Optimization of left ventricular pacing site plus multipoint pacing improves remodeling and clinical response to cardiac resynchronization therapy at 1 year

n/

Multipoint pacing by a left ventricular quadripolar lead improves the acute hemodynamic response to CRT compared with conventional biventricular pacing at any site

n/

Determination of the Longest Intrapatient Left Ventricular Electrical Delay May Predict Acute Hemodynamic Improvement in Patients After Cardiac Resynchronization Therapy

Background One of the reasons for patient nonresponse to cardiac resynchronization therapy is a suboptimal left ventricular (LV) pacing site. LV electric delay (Q-LV interval) has been indicated as a prognostic parameter of cardiac resynchronization therapy response. This study evaluates the LV delay for the optimization of the LV pacing site. Methods and Results Thirty-two consecutive patients (23 men; mean age, 7111 years; LV ejection fraction, 30 +/- 6%; 18 with ischemic cardiomyopathy; QRS, 181 +/- 25 ms; all mean +/- SD) underwent cardiac resynchronization therapy device implantation. All available tributary veins of the coronary sinus were tested, and the Q-LV interval was measured at each pacing site. The hemodynamic effects of pacing at different sites were evaluated by invasive measurement of LV dP/dt(max) at baseline and during pacing. Overall, 2.9 +/- 0.8 different veins and 6.4 +/- 2.3 pacing sites were tested. In 31 of 32 (96.8%) patients, the highest LV dP/dt(max) coincided with the maximum Q-LV interval. Q-LV interval correlated with the increase in LV dP/dt(max) in all patients at each site (AR1 =0.98; P95 ms corresponded to a >10% in LV dP/dt(max). An inverse correlation between paced QRS duration and improvement in LV dP/dt(max) was seen in 24 patients (75%). Conclusions Pacing the LV at the latest activated site is highly predictive of the maximum increase in contractility, expressed as LV dP/dt(max). A positive correlation between Q-LV interval and hemodynamic improvement was found in all patients at every pacing site, a value of 95 ms corresponding to an increase in LV dP/dt(max) of 10%

Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/ mTOR signaling

PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways