Heat Shock Protein 70 Is Associated With Cardioversion Outcome and Recurrence of Symptomatic Recent Onset Atrial Fibrillation in Hypertensive Patients.

ABSTRACT: Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating serum HSP70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (the duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, serum interleukin-2 (sIL-2), and serum interleukin-4 (sIL-4) with the presence of cardioversion and AF recurrence within a year was investigated. Toll-like receptor 4 (TLR4) signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared with controls. Serum HSP70 was independently associated with ROAF (P = 0.005) and correlated with sIL-2 (r = 0.494, P < 0.001) and sIL-4 (r = -0.550, P < 0.001). By 48 hours, 71 of the 90 patients were cardioverted, with noncardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38 of the 71 cardioverted patients in 1 year. A cutoff value of sHSP70 ≥0.65 ng/mL and sIL-2 ≥0.21 pg/mL was the only independent factor associated with AF recurrence (hazard ratio: 3.311, 95% confidence interval: 1.503-7.293, P = 0.003 and hazard ratio: 3.144, 95% confidence interval: 1.341-7.374, P = 0.008, respectively). The exposure of smooth muscle cell to HSP70 in vitro increased the expression of IL-2 (5×) and IL-4 (1.5×) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF.

Antiapoptotic Effect of ß1 Blockers in Ascending Thoracic Aortic Smooth Muscle Cells: The Role of HSP70 Expression.

Heat shock proteins (HSPs) play an important role in the cellular adaptation to stress, a requisite for cell survival. The aortic wall appears to be a target for increased expression of HSPs during surgical stress. We aimed to define the expression and function of aortic HSP70 in 31 patients with normal ascending thoracic aortic diameter who underwent aortic valve replacement due to aortic valve stenosis and in 35 patients with dilated ascending thoracic aorta who underwent replacement of an ascending thoracic aortic aneurysm. To elucidate responsible signaling mechanisms we used an in vitro model of rat hypoxic aortic vascular smooth muscle cell (AVSMC) cultures. We demonstrated an increase in AVSMC HSP70 and an attenuation of the apoptotic markers (TUNEL-positive nuclei, caspase-3 activity, Bax/Bcl2 ratio) in aortic wall tissue specimens from both aortic valve stenosis and ascending thoracic aortic aneurysm patients on ß1 blockade with metoprolol. In vitro, metoprolol treatment of hypoxic rat AVSMCs increased nitric oxide (NO) production, induced heat shock factor 1 transport to the nucleus, upregulated HSP70, decreased p53 phosphorylation and attenuated apoptosis. Blockade of NO production, resulted in decreased HSP70 and prevented the metoprolol-induced anti-apoptotic response of hypoxic AVSMCs. We demonstrate an anti-apoptotic effect of metoprolol dependent on NO-induced HSP70 expression, and thus augmentation of HSP70 expression should be considered as a therapeutic approach to limit apoptosis in the human ascending thoracic aorta of patients undergoing cardiac surgery.

Circadian pattern of symptoms onset in patients ≤35 years presenting with ST-segment elevation acute myocardial infarction.

BACKGROUND: There are scarce data regarding the circadian pattern of symptoms onset in young patients presenting with acute myocardial infarction (AMI). We explored whether young patients with ST-segment elevation AMI exhibit a circadian variation in symptoms onset. METHODS: We recruited prospectively 256 consecutive patients who had survived their first ST-segment elevation AMI ≤35 years of age. Patients were categorized into 4 groups by 6-h intervals over 24 h. RESULTS: In 49 patients (19.1%) the clinical presentation of AMI was atypical. The symptoms onset was as follows: 00:01 to 06:00, 19.1%, 06:01 to 12:00, 32.4%; 12:01 to 18:00, 28.1%; and 18:01 to 24:00, 20.3%. There was a significant association between the time of day and the likelihood of symptoms onset (Rayleigh test, p<0.001). Between 00:01 and 06:00 the incidence of AMI onset was lower than expected and between 06:01 and 12:00 was higher (p=0.034 and p=0.011, respectively), whereas in the other 6-h period groups no difference was found between expected and observed AMI incidence (p=0.280 and p=0.131). No significant differences were found regarding clinical characteristics, i.e. traditional risk factors, reperfusion treatment of AMI, ejection fraction of left ventricle, time interval from pain onset to hospital arrival, dietary habits and physical activity, among the 6-h period groups. CONCLUSIONS: ST-segment elevation AMI in individuals ≤35 years of age follows a circadian pattern with a morning peak. This information might be useful for the prompt diagnosis and treatment of AMI in very young patients which occurs rarely and frequently with atypical clinical presentation.

The impact of smoking on long-term outcome of patients with premature (≤35years) ST-segment elevation acute myocardial infarction.

BACKGROUND: There are few data regarding the long-term prognosis of young survivors of acute myocardial infarction (AMI). We explored the long-term outcome in individuals who had sustained a premature ST-segment elevation AMI. METHODS: We recruited 257 consecutive patients who had survived their first AMI ≤35years of age. Patients were followed up for up to 18years. Clinical end points included all major adverse coronary events (MACE): cardiac death, readmission for acute coronary syndrome, arrhythmias, or coronary revascularization due to clinical deterioration. RESULTS: The most prevalent risk factor at presentation was smoking (93.7%). Follow-up data were obtained from 237 patients (32.2±3.7years old). The median follow-up period was 9.1years. During follow-up, 139 (58.6%) patients reported continuation of smoking. Ninety-one (38.4%) patients had recurrent MACE (13 deaths, 59 acute coronary syndromes, 2 arrhythmias, and 17 revascularizations). Multivariable Cox regression analysis showed that persistence of smoking, left ventricular ejection fraction (LVEF), and reperfusion therapy (fibrinolysis or primary coronary angioplasty) were independent predictors of MACE after adjustment for conventional risk factors. Continuation of smoking remained an independent predictor for MACE after additional adjustments for LVEF (hazard ratio 2.154, 95% CI 1.313-3.535, P=.002) or reperfusion treatment (hazard ratio 2.327, 95% CI 1.423-3.804, P=.001). Harrell c statistic showed that the model with persistent smoking had the best discriminatory power compared with models with LVEF or reperfusion treatment. CONCLUSIONS: In the era of statins and reperfusion treatment, continuation of smoking is the strongest independent long-term predictor for recurrent MACE in young survivors of premature AMI.

Churg-Strauss syndrome masquerading as an acute coronary syndrome.

Churg-Strauss Syndrome (CSS) is a rare vasculitis with multiorgan involvement. Cardiac manifestations are common causing serious complications. We report a case of CSS masquerading as a non-ST elevation myocardial infarction with heart failure. CSS should be considered in the differential diagnosis of an acute coronary syndrome(ACS)with normal coronary arteries when history of asthma, peripheral eosinophilia and multisystemic involvement is present.

Coronary artery ectasia and inflammatory cytokines: link with a predominant Th-2 immune response?

OBJECTIVE: The role of inflammation in coronary artery ectasia (CAE) remains controversial. We evaluated the hypothesis that CAE might be associated with a specific pattern of T helper (Th) lymphocyte activation by measuring the Th-1 cytokine, interleukin-2 (IL-2) and the Th-2 cytokines, interleukin-4 (IL-4) and interleukin-6 (IL-6) in patients with CAE, obstructive coronary artery disease (CAD) and controls. METHODS: Serum levels of IL-2, IL-4 and IL-6 were measured in 74 patients undergoing an elective cardiac catheterization due to angina pectoris and positive or equivocal non-invasive screening for cardiac ischaemia: 34 had CAE and non-obstructive CAD (Group A), 22 had obstructive CAD (Group B) and 18 had normal coronaries (Group C). RESULTS: Group A had significantly higher IL-4 than Group B and Group C (p<0.001 and p=0.006, respectively). In contrast, Group A had markedly lower IL-2 than Group B and Group C (p<0.001 for both comparisons). Group C had higher IL-4 and lower IL-2 than Group B (p<0.001 for both comparisons). Interleukin-6 was significantly higher in Groups A and B compared to Group C (p<0.001 for both comparisons), whilst it was comparable between Group A and Group B. Multivariate logistic regression analysis showed that higher levels of IL-4 and lower levels of IL-2 were the strongest independent predictors associated with CAE (OR: 3.846, CI: 1.677-8.822, p=0.001 and OR: 0.567, CI: 0.387-0.831, p=0.004, respectively). CONCLUSIONS: Our data demonstrates that Th-2 immune response, exhibited through increased IL-4 and low IL-2, constitutes a fundamental feature of CAE.

Novel association patterns of cardiac remodeling markers in patients with essential hypertension and atrial fibrillation.

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are essential for the cardiac extracellular matrix (ECM) remodeling. We investigated differences in serum levels of these markers between patients with atrial fibrillation (AF) and sinus rhythm (SR). METHODS: Serum levels of MMP-2, MMP-3, MMP-9 and TIMP-1 were measured in 86 patients: 27 on SR without any AF history, 33 with paroxysmal and 26 with permanent AF. All subjects had essential hypertension, normal systolic function and no coronary artery disease. RESULTS: Patients with AF had higher MMP-2, MMP-3 and MMP-9 and lower TIMP-1 compared to SR subjects (all p < 0.001). Paroxysmal AF was associated with higher MMP-2 levels compared to permanent AF (p < 0.001). Matrix metalloproteinase-9 but not MMP-3 was higher in permanent compared to paroxysmal AF group (p < 0.001). Patients with AF had lower levels of TIMP-1 compared to those with SR while permanent AF subjects had lower TIMP-1 levels than those with paroxysmal AF (p < 0.001 for both comparisons). Lower TIMP-1 was the only independent factor associated with AF (OR: 0.259, 95%CI: 0.104-0.645, p = 0.004). CONCLUSIONS: In hypertensives, paroxysmal AF and permanent AF differ with respect to serum MMPs. Increased MMP-2 is associated with paroxysmal, whereas increased MMP-9 with permanent AF. Additionally, lower levels of TIMP-1 had a strong association with AF incidence.

Interleukin-2 serum levels variations in recent onset atrial fibrillation are related with cardioversion outcome.

We evaluated the hypothesis that a relationship exists between inflammation and the outcome of pharmaceutical cardioversion with amiodarone in recent onset atrial fibrillation. We studied 86 patients with symptomatic recent onset AF and coexisting hypertension and/or chronic stable coronary artery disease. All study participants underwent evaluation with a standardized protocol including echocardiography, cytokine level measurement [interleukin-2 (IL-2), interleukin-6 (IL-6) and high sensitivity C reactive protein (hsCRP)] on admission and at 48h, and administration of intravenous amiodarone. By 48h, 70 patients cardioverted to sinus rhythm. Median serum IL-2 levels on admission were higher in non-cardioverted compared to cardioverted patients (P=0.002). At 48h, non-cardioverted had significantly higher IL-6 (P=0.005) and hsCRP values (P=0.001) compared to cardioverted. Multivariate logistic regression analysis showed that lower IL-2 admission levels were a powerful independent predictor for successful cardioversion (OR: 0.154, 95% CI: 0.043-0.552, P=0.004). In patients with hypertension and/or chronic stable coronary artery disease and symptomatic recent onset AF, low serum IL-2 levels on admission are associated with successful cardioversion with amiodarone. This observation highlights the role of inflammation in AF and might have further prognostic and therapeutic implications.