Citations

Background— β-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Methods and Results— Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol ( r =−0.72, P <0.0001) and was the most significant multivariate predictor of change in LVEF ( P =0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687±333 versus 420±246 pg/mL, P <0.05) and greater decrease in plasma norepinephrine in response to bucindolol (−249±171 versus −35±277 pg/mL, P <0.05). Conclusions— This study suggests a direct relationship between contractile reserve and improvement in LVEF with β-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Background— Traditionally, increased pericardial thickness has been considered an essential diagnostic feature of constrictive pericarditis. Although constriction with a normal-thickness pericardium has been demonstrated clinically by noninvasive imaging, the details of clinicopathological correlates have not been described. Methods and Results— A total of 143 patients with proven constriction underwent pericardiectomy at Mayo Clinic between 1993 and 1999. Their baseline characteristics, operative data, and pathological specimens were reviewed retrospectively. The pericardium was of normal thickness (≤2 mm) in 26 patients (18%; group 1) and was thickened (>2 mm) in 117 (82%; group 2). The most common causes of constriction in group 1 included previous cardiac surgery, chest irradiation, previous infarction, and idiopathic disease. There was little difference in symptoms and findings on physical examination between the 2 groups. Microscopically, no patient had an entirely normal pericardium. Histopathological abnormalities in group 1 were mild and focal, including fibrosis, inflammation, calcification, fibrin deposition, and focal noncaseating granulomas. Pericardiectomy was equally effective in relieving symptoms regardless of the presence or absence of increased thickness. Conclusions— Pericardial thickness was not increased in 18% of patients with surgically proven constrictive pericarditis, although the histopathological appearance was focally abnormal in all cases. When clinical, echocardiographic, or invasive hemodynamic features indicate constriction in patients with heart failure, pericardiectomy should not be denied on the basis of normal thickness as demonstrated by noninvasive imaging.

Background— After acute myocardial infarction (AMI), diastolic function assessed by Doppler echocardiography provides important prognostic information that is incremental to systolic function. However, Doppler variables are affected by multiple factors and may change rapidly. In contrast, left atrial (LA) volume is less influenced by acute changes and reflects subacute or chronic diastolic function. This may be of importance when one assesses risk in patients with AMI. Methods and Results— Three hundred fourteen patients with AMI who had a transthoracic echocardiogram with assessment of left ventricular (LV) systolic and diastolic function and measurement of LA volume during admission were identified. The LA volume was corrected for body surface area, and the population was divided according to LA volume index of 32 mL/m 2 (2 SDs above normal). LA volume index was >32 mL/m 2 in 142 (45%). The primary study end point was all-cause mortality. During follow-up of 15 (range 0 to 33) months, 46 patients (15%) died. LA volume index was a powerful predictor of mortality and remained an independent predictor (hazard ratio 1.05 per 1-mL/m 2 change, 95% CI 1.03 to 1.06, P <0.001) after adjustment for clinical factors, LV systolic function, and Doppler-derived parameters of diastolic function. Conclusions— Increased LA volume index is a powerful predictor of mortality after AMI and provides prognostic information incremental to clinical data and conventional measures of LV systolic and diastolic function.

Abstract We tested the hypothesis that cells of ventilator-injured lungs are subject to reversible plasma membrane stress failure. Rat lungs were perfused with the membrane impermeable fluorescent marker propidium iodide and randomized to one of four ventilation strategies. Subpleural lung regions were imaged with confocal microscopy, and cell injury was quantified as the number of propidium iodide–positive cells per alveolus. The number of injured cells was significantly greater in lungs ventilated with large tidal volumes and zero end-expiratory pressure than in lungs ventilated with small tidal volumes and positive end-expiratory pressure (p &lt; 0.01). Cell injury correlated with lung weight gain, change in dynamic compliance, and histologic injury scores. In a second set of experiments, lungs were mechanically ventilated for 30 minutes at high tidal volume settings, whereas propidium iodide was perfused either during or after injurious ventilation. Labeling after removal of injurious stress revealed significantly fewer injured cells (0.25 ± 0.09 to 0.08 ± 0.08, p &lt; 0.01). We conclude that cells of ventilator-injured lungs are subject to reversible plasma membrane stress failure.

ABSTRACTOn viral infection, infected cells can become the target of host immune responses or can go through a programmed cell death process, called apoptosis, as a defense mechanism to limit the ability of the virus to replicate. To prevent this, viruses have evolved elaborate mechanisms to subvert the apoptotic process. Here, we report the identification of a novel antiapoptotic K7 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) which expresses during lytic replication. The KSHV K7 gene encodes a small mitochondrial membrane protein, and its expression efficiently inhibits apoptosis induced by a variety of apoptogenic agents. The yeast two-hybrid screen has demonstrated that K7 targets cellular calcium-modulating cyclophilin ligand (CAML), a protein that regulates the intracellular Ca2+concentration. Similar to CAML, K7 expression significantly enhances the kinetics and amplitudes of the increase in intracellular Ca2+concentration on apoptotic stimulus. Mutational analysis showed that K7 interaction with CAML is required for its function in the inhibition of apoptosis. This indicates that K7 targets cellular CAML to increase the cytosolic Ca2+response, which consequently protects cells from mitochondrial damage and apoptosis. This is a novel viral antiapoptosis strategy where the KSHV mitochondrial K7 protein targets a cellular Ca2+-modulating protein to confer resistance to apoptosis, which allows completion of the viral lytic replication and, eventually, maintenance of persistent infection in infected host.

Background— Chronobiological rhythms have been shown to influence the occurrence of a variety of cardiovascular disorders. However, the effects of the time of the day, the day of the week, or monthly/seasonal changes on acute aortic dissection (AAD) have not been well studied. Methods and Results— Accordingly, we evaluated 957 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2000 (mean age 62±14 years, type A 61%). A χ 2 test for goodness of fit and partial Fourier analysis were used to evaluate nonuniformity and rhythmicity of AAD during circadian, weekly, and monthly periods. A significantly higher frequency of AAD occurred from 6:00 am to 12:00 noon compared with other time periods (12:00 noon to 6:00 pm , 6:00 pm to 12:00 midnight, and 12:00 midnight to 6:00 am ; P <0.001 by χ 2 test). Fourier analysis showed a highly significant circadian variation ( P <0.001) with a peak between 8:00 am and 9:00 am . Although no significant variation was found for the day of the week, the frequency of AAD was significantly higher during winter ( P =0.008 versus other seasons by χ 2 test). Fourier analysis confirmed this monthly variation with a peak in January ( P <0.001). Subgroup analysis identified a significant association for all subgroups with circadian rhythmicity. However, seasonal/monthly variations were observed only among patients aged <70 years, those with type B AAD, and those without hypertension or diabetes. Conclusions— Similar to other cardiovascular conditions, AAD exhibits significant circadian and seasonal/monthly variations. Our findings may have important implications for the prevention of AAD by tailoring treatment strategies to ensure maximal benefits during the vulnerable periods.