Objectives Aims were to investigate 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; 3) expression of ST2, membrane-anchored ST2L, and its ligand, IL-33, in myocardium, endothelium and leukocytes from patients with LV pressure overload and congestive cardiomyopathy. Background Serum levels of ST2 are elevated in heart failure. Relationship of ST2 with hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown. Methods Serum ST2 (pg/mL; median [25th-75th]) was measured in patients with LV hypertrophy (aortic stenosis, AS, N=45), congestive cardiomyopathy (CCM N=53), and Controls (N=23). ST2 was correlated to NT-pro BNP, CRP and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. ST2, ST2L and IL-33 were measured (RT-PCR) in myocardial biopsies and leukocytes; ST2 protein production was evaluated in human endothelial cells. IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium Results ST2 was elevated in AS (103[65-165], p<0.05) and CCM (194[69-551], p<0.01) vs. Controls (49[4-89]) and correlated with BNP (r=0.5; p<0.05), CRP (r=0.6; p<0.01) and LV EDP (r=0.38, p<0.03). LV ST2 mRNA was similar in AS and CCM vs. Control (NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r=0.97, p<0.001). Conclusions In human hypertrohy and failure, serum ST2 correlates with diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial.

In HF patients with electromechanical cardiac dyssynchrony, functional improvement related to CRT is associated with favorable changes in established molecular markers of HF, including genes that regulate contractile function and pathologic hypertrophy.

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The MA of rs5065 ANP gene variant associates with increased susceptibility to ACS and has unfavorable prognostic value in CAD.

Background: b2-adrenergic receptor Thr164Ile (threonine (Thr) is replaced by an isoleucine (Ile) at codon 164) polymorphism was postulated to contribute to lower exercise tolerance and poor prognosis in patients with congestive heart failure. However, heart failure is associated with several abnormalities of b receptor signalling, and underlying mechanisms are not clear. Objectives: To investigate whether Thr164Ile polymorphism negatively modulates myocardial contractile performance and is associated with adverse long-term prognosis of patients with congestive heart failure. Methods: Among 55 subjects, cardiac contractile response to the b2-adrenergic receptor agonist terbutaline was assessed from the peak myocardial velocity of systolic shortening (Sm) in 18 subjects with the Ile-164 variant and 37 matched controls. In total, 24 subjects had normal left ventricular (LV) function and 31 presented with congestive heart failure due to idiopathic dilated cardiomyopathy. Results: In patients with normal LV function, peak terbutaline-induced increase (D) in Sm was lower in subjects with the Ile-164 variant than in controls (D33% (4%) vs D56% (4%), p,0.01). In patients with heart failure, subjects with Ile-164 showed further severe reduction of b2-adrenergic-mediated increase in Sm as compared with controls with heart failure (D20% (5%) vs D39% (4%), p,0.05). Patients with heart failure with Ile-164 showed a severely blunted force-frequency relationship in response to agonist stimulation. At 2-years of follow-up, patients with heart failure with the Ile-164 variant showed higher incidence of adverse events than controls with heart failure (75% (6/8)] vs 30% (7/23), p,0.05). Conclusions: The b2-adrenergic Thr164Ile polymorphism directly modulates adrenergic-mediated cardiac responses in patients with normal and failing myocardium. Furthermore, blunted b2 adrenergic-mediated myocardial contractile response in patients with Ile-164 variant seems to adversely modulate the course of congestive heart failure.

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Bone marrow (BM) cells may interact with coronary endothelium and modulate coronary atherosclerosis. We investigated the time course of coronary luminal loss and changes in conductance after intracoronary injection of enriched hematopoietic BM stem cells in patients with previous myocardial infarction (MI). Among 24 patients with acute MI, 13 were randomized to early (<7 days) and 11 to late (4 months) intracoronary injection of CD133 + cells after the infarction. Segmental quantitative coronary angiography and fractional flow reserve (FFR) measurements of the infarct-related (IR) artery (A) and contralateral artery (control) were performed. In the early group, at 4 months, cumulative luminal loss (LL) of the minimal luminal diameter (MLD) of the IRA distal to the stented segment was −0.39 (−0.51-0.10) mm (p < 0.05 vs. control). There was no further change in LL between 4 and 8 months [−0.09 (−0.26-0.15 INTRODUCTIONinfused early after myocardial infarction, exerted beneficial effects on cardiac recovery in patients with reperfused myocardial infarction, but they appeared to be asCell-induced angiogenesis is mainly mediated by paracrine effects through the release of cytokines, adhesion sociated with higher luminal loss of downstream distal segments at 4 months follow-up. Therefore, we investimolecules, and growth factors. However, similar cytokines and molecules participate in pathogenesis of athgated long-term effects of intracoronary CD133 + -enriched cells on luminal loss of distal nonstented segments of erosclerosis, and striking similarities in the molecular mechanisms underlying both processes are well docuthe infarct-related artery in a separate group of patients with recent myocardial infarction treated with stented mented (6). Furthermore, opposing effects on angiogenesis and atherogenesis were observed in studies using angioplasty randomized to early and late stem cell treatment. cytokines or growth factors involved in both processes (5,8,9,13,17,21). This led to the hypothesis that interre- MATERIALS AND METHODS lated tradeoffs may be inherent to therapies designed toPatients and Study Protocol enhance collateral formation (6). The concept coined as "Janus-like" phenomenon (6) may have important cliniThe study population consisted of 24 patients with acute myocardial infarction (MI) due to occlusion of the cal implications for intracoronary stem cell therapy. In our previous studies (1,14), CD133 angioplasty. All patients underwent cardiac catheterizaCardiac Catheterization tion between 5 and 7 days after the infarction (baseline), LV volumes and ejection fraction were calculated usand at 4 and 8 months follow-up. Patients were randoming the area-length method. Regional wall motion was ized into two groups. The first group received intracoroanalyzed using the centerline method. nary cell therapy at baseline (early group) within 7 days Assessment of Luminal Loss by Quantitative following the MI and the second group received cells at Coronary Angiography 4 months (late group). In all patients and at al...