Sumário 1. Definição, Epidemiologia e Prevenção Primária 528 1.1 Definição de Hipertensão Arterial 528 […] Diretrizes Brasileiras de Hipertensão Arterial – 2020 Sumário 1. Definição, Epidemiologia e Prevenção Primária 528 1.1 Definição de Hipertensão Arterial 528 […] Diretrizes Brasileiras de Hipertensão Arterial – 2020

Previously we reported that the rapid activation of the Fak/Src multicomponent signaling complex mediates load-induced activation of growth and survival signaling pathways in adult rat heart. In this study, we report that 5% to 20% (10-minute) cyclic stretch (1 Hz) of neonatal rat ventricular myocytes (NRVMs) was paralleled by increases of Fak phosphorylation at Tyr-397 (from 1.5- to 2.8-fold), as detected by anti-Fak-pY ³⁹⁷ phosphospecific antibody. Moreover, 15% cyclic stretch lasting from 10 to 120 minutes increased Fak phosphorylation at Tyr-397 by 2.5- to 3.5-fold. This activation was accompanied by a dramatic change in Fak localization in NRVMs from densely concentrated in the perinuclear regions in nonstretched cells to aggregates regularly distributed along the myofilaments in stretched cells. Furthermore, a 4-hour cyclic stretch enhanced the activity of an atrial natriuretic factor (ANF) promoter-luciferase reporter gene by 2.7-fold. Disrupting endogenous Fak/Src signaling either by expression of a dominant-negative Fak mutant with phenylalanine substituted for Tyr-397 or by treatment with a c-Src pharmacological inhibitor (PP-2) markedly attenuated stretch-induced Fak activation and clustering at myofilaments and inhibited stretch-induced ANF gene activation. On the other hand, overexpression of wild-type Fak potentiated the stretch-induced Fak phosphorylation but did not enhance either baseline or stretch-induced ANF promoter-luciferase reporter gene activity compared with the responses of nontransfected NRVMs. These findings identify Fak as an important element in the early responses induced by stretch in cardiac myocytes, indicating that it may coordinate the cellular signaling machinery that controls gene expression program associated with load-induced cardiac myocyte hypertrophy.

Background: This study aimed to compare the independent and incremental prognostic value of peak oxygen consumption ( VO ₂ ) and minute ventilation/carbon dioxide production ( VE / VCO ₂ ) in heart failure ( HF ) with preserved ( HF p EF ), midrange ( HF m EF ), and reduced ( HF r EF ) ejection fraction ( LVEF ). Methods and Results: In 195 HF p EF ( LVEF ≥50%), 144 HF m EF ( LVEF 40–49%), and 630 HF r EF ( LVEF <40%) patients, we assessed the association of cardiopulmonary exercise testing variables with the composite outcome of death, left ventricular assist device implantation, or heart transplantation (256 events; median follow‐up of 4.2 years), and 2‐year incident HF hospitalization (244 events). In multivariable Cox regression analysis, greater association with outcomes in HF p EF than HF r EF were noted with peak VO ₂ ( HR [95% confidence interval ]: 0.76 [0.67–0.87] versus 0.87 [0.83–0.90] for the composite outcome, P _interaction =0.052; 0.77 [0.69–0.86] versus 0.92 [0.88–0.95], respectively for HF hospitalization, P _interaction =0.003) and VE / VCO ₂ slope (1.11 [1.06–1.17] versus 1.04 [1.03–1.06], respectively for the composite outcome, P _interaction =0.012; 1.10 [1.05–1.15] versus 1.04 [1.03–1.06], respectively for HF hospitalization, P _interaction =0.019). In HF m EF , peak VO ₂ and VE / VCO ₂ slope were associated with the composite outcome (0.79 [0.70–0.90] and 1.12 [1.05–1.19], respectively), while only peak VO ₂ was related to HF hospitalization (0.81 [0.72–0.92]). In HF p EF and HF r EF , peak VO ₂ and VE / VCO ₂ slope provided incremental prognostic value beyond clinical variables based on the C‐statistic, net reclassification improvement, and integrated diagnostic improvement, with models containing both measures demonstrating the greatest incremental value. Conclusions: Both peak VO ₂ and VE / VCO ₂ slope provided incremental value beyond clinical characteristics and LVEF for predicting outcomes in HF p EF . Cardiopulmonary exercise testing variables provided greater risk discrimination in HF p EF than HF r EF .