Vascular compliance and left ventricular compliance cross talk: Implications for using long-term heat acclimation in cardiac care.

1) The first evidence of the beneficial impact of Long-Term-Heat-Acclimation (LTHA) on cardio-vascular compliance was the positive inotropic response and improved left ventricular (LV) compliance noted when isolated hearts from LTHA rats were studied. Human echo study demonstrates that passive HA affects the right ventricle and the atria as well. 2) There is a cross-talk between vascular and cardiac compliance. Vascular compliance per se is defined by central venous pressure-Blood volume relationship-Global Vascular Compliance (GVC). It is determined by the sum of the vascular compliance of the vessels in every organ in any physiological state, varies with LTHA and thus influences cardiac performance. LTHA improves endothelial function, increases NO (nitric oxide) production, in-turn stimulating alterations in ECM (extracellular matrix) via the TGF ß1-SMAD pathway. 3) LTHA is associated with transformation from fast to slow myosin, heat acclimation ischemic/hypoxic cross-tolerance and alterations in the extracellular matrix. 4) A human translational study demonstrated improved LV compliance following bypass surgery in LTHA subjects compared to controls. 5) Diastolic dysfunction and the impact of comorbidities with vascular and non- vascular origins are major contributors to the syndrome of heart failure with preserved ejection function (HFPEF). Unfortunately, there is a paucity of treatment modalities that improve diastolic dysfunction. 6) In the current mini-review we suggest that LTHA may be beneficial to HFPEF patients by remodeling cardiac compliance and vascular response.

Heat Acclimatization Protects the Left Ventricle from Increased Diastolic Chamber Stiffness Immediately after Coronary Artery Bypass Surgery: A Lesson from 30 Years of Studies on Heat Acclimation Mediated Cross Tolerance.

During the period of 1986-1997 the first 4 publications on the mechanical and metabolic properties of heat acclimated rat's heart were published. The outcome of these studies implied that heat acclimation, sedentary as well as combined with exercise training, confers long lasting protection against ischemic/reperfusion insult. These results promoted a clinical study on patients with coronary artery disease scheduled for elective coronary artery bypass operations aiming to elucidate whether exploitation of environmental stress can be translated into human benefits by improving physiological recovery. During the 1998 study, immediate-post operative chamber stiffness was assessed in patients acclimatized to heat and low intensity training in the desert (spring in the Dead Sea, 17-33°C) vs. patients in colder weather (spring in non-desert areas, 6-19°C) via echocardiogram acquisition simultaneous with left atrial pressure measurement during fast intravascular fluid bolus administration. We showed that patients undergoing "heat acclimatization combined with exercise training" were less susceptible to ischemic injury, therefore expressing less diastolic dysfunction after cardiopulmonary bypass compared to non-acclimatized patients. This was the first clinical translational study on cardiac patients, while exploiting environmental harsh conditions for human benefits. The original experimental data are described and discussed in view of the past as well as the present knowledge of the protective mechanisms induced by Heat Acclimation Mediated Cross-tolerance.

Who should manage patients with chest pain in the emergency room?

A concise management scheme is discussed for the best outcome in patients with chest pain.

Serum corin is reduced and predicts adverse outcome in non-ST-elevation acute coronary syndrome.

BACKGROUND AND OBJECTIVES: The aim of the current study was to describe the role of corin, an enzyme that cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide into their active peptides, in patients with acute coronary syndrome (ACS). METHODS: Serum corin level was studied in patients with non-ST-elevation ACS who underwent percutaneous coronary intervention (n=152) and in control volunteers (n=103). RESULTS: The corin level was lower in acute coronary syndrome patients (798±288 pg/ml) than in the controls (1165±613 pg/ml, p<0.0001). Those acute coronary syndrome patients who developed major adverse cardiovascular events (MACE; 60.9%) within 3 years of discharge had lower corin levels than the patients who did not experience major adverse cardiovascular events (698.16±233.67 vs. 952.1±297.81 pg/ml, p<0.0001). Using a multiple logistic regression model, corin level was a significant predictor of post-ACS MACE: p=0.0004 for 50 pg/ml steps, AUC 0.791, while p<0.0001, and AUC 0.804 using corin and brain natriuretic peptide as predictors. CONCLUSIONS: Patients with non-ST-elevation ACS have lower serum corin levels than controls. Corin levels are lower in ACS patients who later experience MACE and thus might be predictor for MACE. This new putative biomarker may be useful, either alone or in combination with other biomarkers, for cardiovascular risk stratification assessment and outcome prediction in ACS patients.

Targeted anti-inflammatory systemic therapy for restenosis: the Biorest Liposomal Alendronate with Stenting sTudy (BLAST)-a double blind, randomized clinical trial.

BACKGROUND: Activation of systemic innate immunity is critical in the chain of events leading to restenosis. LABR-312 is a novel compound that transiently modulates circulating monocytes, reducing accumulation of these cells at vascular injury sites and around stent struts. The purpose of the study was to examine the safety and efficacy of a single intravenous bolus of LABR-312 in reducing restenosis in patients treated for coronary narrowing. Patient response was examined in light of differential inflammatory states as evidenced by baseline circulating monocyte levels, diabetes mellitus, and acute coronary syndrome. METHODS: BLAST is a Phase II prospective, randomized, multicenter, double-blind, placebo-controlled trial that assessed the safety and efficacy of LABR-312. Patients were randomized to receive LABR-312 at 2 dose levels or placebo as an intravenous infusion during percutaneous coronary intervention and bare metal stent implantation. The primary end point was mean angiographic in-stent late loss at 6 months. RESULTS: Patients (N = 225) were enrolled at 12 centers. There were no safety concerns associated with the study drug. For the overall cohort, there were no differences between the groups in the primary efficacy end point (in-stent late loss of 0.86 ± 0.60 mm, 0.83 ± 0.57 mm, and 0.81 ± 0.68 mm for the placebo, low-dose, and high-dose group, respectively; P = not significant for all comparisons). In the prespecified subgroups of patients with a baseline proinflammatory state, patients with diabetes mellitus, and patients with high baseline monocyte count, there was a significant treatment effect. CONCLUSIONS: Intravenous administration of LABR-312 to patients undergoing percutaneous coronary intervention is safe and effectively modulates monocyte behavior. The average late loss did not differ between the treatment and placebo groups. However, in the inflammatory patient group with baseline monocyte count higher than the median value, there was a significant reduction in late loss with LABR-312.

Facilitation of left ventricular function recovery post percutaneous coronary intervention by levosimendan.

BACKGROUND: Efficiency of percutaneous revascularization and the utility of levosimendan for advanced ischemic heart failure (HF) is unclear. We examined the efficacy of revascularization and levosimendan on left ventricular ejection fraction (LVEF) and mortality of patients admitted with acute decompensated HF and severe left ventricular dysfunction. METHODS: A prospective case control study that enrolled 84 patients with ischemic decompensated HF with LVEF <35% and preserved LV wall thickness. Group A: 42 patients whose LVEF improved post percutaneous coronary intervention (PCI). Group B1: 22 patients whose LVEF did not improve post-PCI alone but improved after levosimendan. Group B2: 20 patients whose LVEF did not improve neither post-PCI nor post levosimendan. RESULTS: LVEF increased in group A from 22 ± 5 to 29 ± 5% post PCI and continued to improve at the 6 month follow-up (36 ± 4%). In group B1 LVEF did not improve after PCI, but increased after levosimendan from 23 ± 4% to 32 ± 4% and remained constant at 6 months. In group B2 LVEF 26 ± 4% did not change following both interventions. Reverse remodeling with a decrease in end-diastolic and end-systolic diameters was observed only in groups A and B1. Group B2 had a dismal prognosis with 36% in-hospital and 43% six month mortality. Groups A and B1 had a lower in hospital (4.7%, 4.5%) and mid term (11%, 11%) mortality. CONCLUSION: Improvement of LV size and function with better prognosis can be expected in the majority of patients undergoing PCI for decompensated ischemic HF. Levosimendan enhanced the recovery of LV function post PCI.

Endothelial progenitor cells are suppressed in anemic patients with acute coronary syndrome.

OBJECTIVE: Anemia is an independent predictor of poor prognosis in acute coronary syndrome. Endothelial progenitor cells are bone marrow-derived cells that are mobilized into the circulation in response to ischemia. The number of circulating endothelial progenitor cells increases within days of acute coronary syndrome. There is no confirmation regarding the correlation between the occurrence of anemia and the deficiency in endothelial progenitor cells in patients with acute coronary syndrome. The correlation between chronic anemia and endothelial progenitor cells in patients with acute coronary syndrome was investigated. METHODS: Endothelial progenitor cells were examined in 26 patients with acute coronary syndrome. Fifteen patients had chronic nonprogressive anemia, and 11 patients had a normal blood count. Blood samples were drawn on the first day of admission and 4 to 7 days later. Mononuclear cells were separated and cultured on fibronectin-coated plates with EndoCult medium (StemCell Technologies, Vancouver, BC, Canada) for 5 days. Colony forming unit count and a migration assay were performed at each time point. RESULTS: Baseline colony forming unit in the non-anemic group was higher than in the anemic group (P<.0001). There was a highly significant correlation between admission hemoglobin and colony forming unit count (R=0.83, P<.0001). Colony forming units increased in both groups on the second measurement but to a lower extent in the anemic group (P = .0004). The migration assay in the non-anemic group was higher than in the anemic group at baseline (P = .017) and 4 to 7 days later (P = .0054). CONCLUSION: Patients with acute coronary syndrome with anemia demonstrate a reduced number of peripheral endothelial progenitor cells with impaired function, possibly representing a lower capacity for vascular healing. These phenomena may partly explain the poor prognosis observed in patients with acute coronary syndrome and anemia.

Unprotected left main stenting, short- and long-term outcomes.

BACKGROUND: Coronary bypass surgery is recommended for the treatment of left main coronary stenosis. Recently a percutaneous approach has been described as a feasible option. OBJECTIVES: To present the in-hospital and long-term clinical and angiographic outcome of a consecutive group of patients undergoing stenting for unprotected left main coronary artery (LMCA) disease, and to compare the clinical and angiographic outcomes of drug-eluting stent (DES) versus metal stent (BMS). METHODS: 238 consecutive patients underwent unprotected LMCA stenting. 165 received BMS and 73 received DES. Most patients (88.7%) presented with acute coronary syndrome. Clinical (100%) and angiographic (84%) follow-up was obtained. RESULTS: Patients' presentation: STEMI (7.2%), non-STEMI (13.5%), unstable angina (67.6%), stable angina (11.7%). Procedural success rate was 100%. In-hospital mortality was 2.1%, all in patients presented with unstable hemodynamic conditions. None of the patients needed emergent CABG. In the long-term follow-up (average three years) there were 12 deaths (5%), 3 patients required CABG and 25 patients required TVR. The overall angiographic LM restenosis rate show a trend toward lower rate in the DES group than the BMS group (9.6% versus 13.8%, P = 0.08). There was no difference in one year mortality (4.1% versus 4.2%) and AMI (2.7% versus 2.8%) between DES and BMS. CONCLUSIONS: Stenting for LM stenosis can be performed safely with acceptable in hospital and long-term outcome. Reconsideration of current guidelines should be considered. Drug-eluting stent implantation for unprotected LMCA stenosis appears safe with regard to acute and long-term complications and is more effective in preventing restenosis compared to BMS implantation.

Recommendations for the use of cardiac troponin measurement in acute cardiac care.

The release of cardiomyocyte components, i.e. biomarkers, into the bloodstream in higher than usual quantities indicates an ongoing pathological process. Thus, detection of elevated concentrations of cardiac biomarkers in blood is a sign of cardiac injury which could be due to supply-demand imbalance, toxic effects, or haemodynamic stress. It is up to the clinician to determine the most probable aetiology, the proper therapeutic measures, and the subsequent risk implied by the process. For this reason, the measurement of biomarkers always must be applied in relation to the clinical context and never in isolation. There are a large number of cardiac biomarkers, but they can be subdivided into four broad categories, those related to necrosis, inflammation, haemodynamic stress, and/or thrombosis. Their usefulness is dependent on the accuracy and reproducibility of the measurements, the discriminatory limits separating pathology from physiology, and their sensitivity and specificity for specific organ damage and/or disease processes. In recent years, cardiac biomarkers have become important adjuncts to the delivery of acute cardiac care. Therefore, the Working Group on Acute Cardiac Care of the European Society of Cardiology established a committee to deal with ongoing and newly developing issues related to cardiac biomarkers. The intention of the group is to outline the principles for the application of various biomarkers by clinicians in the setting of acute cardiac care in a series of expert consensus documents. The first of these will focus on cardiac troponin, a pivotal marker of cardiac injury/necrosis.

Hypothyroid dependent myocardial angiotensin receptor trafficking is involved in improved cardiac performance after heat acclimation.

AIMS: The renin-angiotensin system (RAS) plays a key role in heat acclimation, a process which induces adaptive changes in cardiac function. These changes are mediated in part by reduced thyroid hormone activity and improve myocardial function during and following exposure to various (non-heat) stresses such as ischemia. The aim of this study was to examine the role of RAS in the development of the heat acclimated protected heart. MAIN METHODS: Three treatment groups were used: (1) C, controls; (2) AC, heat acclimated rats (1mo 34 degrees C,); and (3) HAEL, heat acclimated euthyroid rats treated with 3ng/ml of eltroxine. A Langendorff perfusion apparatus was used to measure hemodynamic parameters at baseline and following administration of angiotensin-II, losartan and PD123319 in isolated hearts. Protein and mRNA levels of angiotensin receptors were measured. KEY FINDINGS: Both C and HAEL animals showed increased contractility and a drop in coronary flow during angiotensin II exposure whereas AC animals did not have an inotropic response or vasoconstriction. Significantly different patterns of AT1 and AT2 receptor densities (a 50% reduction and a 30% increase in outer cell membrane AT1 and AT2 receptors respectively) were observed in AC animals compared to the other two groups. AT receptor mRNA levels were similar in all treatment groups. SIGNIFICANCE: The attenuated response of heat acclimated hearts to angiotensin is mediated by reduced thyroxine levels and is associated with a shift in AT1 receptors from the outer to the inner membrane. This shift appears to be caused by modified posttranslational trafficking of AT receptors.

Enzyme-linked immunoabsorbent assay for detection of human serine protease corin in blood.

BACKGROUND: Corin is a tissue type II transmembrane protein that converts pro-atrial natriuretic peptides and pro-brain natriuretic peptide to their active forms. Despite their protecting effect, high levels of these peptides indicate a bad prognosis. One of the possible explanations to this paradox is reduced cleavage due to low corin levels. The purpose of this study was to develop an assay to detect blood levels of corin. METHODS: ELISA was developed using rat monoclonal antibody to recombinant human corin as capture antibody, and biotinylated goat anti-human corin as detection antibody. RESULTS: Based on known corin concentration as standards, the ideal capture antibody concentration was 500 ng/ml, and 200 ng/ml for detection antibody. The coefficient of variation was 5.7% for inter-assay and 3.9% for intra-assay precision. Corin levels were stable when stored at room temperature for 1 day, for 3 days at 4 degrees C or up to 1 year in -35 degrees C. Human serum corin levels were reproducibly measured in individuals and found to range from 296 to 2590 pg/ml. CONCLUSIONS: The immunoabsorbent assay developed in this study can accurately and reliably determine human serum corin levels, and is suitable for simple screening of corin in clinical practice.

Comparison of treatment and outcome of acute coronary syndrome in patients with versus patients without diabetes mellitus.

The aim was to evaluate management and outcomes in patients with diabetes mellitus (DM) with acute coronary syndrome (ACS). The EHS-ACS-II was a multinational survey conducted in 2004 that included 6,385 consecutive patients with ACS. The management and outcomes of patients with and without DM were compared. DM was recognized in 1,587 patients (25%) with ACS. Patients with DM had a less favorable risk-factor profile, less typical presentation, and longer delay in seeking medical attention; presented more frequently with arrhythmias, heart failure, renal failure, and major bleeding; and had higher in-hospital and 1-year mortality. They were treated more often with diuretics and inotropic agents and less often with antiaggregants (glycoprotein IIb/IIIa and clopidogrel). Insulin was administered to 53% of patients with DM during hospitalization and 31% at discharge. Patients with DM with ST-elevation (STE) myocardial infarction underwent similar primary percutaneous and coronary interventions (but received less thrombolytic therapy). Patients with DM with non-STE ACS underwent less in-hospital revascularization and had significantly higher 1-year mortality. Multivariable analyses showed DM as a predictor of 1-year mortality (odds ratio 1.37, 95% confidence interval 1.09 to 1.71), but not in-hospital mortality. In conclusion, given the current treatment, patients with and without DM with ACS had similar in-hospital adjusted mortality, but patients with DM had increased 1-year mortality. Patients with DM with non-STE ACS posed a higher risk group.

Loss of systemic endothelial function post-PCI.

Loss of endothelial function (LEF) post-PCI may contribute to both acute and long-term complications. A protective effect of BNP on endothelium was suggested previously. Flow-mediated vasodilation (FMD) of the brachial artery, as well as plasma levels of endothelin, BNP, Pro BNP and corin were measured before and following routine PCI. 49 patients with normal baseline endothelial function were recruited. 30 patients developed LEF and were randomized to i.v. nesiritide (the commercially available recombinant form of human BNP) or saline infusion for 3 h. Patients who developed LEF post-PCI had reduced baseline plasma corin levels and their BNP/ProBNP ratio was reduced after the procedure. Nesiritide infusion significantly improved FMD both immediately (Nesiritide versus saline: 2.87+/-0.78% versus 0.51+/-0.25%, P=0.007) and 24 h after the treatment (2.52+/-0.69% versus 0.72+/-0.32%, P=0.025). The elevated plasma ET-1 was reduced by Nesiritide (0.38+/-0.11 fmol/ml 24 h post-PCI versus 0.16+/-0.02 fmol/ml 24 h post BNP, P=0.047), but remained unchanged in saline group (0.39+/-0.21 fmol/ml versus 0.42+/-0.23 fmol/ml, P=0.749). Systemic LEF post-PCI is a frequent event. It may be related to impaired cleavage of ProBNP to BNP. Short-term i.v. nesiritide improves systemic LEF post-PCI.