Reduced levels of circulating endothelial progenitor cells in acute myocardial infarction patients with diabetes or pre-diabetes: accompanying the glycemic continuum.

BACKGROUND: Diabetic patients have a significantly worse prognosis after an acute myocardial infarction (AMI) than their counterparts. Previous studies have shown that the number of circulating endothelial progenitor cells (EPCs) significantly increase early after an AMI in normoglycemic patients. However, it is well known that type 2 diabetes mellitus (DM) is associated with impaired function and reduced circulating EPCs levels. Nonetheless, few studies have analyzed EPCs response of diabetics to an AMI and the EPC response of pre-diabetic patients has not been reported yet. Therefore, we hypothesized that in the acute phase of an AMI, diabetic and pre-diabetics have lower circulating EPCs levels than patients with normal glucose metabolism. We also evaluated the possible capacity of chronic antidiabetic treatment in the recovery of EPCs response to an AMI in diabetics. METHODS: One-hundred AMI patients were prospectively enrolled in the study. Using the high-performance flow cytometer FACSCanto II, circulating EPCs (CD45dimCD34+KDR+ and CD45dimCD133+KDR+ cells) were quantified, within the first 24 hours of admission. In addition, as an indirect functional parameter, we also analyzed the fraction of EPCs coexpressing the homing marker CXCR4. RESULTS: We found that in the acute phase of an AMI, diabetic patients presented significantly lower levels of circulating CD45dimCD34+KDR+ and CD45dimCD133+KDR+ EPCs by comparison with nondiabetics, with a parallel decrease in the subpopulations CXCR4+ (p < 0.001). Indeed, this study suggests that the impaired response of EPCs to an AMI is an early event in the natural history of DM, being present even in pre-diabetes. Our results, also demonstrated that numbers of all EPCs populations were inversely correlated with HbA1c (r = -0.432, p < 0.001 for CD45dimCD34+KDR+ cells). Finally, this study suggests that previous chronic insulin therapy (but not oral antidiabetic drugs) attenuate the deficient response of diabetic EPCs to an AMI. CONCLUSION: This study indicates that there is a progressive decrease in EPCs levels, from pre-diabetes to DM, in AMI patients. Moreover, glycemic control seems to be determinant for circulating EPCs levels presented in the acute phase of an AMI and chronic insulin therapy may probably attenuate the deficit in EPCs pool seen in diabetics.

Impact of prior chronic statin therapy and high-intensity statin therapy at discharge on circulating endothelial progenitor cell levels in patients with acute myocardial infarction: a prospective observational study.

BACKGROUND: Endothelial progenitor stem cells (EPCs) are mobilized to the peripheral circulation in response to myocardial ischemia, playing a crucial role in vascular repair. Statins have been shown to stimulate EPCs. However, neither the impact of previous statin therapy on EPC response of acute myocardial infarction (AMI) patients nor the effect of post-AMI high-intensity statin therapy on the evolution of circulating EPC levels has yet been addressed. Therefore, we aimed to compare circulating EPC levels between patients receiving long-term statin therapy before the AMI and statin-naive patients and to assess the impact of high-intensity statin therapy at discharge on the evolution of circulating EPCs post-AMI. METHODS: This is a prospective observational study of 100 AMI patients. Circulating EPCs (CD45dimCD34 + KDR + cells) and their subpopulation coexpressing the homing marker CXCR4 were quantified by the high-performance flow cytometer FACSCanto II in whole blood, in two different moments: within the first 24 h of admission and 3 months post-AMI. Patients were followed up clinically for 2 years. RESULTS: Patients previously treated with statins had significantly higher levels of EPCs coexpressing CXCR4 (1.9 ± 1.4 vs. 1.3 ± 1.0 cells/1,000,000 events, p = 0.031) than statin-naive patients. In addition, the subanalysis of diabetics (N = 38) also revealed that patients previously on statins had significantly greater numbers of both CD45dimCD34 + KDR + CXCR4+ cells (p = 0.024) and CD45dimCD34 + KDR + CD133+ cells (p = 0.022) than statin-naive patients. Regarding the evolution of EPC levels after the AMI, patients not on a high-intensity statin therapy at discharge had a significant reduction of CD45dimCD34 + KDR + and CD45dimCD34 + KDR + CXCR4+ cells from baseline to 3 months follow-up (p = 0.031 and p = 0.005, respectively). However, patients discharged on a high-intensity statin therapy maintained circulating levels of all EPC populations, presenting at 3 months of follow-up significantly higher EPC levels than patients not on an intensive statin therapy. Moreover, the high-intensity statin treatment group had significantly better clinical outcomes during the 2-year follow-up period than patients not discharged on a high-intensity statin therapy. CONCLUSION: Chronic statin therapy prior to an AMI strongly enhances the response of EPCs to myocardial ischemia, even in diabetic patients. Furthermore, high-intensity statin therapy after an AMI prevents the expected decrease of circulating EPC levels during follow-up. These results reinforce the importance of an early and intensive statin therapy in AMI patients.

Circulating endothelial progenitor cells as a predictor of response to cardiac resynchronization therapy: the missing piece of the puzzle?

BACKGROUND: It would be important to better identify heart failure (HF) patients most likely to respond to cardiac resynchronization therapy (CRT). Because endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular endothelium integrity, we hypothesize that patients who have higher circulating EPCs levels have greater neovascularization potential and are more prone to be responders to CRT. METHODS: Prospective study of 30 consecutive patients, scheduled for CRT. Echocardiographic evaluation was performed before implant and 6 months after. Responders to CRT were defined as patients who were still alive, have not been hospitalized for HF management, and demonstrated ≥15% reduction in left ventricular end-systolic volume (LVESV) at the 6-month follow-up. EPCs were quantified before CRT, from peripheral blood, by flow cytometry using five different conjugated antibodies: anti-CD34, anti-KDR, anti-CD133, anti-CD45, and anti-CXCR4. We quantified five different populations of angiogenic cells: CD133(+) /CD34(+) cells, CD133(+) /KDR(+) cells, CD133(+) /CD34(+) /KDR(+) cells, CD45(dim) CD34(+) /KDR(+) cells, and CD45(dim) CD34(+) /KDR(+) /CXCR4(+) cells. RESULTS: The proportion of responders to CRT at the 6-month follow-up was 46.7%. Responders to CRT presented higher baseline EPCs levels than nonresponders (0.0003 ± 0.0006% vs 0.0001 ± 0.0002%, P = 0.04, for CD34(+) /CD133(+) /KDR(+) and 0.0006 ± 0.0005% vs 0.0003 ± 0.0003%, P = 0.009, for CD45(dim) CD34(+) /KDR(+) /CXCR4(+) cells). In addition, baseline levels of CD45(dim) CD34(+) /KDR(+) /CXCR4(+) cells were positively correlated with the reduction of LVESV verified 6 months after CRT (r = 0.497, P = 0.008). CONCLUSIONS: High circulating EPCs levels may identify the subset of HF patients who are more likely to undergo reverse remodeling and benefit from CRT. Addition of EPCs levels assessment to current selection criteria may improve the ability to predict CRT response.

One-shot diagnostic and prognostic assessment in intermediate- to high-risk acute pulmonary embolism: the role of multidetector computed tomography.

INTRODUCTION: Contrast-enhanced multidetector computed tomography (MDCT) is useful for the diagnosis of pulmonary embolism (PE). However, current guidelines do not support its use for risk assessment in acute PE patients. OBJECTIVES: We compared the prognostic impact of MDCT-derived indices regarding medium-term mortality in a population of intermediate- to high-risk PE patients, mostly treated by thrombolysis. METHODS: Thirty-nine consecutive patients admitted to an intensive care unit with acute PE were studied. All patients had a pulmonary MDCT on admission to the emergency room as part of the diagnostic algorithm. We assessed the following MDCT variables: right ventricular/left ventricular diameter (RV/LV) ratio, arterial obstruction index, pulmonary artery-to-aorta diameter ratio and azygos vein diameter. A 33-month follow-up was performed. RESULTS: Mean age was 59.1±19.6 years, with 80% of patients receiving thrombolysis. Follow-up all-cause mortality was 12.8%. Of the MDCT-derived variables, only the RV/LV ratio had significant predictive value, being higher in patients who suffered the endpoint (1.6±0.5 vs. 1.9±0.4, p=0.046). Patients with an RV/LV ratio ≥1.8 had 11-fold higher medium-term all-cause mortality (3.8% vs. 38.8%, p<0.001). Regarding this endpoint, the c-statistic was 0.78 (95% CI, 0.60-0.96) for RV/LV ratio and calibration was good (goodness-of-fit p=0.594). No other radiological index was predictive of mortality. CONCLUSIONS: MDCT gives the possibility, in a single imaging procedure, of diagnosing and assessing the prognosis of patients with intermediate- to high-risk PE. Although further studies are needed, the simple-to-calculate RV/LV ratio has good discrimination and calibration for predicting poorer outcomes in patients with acute PE.

[Emery-Dreifuss muscular dystrophy: case report]. / Distrofia muscular de Emery-Dreifuss: a propósito de um caso clínico.

Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a familial disease with X-Linked recessive transmission, caused by a mutation in a nuclear envelope protein, emerin. Clinical manifestations usually occur in adolescence and include contractures, muscle atrophy and weakness, and cardiac conduction disturbances. We describe the case of a young male, aged 16, with first-degree atrioventricular (AV) block and limited extension of both forearms. He had elevated CK, and cardiac monitoring showed severe conduction tissue disease, with significant sinus pauses, chronotropic incompetence and periods of AV dissociation during exercise. Immunohistochemical staining using an emerin antibody showed absence of the protein in a fragment of muscle tissue and genetic study identified a mutation associated with EDMD1. Study of his brother, aged 21, also established a diagnosis of EDMD1. Both individuals received a permanent pacemaker but musculoskeletal manifestations at that time did not warrant any other intervention: Screening for certain genetic diseases, including muscular dystrophies, is mandatory following identification of conduction abnormalities in young people.

Mean pulmonary arterial pressure after percutaneous mitral valvuloplasty predicts long-term adverse outcomes.

INTRODUCTION AND AIM: Percutaneous mitral valvuloplasty (PMV) is an effective treatment option for mitral stenosis (MS), but its success is assessed on the basis of clinical and echocardiographic outcomes in studies with relatively short follow-up. We aimed to characterize a cohort of patients undergoing PMV with long-term follow-up and to determine independent predictors of post-PMV mitral re-intervention and event-free survival. METHODS: We studied 91 consecutive patients with MS who underwent PMV with a median clinical follow-up duration of 99 months. Two endpoints were considered: post-PMV mitral re-intervention (PMV or mitral surgery) and a composite clinical events endpoint including cardiovascular death, mitral valve re-intervention and hospital admission due to decompensated heart failure. We compared patients who required post-PMV mitral re-intervention with those who did not during follow-up. RESULTS: The study population included 83.5% females and mean age was 48.9±13.9 years. The 1-, 3-, 5-, 7- and 9-year rates of clinical event-free survival were 93.0±2.8%, 86.0±3.9%, 81.0±4.4%, 70.6±5.6%, and 68.4±5.8%, respectively. The 1-, 3-, 5-, 7- and 9-year rates of mitral re-intervention-free survival were 98.8±1.2%, 97.5±1.7%, 92.1±3.1%, 85.5±4.5%, and 85.5±4.5%, respectively. The median time to mitral re-intervention was 6.2 years. Patients who required mitral re-intervention during follow-up were younger (43.3 vs. 51.2 years, p=0.04) and had higher pre- and post-PMV mitral gradient (14.9 vs. 11.5 mmHg, p=0.02 and 6.4 vs. 2.1 mmHg, p<0.001) and higher post-PMV mean pulmonary artery pressure (mPAP) (30.0 vs. 23.2 mmHg, p=0.01). In a Cox proportional hazards model, mPAP ≥25 mmHg was the sole predictor of both mitral re-intervention (HR 5.639 [1.246-25.528], p=0.025) and clinical events (HR 3.622 [1.070-12.260], p=0.039). CONCLUSION: In our population, immediate post-PMV mPAP was the sole predictor of post-PMV mitral intervention. These findings may help identify patients in need of closer post-PMV follow-up.

[Fulminant myocarditis]. / Miocardite fulminante - a propósito de um caso clínico.

A 46-year-old woman was admitted due to diplopia because of ophthalmoplegia, which improved with corticosteroid therapy. Eight days later, she was admitted with fulminant myocarditis in cardiogenic shock, with severe left ventricular dysfunction and frequent episodes of nonsustained ventricular tachycardia. As there was no clinical improvement, an endomyocardial biopsy was performed that revealed inflammatory infiltrate, vasculitis, and PCR positive for cytomegalovirus, Epstein-Barr virus, parvovirus B19 and enterovirus. Left ventricular function recovered with heart failure treatment and corticosteroids. Three months later, after progressive withdrawal of prednisolone, there was recurrence of myocarditis and left ventricular dysfunction, which was successfully treated by restarting corticosteroid therapy. One month later she was readmitted with fulminant myocarditis which again responded to steroids. She intermittently presented cutaneous purpura lesions. At this time the provisional diagnosis was vasculitis and she started monthly cycles of cyclophosphamide. Before the second cycle she was admitted with pneumonia and ventricular dysfunction and died.

CYP2C19*2 and prognosis after an acute coronary syndrome: Insights from a Portuguese center.

BACKGROUND: Clopidogrel requires oxidation dependent on the cytochrome P450 enzyme 2C19 (CYP2C19) to form its active metabolite. The importance of loss-of-function alleles (particularly CYP2C19*2, 681G>A) in poor platelet response to clopidogrel is well recognized. OBJECTIVE: To investigate the prevalence and prognostic impact of the CYP2C19*2 allele in a local acute coronary syndrome (ACS) population. METHODS: We performed a prospective, longitudinal study of 95 patients admitted for an ACS between March and October 2009 to a single coronary care unit. Patients aged under 75 who survived hospital stay and for whom clopidogrel was prescribed were included. At discharge, CYP2C19 was genotyped using a commercially available kit. Patients were divided into two groups: Group A (non-carriers, normal metabolizers, CYP2C19*1/*1), n=69; and Group B (carriers, slow metabolizers, CYP2C19*2/*1 or *2/*2), n=26. The primary endpoint was a combined outcome of cardiovascular death, non-fatal myocardial infarction or re-admission for unstable angina; median follow-up was 136.0 (79.0-188.0) days. RESULTS: The median age of the population was 62.0 (51.0-68.0) years, and 83.2% were male. The CYP2C19*2 (A) allele had a frequency of 14.2%. There were no differences between the groups with respect to demographic data or history of cardiovascular disease. Coronary anatomy, left ventricular ejection fraction and renal function were also similar. The groups were also homogenous with respect to GRACE risk score (118.0 (95.0-136.5) vs. 115.0 (96.0-133.0), p=0.68), medical treatment and percutaneous revascularization during hospital stay. Event-free survival was higher for Group A (94.0% vs. 75.0%, log-rank p=0.010). Three readmissions for MI were documented, all in the slow metabolizers group. CONCLUSION: In our ACS population, the CYP2C19*2 allele was a medium-term prognostic marker.

Platelet aggregation at discharge: a useful tool in acute coronary syndromes?

INTRODUCTION: Inhibition of platelet aggregation appears two hours after the first dose of clopidogrel, becomes significant after the second dose, and progresses to a steady-state value of 55% by day seven. Low response to clopidogrel has been associated with increased risk of stent thrombosis and ischemic events, particularly in the context of stable heart disease treated by percutaneous coronary intervention. OBJECTIVE: To stratify medium-term prognosis of an acute coronary syndrome (ACS) population by platelet aggregation. METHODS: We performed a prospective longitudinal study of 70 patients admitted for an ACS between May and August 2009. Platelet function was assessed by ADP-induced platelet aggregation using a commercially available kit (Multiplate(®) analyzer) at discharge. The primary endpoint was a combined outcome of mortality, non-fatal myocardial infarction, or unstable angina, with a median follow-up of 136.0 (79.0-188.0) days. RESULTS: The median value of platelet aggregation was 16.0U (11.0-22.5U) with a maximum of 41.0U and a minimum of 4.0U (normal value according to the manufacturer: 53-122U). After ROC curve analysis with respect to the combined endpoint (AUC 0.72), we concluded that a value of 18.5U conferred a sensitivity of 75.0% and a specificity of 68% to that result. We therefore created two groups based on that level: group A - platelet aggregation <18.5U, n=44; and group B - platelet aggregation ≥18.5U, n=26. The groups were similar with respect to demographic data (age 60.5 [49.0-65.0] vs. 62.0 [49.0-65.0] years, p=0.21), previous cardiovascular history, and admission diagnosis. There were no associations between left ventricular ejection fraction, GRACE risk score, or length of hospital stay and platelet aggregation. The groups were also similar with respect to antiplatelet, anticoagulant, proton pump inhibitor (63.6 vs. 46.2%, p=0.15) and statin therapy. The variability in platelets and hemoglobin was also similar between groups. Combined event-free survival was higher in group A (96.0 vs. 76.7%, log-rank p<0.01). Platelet aggregation higher than 18.5U was an independent predictor of the combined event (HR 6.75, 95% CI 1.38-32.90, p=0.02). CONCLUSION: In our ACS population platelet aggregation at discharge was a predictor of medium-term prognosis.

Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury.

AMPK activation during ischemia helps the myocardium to cope with the deficit of energy production. As AMPK activity is considered to be impaired in diabetes, we hypothesized that enhancing AMPK activation during ischemia above physiological levels would protect the ischemic diabetic heart through AMPK activation and subsequent inhibition of mitochondrial permeability transition pore (mPTP) opening. Isolated perfused hearts from normoglycemic Wistar or diabetic Goto-Kakizaki (GK) rats (n ≥ 6/group) were subjected to 35 min of ischemia in the presence of 10, 20, and 40 µM of A-769662, a known activator of AMPK, followed by 120 min of reperfusion with normal buffer. Myocardial infarction and AMPK phosphorylation were assessed. The effect of A-769662 on mPTP opening in adult cardiomyocytes isolated from both strains was also determined. A-769662 at 20 µM reduced infarct size in both Wistar (30.5 ± 2.7 vs. 51.8 ± 3.9% vehicle; P < 0.001) and GK hearts (22.7 ± 3.0 vs. 48.5 ± 4.7% vehicle; P < 0.001). This protection was accompanied by a significant increase in AMPK and GSK-3ß phosphorylation. In addition, A-769662 significantly inhibited mPTP opening in both Wistar and GK cardiomyocytes subjected to oxidative stress. We demonstrate that AMPK activation during ischemia via A-769662 reduces myocardial infarct size in both the nondiabetic and diabetic rat heart. Furthermore, this cardioprotective effect appears to be mediated through inhibition of mPTP opening. Our findings suggest that improving AMPK activation during ischemia can be another mechanism for protecting the ischemic heart.

Apolipoprotein E epsilon-4 polymorphism is associated with younger age at referral to a lipidology clinic and a poorer response to lipid-lowering therapy.

BACKGROUND: The risk of coronary heart disease (CHD) is related to environmental factors and genetic variants. Apolipoprotein E (apoE) polymorphisms are heritable determinants of total and low-density lipoprotein cholesterol, with some authors suggesting an association between the ε4 allele and CHD. We investigated the relationship between apoE genotype and age at referral to a specialized lipid clinic by the primary care physician and whether the benefits of treatment with statin differed between genotypes. METHODS: We assessed individual apoE genotypes and lipid blood profile in a total of 463 patients followed at a specialized lipid clinic due to dyslipidemia, with a 3-year median follow-up time. The primary care physician at the time of the referral had no access to the apoE genotyping results. Carriers of apoE ε4/ε2 genotype were excluded. RESULTS: The frequencies of ε2, ε3 and ε4 alleles were 7.8, 78.9 and 13.3%, respectively. There were no significant differences between genders. Although with similar lipid profiles and antidyslipidemic drug usage at baseline, ε4-carriers were referred to the clinic at a younger age (44.2 ± 14.7 years) compared with non-ε4 carriers (50.6 ± 13.8 years) (p < 0.001), with a substantially younger age of referral for homozygous E4/4 and for all genotypes with at least one copy of the ε4 allele (p < 0.001 for trend). Although both ε4 and non-ε4 carriers achieved significant reductions in total cholesterol during follow-up (p < 0.001 vs. baseline), the mean relative decrease in total cholesterol levels was higher in non-ε4 carriers (-19.9 ± 2.3%) compared with ε4 carriers (-11.8 ± 2.3%), p = 0.003. CONCLUSION: Our findings support the concept that there is a reduced response to anti-dyslipidemic treatment in ε4 carriers; this can be a contributing factor for the earlier referral of these patients to our specialized lipid clinic and reinforces the usefulness of apoE genotyping in predicting patients response to lipid lowering therapies.

Anemia: only a marker or an independent predictor of mortality in advanced heart failure?

INTRODUCTION AND OBJECTIVES: Advanced heart failure (HF) remains a major cause of mortality. Identification of new prognostic risk factors is therefore a priority. Anemia, a frequent comorbidity in HF patients and a recognized trigger of symptoms, has recently received considerable attention in this context. Several studies have demonstrated an association between anemia and increased mortality in stable chronic HF patients. However, the prognostic impact of this comorbidity on the survival of advanced HF patients remains unclear. Our aim was to assess whether anemia is not only a marker of advanced HF, but also an independent predictor of mortality. METHODS: We performed a retrospective study of 391 consecutive patients admitted to a single advanced HF care unit and divided into two groups according to the presence or absence of anemia at admission. Demographic, clinical, laboratory and therapeutic data were compared between the groups. Anemia was defined as hemoglobin at admission of <12 g/dl for women and <13 g/dl for men. Appropriate statistical tests and multivariate analysis were used to identify independent predictors of one-year and overall mortality. Median follow-up was 3.2 years. RESULTS: Group A, anemic patients (n=169, 43.2%), were older (61.7 +/- 14.7 vs. 58.0 +/- 14.5 years, p = 0.01) and included a higher number of patients with ischemic cardiomyopathy (40.7% vs. 28.6%, p = 0.01), but fewer with dilated cardiomyopathy (41.0% vs. 55.8%, p = 0.004). At admission, group A had lower systolic blood pressure (110.1 +/- 24.8 mmHg vs. 115.2 +/- 22.0 mmHg, p = 0.03) and higher mean C-reactive protein (1.90 +/- 3.6 mg/dl vs. 1.19 +/- 2.6 mg/dl, p = 0.004) and creatinine (1.50 +/- 0.9 mg/dl vs. 1.20 +/- 0.5 mg/dl, p < 0.001). Gender, prevalence of cardiovascular risk factors, previous medication and left ventricular ejection fraction were not statistically different between the groups. At discharge, fewer anemic patients received digoxin (71.1% vs. 81.8%, p = 0.03). Mortality rates at 3 months (13.6% vs. 6.7%, p = 0.05), one year (22.9% vs. 11%, p = 0.006) and during follow-up (39.8 % vs. 23.8%, p = 0.002) were significantly higher in Group A. Multivariate analysis demonstrated that anemia was an independent predictor of mortality at one year (p = 0.035) and during median follow-up: (p = 0.014). In the anemic group a linear relationship between hemoglobin levels and mortality was also detected. CONCLUSIONS: In our population, anemia was a frequent comorbidity and had an independent and negative impact on long-term mortality. Its correction could improve outcomes in advanced HF patients.

Ascending aortic aneurysm and patent foramen ovale: a rare cause of platypnea-orthodeoxia.

Platypnea-orthodeoxia is a rare syndrome characterized by dyspnea and hypoxia induced by the upright position and relieved by the supine position. Several factors related to atrial anatomy can facilitate shunting through an atrial septal defect; in many cases, the syndrome is associated with patent foramen ovale and right-to-left shunt, and has also been linked to aortic aneurysm. We present a case of platypnea-orthodeoxia syndrome in a 61-year-old woman with patent foramen ovale and ascending aortic aneurysm.

Predictors of adverse outcome in a diabetic population following acute coronary syndromes.

INTRODUCTION: People with diabetes are at increased risk for heart failure (HF), major adverse cardiovascular events (MACE) and death following acute coronary syndromes (ACS). It is important to recognize the most powerful predictors of these events after an ACS as early as possible, in order to address them more aggressively. This is particularly important considering that various studies have shown that this population is undertreated in the setting of ACS. OBJECTIVES: To characterize a diabetic population presenting with ACS and to determine independent predictors of HF, MACE and mortality on follow-up. METHODS: This was a longitudinal, observational, retrospective study including 471 consecutive diabetic patients, both previously known and newly diagnosed, hospitalized for ACS in a single center between May 2004 and December 2006. A mean 12-month follow-up was conducted. Cox regression analysis was used to determine the independent predictors of HF, MACE and mortality on follow-up, divided into different periods--1 month, 6 months and 1 year. RESULTS: Of the overall diabetic population, 67.3% were male and mean age was 69 +/- 11 years. Mean glomerular filtration rate (GFR) was 62 +/- 22 ml/min and mean left ventricular ejection traction (LVEF) was 50%. diagnosis on admission was ST-elevation myocardial infarction (STEMI) in 31.3%, non-ST elevation myocardial infarction (NSTEMI) in 50.1%, unstable angina (UA) in 14.3% and ACS with left bundle branch block or pacemaker in 4.2%. Cardiac catheterization was performed in 55.6% of the patients during the index hospitalization. Mortality during hospitalization and at 1 year was 6.4% and 10.4%, respectively. The one-year MACE rate was 20.4% and hospitalization for HF occurred in 10.1% of the patients. The independent predictors of HF at 1 year were blood glucose on admission > 184.5 mg/dl, GFR < 63.8 ml/min, LVEF < 46.5% and NSTEMI, while predictors of mortality were LVEF < 40.5% and Killip class on admission > I. Blood glucose on admission > 130.5 mg/dl and LVEF < 49.5% were independent predictors of MACE, whereas cardiac catheterization was a protective factor. CONCLUSION: Following ACS diabetic patients have high rates of mortality, HF and MACE. The low rate of invasive strategy may contribute to this situation. HF during hospitalization, whether by low LVEF or Killip class > I, and higher blood glucose on admission were powerful predictors of poorer outcome. Moreover, the use of recommended cardiovascular agents and procedures were protective factors. These findings suggest that diabetic patients should not be excluded from recommended cardiovascular interventions. Efforts should be made to identify these high-risk patients as early as possible in order to manage them carefully and aggressively to improve their poor prognosis.

Ischemic versus non-ischemic cardiomyopathy--are there differences in prognosis? Experience of an advanced heart failure center.

INTRODUCTION: Previous studies have associated heart failure (HF) of ischemic etiology with worse prognosis compared to HF from non-ischemic cardiomyopathy. HF treatment has evolved significantly in recent years. Has this evolution had an impact on this prognostic gap? OBJECTIVE: The aim of our study was to compare patients with advanced HF--nonischemic versus ischemic etiology--in terms of baseline characteristics, treatment, and in-hospital and long-term prognosis (including death, heart transplantation and hospital readmission). METHODS: We performed a retrospective study including 286 consecutive patients with systolic HF admitted to an HF unit between January 2003 and June 2006. We compared two groups according to HF etiology: Group A--ischemic cardiomyopathy (n = 109); Group B--non-ischemic cardiomyopathy (n = 177). Mean follow-up was 41 months. RESULTS: Group A were older (62.2 +/- 10.4 vs. 55.9 +/- 15.2 years, p < 0.001), with a higher proportion of males (80.7 vs. 67.8%, p = 0.017), diabetes, anemia, dyslipidemia and smokers; they required more prolonged treatment with inotropic drugs and more frequent treatment with statins, antiplatelet agents and nitrates. On admission, Group B patients presented with lower serum sodium and higher aminotransferase levels. There were no differences in the occurrence of cardiogenic shock or dysrhythmias, baseline ECG rhythm, frequency of left bundle branch block, renal function, BNP, left ventricular ejection fraction, heart rate or implantation of intracardiac devices. Group A had higher in-hospital mortality (11.0 vs. 4.0%, p = 0.020). Multivariate analysis showed that the only predictor of in-hospital mortality was serum sodium < 133 mmol/l and also showed that HF etiology was not a predictor of this endpoint; previous medication with angiotensin-converting enzyme inhibitors was a protective factor. On Kaplan-Meier analysis, it was observed that, in the long-term, there were no significant differences in either survival rates (70.0 vs. 76.8%, p = 0.258), or the combined endpoints of survival free of death or heart transplantation (55.7 vs. 54.5%, p = 0.899) and survival free of death, heart transplantation or hospital readmission (38.0 vs. 32.8%, p = 0.386). CONCLUSIONS: Although in-hospital mortality was higher in ischemic cardiomyopathy, this variable was not an independent predictor of mortality and the difference appears to fade in the long-term, in contrast to what had been reported in older studies, but in agreement with more recent data.

Hyperglycaemia at admission in acute coronary syndrome patients: prognostic value in diabetics and non-diabetics.

OBJECTIVE: To evaluate the impact of admission glycaemia on short-term and long-term prognosis in diabetic and non-diabetic patients admitted for acute coronary syndromes (ACS), and to identify the independent predictors of post-ACS mortality in this population. METHODS: This study included 1149 consecutive patients admitted to a single coronary care unit for ACS between May 2004 and December 2006. Our population was divided into four groups according to the quartiles of glycaemia at admission [Q1 <5.77 mmol/l, Q2 (5.77-7.0) mmol/l, Q3 (7.0-9.22) mmol/l and Q4 > or =9.22 mmol/l]. Diabetic (n = 396) and non-diabetic (n = 753) subgroups were then separately analysed. RESULTS: Hyperglycaemia at admission was associated with worse cardiovascular risk profile, high levels of necrosis and inflammation biomarkers and low left ventricle ejection fraction. Considering overall population, in-hospital, 30-day and 3-year mortalities were higher in more elevated glycaemia quartiles. In diabetic patients, there were no significant differences in mortality among glycaemia quartiles; however, in non-diabetic group higher admission glucose levels were associated with successively higher in-hospital and 3-year mortalities. After multivariate regression analysis, glycaemia at admission > or =5.77 mmol/l, age > or =72 years, Killip class >1 and troponin I > or =6.0 ng/ml were independent predictors of in-hospital mortality. CONCLUSION: This study suggests that, in a broad ACS population, hyperglycaemia at admission is a short-term and long-term bad prognosis marker, particularly in non-diabetic patients, being a strong independent predictor of in-hospital mortality.

Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction.

PURPOSE: AMPK plays a crucial role in the regulation of the energy metabolism of the heart. During ischaemia, AMPK activation is a known adaptative prosurvival mechanism that helps to maintain the energy levels of the myocardium. However, it still remains unclear if activation of AMPK during reperfusion is beneficial for the heart. Two known AMPK activators (metformin and AICAR) were used to verify the hypothesis that a transitory activation of AMPK at reperfusion may exert cardioprotection, as reflected in a reduction in myocardial infarct size. METHODS: Perfused rat hearts were subjected to 35 min ischaemia and 120 min reperfusion. Metformin (50 microM) or AICAR (0.5 mM) were added for 15 min at the onset of reperfusion alone or with Compound C (CC, 10 microM), an AMPK inhibitor. Infarct size and alpha-AMPK phosphorylation were measured. RESULTS: Metformin significantly reduced infarct size from 47.8 +/- 1.7% in control to 31.4 +/- 2.9%, an effect abolished by CC when the drugs were given concomitantly. Similarly, AICAR also induced a significant reduction in infarct size to 32.3 +/- 4.8%, an effect also abrogated by CC. However, metformin's protection was not abolished if CC was administered later in reperfusion. In addition, alpha-AMPK phosphorylation was significantly increased in the metformin treated group during the initial 30 min of reperfusion. CONCLUSIONS: Our data demonstrated that, in our ex vivo model of myocardial ischaemia-reperfusion injury, AMPK activation in early reperfusion is associated with a reduction in infarct size.

Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs.

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.

Diabetes mellitus does not affect one-year outcome after heart transplantation.

BACKGROUND AND AIMS: Heart transplantation remains the gold standard treatment for selected patients with end-stage heart failure. However, transplantation in diabetic patients remains controversial. The hyperglycemic effect of immunosuppressant therapy further complicates posttransplantation management of diabetes and, although this is still unproven, could be responsible for a higher incidence of post-transplantation infection, rejection and mortality. In this study, we aimed to compare one-year outcomes of survival and morbidity after cardiac transplantation among recipients with and without diabetes mellitus. METHODS: This was a prospective observational study of 114 patients who underwent first heart transplantation between November 2003 and January 2008, with 1-year follow-up. They were divided into two groups according to whether they had pre-transplantation diabetes (group 1) or not (group 2). Baseline variables and complications were recorded. Logistic regression analysis was used to identify independent predictors of 1-year mortality. RESULTS: Of the 114 patients, 33% were diabetic before transplantation. Diabetic patients were older (57.0 +/- 7.4 vs. 51.2 +/- 12.9 years, p = 0.013), and had a higher prevalence of hypertension (63.6% vs. 16.7%, p = 0.002), lower creatinine clearance (53.5 +/- 16.2 vs. 63.0 +/- 21.8 ml/min, p = 0.020) and higher C-reactive protein levels (1.8 +/- 2.4 vs. 0.9 +/- 1.3 mg/l, p = 0.029) than non-diabetics. They tended to have more peripheral arterial disease (20.8 vs. 14.8%, p = NS) and carotid disease (25.8 vs. 14.3%, p = NS). In diabetic patients fasting glucose levels were significantly lower at one year than before heart transplantation (134.2 +/- 45.3 vs. 158.4 +/- 71.2 mg/dl, p = 0.039). There were no significant differences between diabetic and non-diabetic patients in rejection (16.2 vs. 23.4%, p = 0.467), infection (27.0 vs. 33.8%, p = 0.524) or mortality (16.2 vs. 6.5%, p = 0.171) at 1-year follow-up. On logistic regression analysis, the only predictor of 1-year mortality was baseline creatinine > 1.4 mg/dl (OR: 6.36, 95% CI: 1.12-36.04). Diabetes and impaired fasting glucose before heart transplantation were not independent predictors of 1-year mortality. CONCLUSIONS: These data suggest that diabetes is not associated with worse 1-year survival or higher morbidity in heart transplant patients, as long as good blood glucose control is maintained.

Genetic characterization of warfarin sensitivity in a population of cardiovascular patients on chronic anticoagulation.

BACKGROUND: Genetic factors account for 35-40% of the interindividual variation observed in response to warfarin. The most important genes involved are CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). OBJECTIVES: To determine the prevalence of the different genotypes influencing response to oral anticoagulants in a population of cardiovascular patients on chronic anticoagulation and to investigate the correlation between genotype and the warfarin dose required for optimal anticoagulation. METHODS: A total of 91 chronically anticoagulated consecutive patients were genotyped for CYP2C9 and VKORC1, using PCR and reverse hybridization. RESULTS: Of the 91 patients, 57.1% were male and mean age was 67.4 +/- 13.1 years. most frequent indication for warf was atrial fibrillation (56.8%). We analyzed the prevalence of the different CYP2C9 and VKORC1 genotypes in this population and found that the warfarin doses required to maintain patients at their desired anticoagulation target were significantly different among carriers of the different genotypes. CONCLUSIONS: Our study highlights the importance of genetic study in the clinical management of patients on chronic anticoagulation, increasing the safety and efficacy of warfarin therapy.