Pedro L. Sánchez

Experimental and Clinical Regenerative Capability of Human Bone Marrow Cells After Myocardial Infarction

Bone marrow mononuclear cells (BMCs) from 20 patients with extensive reperfused myocardial infarction (MI) were used to assess their myocardial regenerative capability “in vitro” and their effect on postinfarction left ventricular (LV) remodeling. Human BMCs were labeled, seeded on top of cryoinjured mice heart slices, and cultured. BMCs showed tropism for and ability to graft into the damaged mouse cardiac tissue and, after 1 week, acquired a cardiomyocyte phenotype and expressed cardiac proteins, including connexin43. In the clinical trial, autologous BMCs (78±41×106 per patient) were intracoronarily transplanted 13.5±5.5 days after MI. There were no adverse effects on microvascular function or myocardial injury. No major cardiac events occurred up to 11±5 months. At 6 months, magnetic resonance showed a decrease in the end-systolic volume, improvement of regional and global LV function, and increased thickness of the infarcted wall, whereas coronary restenosis was only 15%. No changes were found in a nonrandomized contemporary control group. Thus, BMCs are capable of nesting into the damaged myocardium and acquire a cardiac cell phenotype in vitro as well as safely benefiting ventricular remodeling in vivo. Large-scale randomized trials are needed now to assess the clinical efficacy of this treatment.

Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial.

AIMS Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. METHODS AND RESULTS Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. CONCLUSION Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients.

Which Patients Benefit From Percutaneous Mitral Balloon Valvuloplasty

Background— Percutaneous mitral balloon valvuloplasty (PMV) results in good immediate results, particularly in patients with echocardiographic scores (Echo-Sc) ≤8. However, which variables relate t...

Prognostic relations between inflammatory markers and mortality in diabetic patients with non-ST elevation acute coronary syndrome

Objective: To determine the differences in the inflammatory status between diabetic and non-diabetic patients and to evaluate the usefulness of C reactive protein, fibrinogen, and leucocyte count as predictors of death in diabetic patients with unstable coronary disease. Design: Nested case-control comparisons of the inflammatory status between diabetic and non-diabetic patients. Prospective cohort analysis of C reactive protein concentration, fibrinogen concentration, and leucocyte count as predictors of cardiovascular death in diabetic patients. Setting: Coronary care unit in Spain. Participants: 83 diabetic patients with non-ST elevation acute coronary syndrome and 83 sex and aged matched patients selected from 361 non-diabetic patients with non-ST elevation acute coronary syndrome. Main outcome measures: Plasma concentrations of C reactive protein and fibrinogen, and leucocyte count. Investigators contacted patients to assess clinical events. Results: Concentrations of C reactive protein and fibrinogen, and leucocyte count on admission were higher in diabetic than in non-diabetic patients (7 mg/l v 5 mg/l, p  =  0.020; 3.34 g/l v 2.90 g/l, p  =  0.013; and 8.8 × 109/l v 7.8 × 109/l, p  =  0.040). Among diabetic patients, these values were also higher in those who died during the 22 month follow up (13 mg/l v 6 mg/l, p  =  0.001; 3.95 g/l v 3.05 g/l, p < 0.001; and 11.4 × 109/l v 8.4 × 109/l, p  =  0.005). After adjustment for confounding factors, diabetic patients in the highest tertile of C reactive protein had a hazard ratio for cardiovascular death of 4.51 (95% confidence interval (CI) 1.62 to 12.55). Similar hazard ratios were for fibrinogen 3.74 (95% CI 1.32 to 10.62) and for leucocyte count 3.64 (95% CI 1.37 to 9.68). Conclusions: Inflammation appears more evident in diabetic than in non-diabetic patients with acute coronary syndrome. C reactive protein concentration, fibrinogen concentration, and leucocyte count constitute independent predictors of cardiovascular death in diabetics with unstable coronary disease.

Association between self-replicating calcifying nanoparticles and aortic stenosis: a possible link to valve calcification.

AIMS Among various hypotheses proposed for pathological tissue calcification, recent evidence supports the possibility that self-replicating calcifying nanoparticles (CNPs) can contribute to such calcification. These CNPs have been detected and isolated from calcified human tissues, including blood vessels and kidney stones, and are referred to as nanobacteria. We evaluated calcific aortic valves for the presence of CNP. METHODS AND RESULTS Calcific aortic valves were obtained from 75 patients undergoing surgical valve replacement. The control group was formed by eight aortic valves corresponding to patients with heart transplants. In the microbiology laboratory, valves were screened for CNP using a 4-6 weeks specific culture method. The culture for CNP was positive in 48 of the 75 valves with aortic stenosis (64.0%) in comparison with zero of eight (0%) for the control group (P = 0.0005). The observation of cultures by way of scanning electron microscopy highlighted the resemblance in size and morphology of CNP. CONCLUSION Self-replicating calcific nanometer-scale particles, similar to those described as CNP from other calcific human tissues, can be cultured and visualized from calcific human aortic valves. This finding raises the question as to whether CNP contribute to the pathogenesis of the disease or whether they are only innocent bystanders.

Patient Registries of Acute Coronary Syndrome Assessing or Biasing the Clinical Real World Data

Background—The risk of selection bias in registries and its consequences are relatively unexplored. We sought to assess selection bias in a recent registry about acute coronary syndrome and to explore the way of conducting and reporting patient registries of acute coronary syndrome. Methods and Results—We analyzed data from patients of a national acute coronary syndrome registry undergoing an audit about the comprehensiveness of the recruitment/inclusion. Patients initially included by hospital investigators (n=3265) were compared to eligible nonincluded (missed) patients (n=1439). We assessed, for 25 exposure variables, the deviation of the in-hospital mortality relative risks calculated in the initial sample from the actual relative risks. Missed patients were of higher risk and received less recommended therapies than the included patients. In-hospital mortality was almost 3 times higher in the missed population (9.34% [95% CI, 7.84 to 10.85] versus 3.9% [95% CI, 2.89 to 4.92]). Initial relative risks diverged from the actual relative risks more than expected by chance (P<0.05) in 21 variables, being higher than 10% in 17 variables. This deviation persisted on a smaller degree on multivariable analysis. Additionally, we reviewed a sample of 129 patient registries focused on acute coronary syndrome published in thirteen journals, collecting information on good registry performance items. Only in 38 (29.4%) and 48 (37.2%) registries was any audit of recruitment/inclusion and data abstraction, respectively, mentioned. Only 4 (3.1%) authors acknowledged potential selection bias because of incomplete recruitment. Conclusions—Irregular inclusion can introduce substantial systematic bias in registries. This problem has not been explicitly addressed in a substantial number of them.

Early Translation of Adipose-Derived Cell Therapy for Cardiovascular Disease

Over the past decade, cell therapy has emerged as a new approach to reversing myocardial ischemia. Several types of adult stem cells have been studied in both preclinical and clinical conditions for this purpose: bone marrow cells, circulating cells, and myoblasts. Nevertheless, the quest for the ideal “anti-ischemic” cell is still ongoing. Recently, the existence of a population of stem cells located in adipose tissue (adipose-derived stem cells) has been observed. These are able to differentiate into multiple cell lineages including cardiomyocytic differentiation. In this review we discuss the basic principles of adipose-derived stem cells (types and characteristics, harvesting, and expansion), the initial experimental studies, and the currently ongoing clinical trials.

Contribution of the Diastolic Vortex Ring to Left Ventricular Filling

BACKGROUND Intraventricular fluid dynamics can be assessed clinically using imaging. The contribution of vortex structures to left ventricular (LV) diastolic function has never been quantified in vivo. OBJECTIVES This study sought to understand the impact of intraventricular flow patterns on filling and to assess whether impaired fluid dynamics may be a source of diastolic dysfunction. METHODS Two-dimensional flow velocity fields from color Doppler echocardiographic sequences were obtained in 20 patients with nonischemic dilated cardiomyopathy (NIDCM), 20 patients with hypertrophic cardiomyopathy (HCM), and 20 control healthy volunteers. Using a flow decomposition method, we isolated the rotational velocity generated by the vortex ring from the surrounding flow in the left ventricle. RESULTS The vortex was responsible for entering 13 ± 6% of filling volume in the control group and 19 ± 8% in the NIDCM group (p = 0.004), but only 5 ± 5% in the HCM group (p < 0.0001 vs. controls). Favorable vortical effects on intraventricular pressure gradients were observed in the control and NIDCM groups but not in HCM patients. Differences in chamber sphericity explained variations in the vortex contribution to filling between groups (p < 0.005). CONCLUSIONS The diastolic vortex is responsible for entering a significant fraction of LV filling volume at no energetic or pressure cost. Thus, intraventricular fluid mechanics are an important determinant of global chamber LV operative stiffness. Reduced stiffness in NIDCM is partially related to enhanced vorticity. Conversely, impaired vortex generation is an unreported mechanism of diastolic dysfunction in HCM and probably other causes of concentric remodeling.

Do GRACE (Global Registry of Acute Coronary events) risk scores still maintain their performance for predicting mortality in the era of contemporary management of acute coronary syndromes

BACKGROUND Although the GRACE risk scores (RS) are the preferred scoring system for risk stratification in acute coronary syndromes (ACS), little is known whether these RS still maintain their performance in the current era. We aimed to investigate this issue in a contemporary population with ACS. METHODS The study population composed of patients enrolled in the MASCARA national registry. The GRACE RS were calculated for each patient. Discrimination and calibration were evaluated with the C statistic and the Hosmer-Lemeshow test, in the whole population and according to the type of ACS, risk strata, and whether the patient had a history of diabetes and/or chronic renal failure. We determined if left ventricular ejection fraction (LVEF) provides incremental prognostic information above that established by the RS and whether percutaneous coronary intervention (PCI) during admission affects the performance of the score for predicting 6-month mortality. RESULTS The 5,985 patients constituted the validation cohort for the in-hospital mortality RS and 5,635 the validation cohort for the 6-month mortality RS. Overall, both GRACE RS demonstrated excellent discrimination (C > 0.80) and calibration (all P values in Hosmer-Lemeshow >.1). Although similar results were seen in all subgroups, the 6-month mortality RS performed significantly less well in patients undergoing PCI compared to those patients who did not (C = 0.73 vs 0.76, P < .004). Adding LVEF to the RS did not convey significant prognostic information. CONCLUSIONS The GRACE RS for predicting in-hospital and 6-month mortality still maintain their excellent performance in a contemporary cohort of patients with ACS. Further studies are needed to investigate the performance of the 6-month mortality GRACE score in patients undergoing in-hospital PCI. Left ventricular ejection fraction did not convey significant information over that provided by the RS.

Improved Prognosis After Using Mild Hypothermia to Treat Cardiorespiratory Arrest Due to a Cardiac Cause: Comparison With a Control Group

INTRODUCTION AND OBJECTIVES Patients who survive a cardiac arrest have a poor short-term prognosis in terms of mortality and neurological function. The use of mild hypothermia has been investigated in only a few randomized studies, but appears to be effective for treating these patients. The aim of this study was to investigate the effect of this treatment on survival and neurological outcomes. METHODS We compared mild hypothermia and usual treatment in patients who had experienced a prolonged cardiac arrest due to ventricular fibrillation or tachycardia and who showed signs of neurological damage. Patient were divided into two groups: a control group of 28 patients and a group of 41 patients who were treated with hypothermia. Patients were assessed at discharge and at 6 months. RESULTS There was no significant difference between the two groups in baseline characteristics, including those of the cardiac arrest, or in the time to treatment. At discharge, neurological status was good in 18 patients (43.9%) in the hypothermia group but in only five (17.9%) in the control group (risk ratio=2.46; 95% confidence interval, 1.11-3.98; P=.029). At 6 months after discharge, neurological status was found to be good in 19 patients (46.3%) in the treatment group and six (21.4%) in the control group (risk ratio=2.16; 95% confidence interval, 1.05-3.36; P=.038). The effect of hypothermia may have been affected by various confounding factors. CONCLUSIONS Our findings demonstrate that hypothermic treatment after cardiac arrest prolonged by ventricular fibrillation or tachycardia helps improve the prognosis of anoxic encephalopathy.