Abstract-In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying 125 I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT 1 and AT 2 on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT 1 density on failing myocytes did not differ from that of NF myocytes, with preserved AT 1 /AT 2 ratio. Conversely, AT 1 density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT 1 density does not change on failing myocytes, and (3)

The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy.

Abstract-A downward titration of antihypertensive drug regimens in summertime is often performed on the basis of seasonal variations of clinic blood pressure (BP). However, little is known about the actual interaction between outdoor air temperature and the effects of antihypertensive treatment on ambulatory BP. Key Words: blood pressure monitoring, ambulatory Ⅲ hypertension Ⅲ aging S everal studies have reported that blood pressure (BP) values obtained both in the clinic and in ambulatory conditions are lower in hot than in cold months, which is also the case in a general population. 1 In summer, a reduction in cardiovascular mortality has also been observed, 2,3 with a reduction in the occurrence of stroke in hypertensive patients. 4,5 These findings might support the practice of downward titration of antihypertensive drug regimens, especially in the elderly. However, this clinical practice is not embodied in any of the guidelines. 6,7 Moreover, there is limited information regarding the effects of changes in daily mean outdoor air temperature (Ta) on ambulatory BP (ABP) in the elderly, in particular, in aged hypertensive subjects. Finally, no information is available on whether a clinic BP-guided reduction in the dosage of antihypertensive drug, in the case of hot weather, might be responsible for a reduced coverage of BP over 24 hours. The need to clarify these issues is underlined by the observation that older hypertensive patients do not show the same reduction in morbidity and mortality during hot months as younger subjects do. 3 The aim of the present study was, therefore, to more deeply investigate the climate-related changes in clinic and ABP and heart rate in subjects referred to our institutions for BP assessment during a 4-year period. This was done with special attention to the possible interaction between outdoor temperature-related BP changes, aging, and prescription of antihypertensive treatment. Methods

BackgroundSystemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap‐junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine‐mediated changes in connexin expression.Methods and ResultsFifty‐four patients with different inflammatory diseases and elevated C‐reactive protein were prospectively enrolled, and electrocardiographic P‐wave dispersion indices, cytokine levels (interleukin‐6, tumor necrosis factor‐α, interleukin‐1, interleukin‐10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C‐reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin‐6 on connexin expression were studied in HL‐1 mouse atrial myocytes. In patients with active inflammatory diseases, P‐wave dispersion indices were increased but rapidly decreased within days when C‐reactive protein normalizes and interleukin‐6 levels decline. In inflammatory disease patients, both P‐wave dispersion indices and interleukin‐6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin‐6 significantly reduced connexin expression in HL‐1 cells.ConclusionsOur data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin‐6 elevation, rapidly induces atrial electrical remodeling by down‐regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.