VO(2) at anaerobic threshold increased from 9 +/- 2 to 12 +/- 3 (p <0.001). All ventilation and metabolic parameters significantly increased following CRT. Similarly, heart rate at rest significantly decreased after CRT (76 +/- 12 vs 72 +/- 12 beats/min, p <0.05), whereas the maximum achieved heart rate increased significantly from 119 +/- 20 to 125 +/- 24 beats/min (p <0.05). The proportion of patients with chronotropic incompetence was significantly reduced after CRT (50% before CRT vs 34.7 after CRT; p <0.05). Patients with the baseline peak VO(2) <14 ml/kg/min benefited most from the implantation of a CRT device. In conclusion, CRT significantly improves all ventilation and metabolic parameters of patients with HF and conduction delay. Patients with more depressed metabolic and ventilation parameters and higher heart rate at baseline seem to benefit most from this therapeutic approach.

Effect of cardiac resynchronization therapy on ventricular remodeling.

Cardiac resynchronization therapy (CRT) is a new non-pharmacological option for patients with advanced heart failure and ventricular conduction delay. Four randomized prospective studies have provided evidence that CRT increases exercise capacity, improves functional class and quality of life. There is also increasing evidence that CRT may trigger an inverse remodeling process leading to reduction of ventricular diameter and eventually of the atrial size. The pathophysiological mechanism throughout CRT may promote inverse remodeling is: (1) reduction of systolic and diastolic mitral regurgitation; (2) reduction of sympathetic/parasympathetic imbalance as well as reduction of neurohumoral activation due to increased systolic blood pressure and improved filling time; (3) reduction of regional wall stress. The structural changes taking place during CRT are directly related to continuous pacing, because lack of pacing immediately shows the new onset of remodeling. The duration of the reported changes of ventricular diameter is still unknown, and it is also unknown whether such reverse remodeling process of the ventricle and of the atria will lead to a reduction of cardiac death and incidence of ventricular arrhythmias.