Henry Quevedo

Bone Marrow Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and Differentiation

Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow–derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow–derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit+ CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2–5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity

The mechanism(s) underlying cardiac reparative effects of bone marrow-derived mesenchymal stem cells (MSC) remain highly controversial. Here we tested the hypothesis that MSCs regenerate chronically infarcted myocardium through mechanisms comprising long-term engraftment and trilineage differentiation. Twelve weeks after myocardial infarction, female swine received catheter-based transendocardial injections of either placebo (n = 4) or male allogeneic MSCs (200 million; n = 6). Animals underwent serial cardiac magnetic resonance imaging, and in vivo cell fate was determined by co-localization of Y-chromosome (Ypos) cells with markers of cardiac, vascular muscle, and endothelial lineages. MSCs engrafted in infarct and border zones and differentiated into cardiomyocytes as ascertained by co-localization with GATA-4, Nkx2.5, and α-sarcomeric actin. In addition, Ypos MSCs exhibited vascular smooth muscle and endothelial cell differentiation, contributing to large and small vessel formation. Infarct size was reduced from 19.3 ± 1.7% to 13.9 ± 2.0% (P < 0.001), and ejection fraction (EF) increased from 35.0 ± 1.7% to 41.3 ± 2.7% (P < 0.05) in MSC but not placebo pigs over 12 weeks. This was accompanied by increases in regional contractility and myocardial blood flow (MBF), particularly in the infarct border zone. Importantly, MSC engraftment correlated with functional recovery in contractility (R = 0.85, P < 0.05) and MBF (R = 0.76, P < 0.01). Together these findings demonstrate long-term MSC survival, engraftment, and trilineage differentiation following transplantation into chronically scarred myocardium. MSCs are an adult stem cell with the capacity for cardiomyogenesis and vasculogenesis which contribute, at least in part, to their ability to repair chronically scarred myocardium.

Prevalence of conduction abnormalities in a systolic heart failure population by race, ethnicity, and gender.

Background: There is paucity of data regarding conduction abnormalities in the Hispanic population with systolic heart failure (HF). We aimed to evaluate the prevalence of electrocardiogram (ECG) abnormalities in a systolic HF population, with attention to the Hispanic population.

Clinical Features of Takotsubo Cardiomyopathy - A Single-Center Experience

Takotsubo cardiomyopathy (TTC), also known as transient apical ballooning syndrome or stress-induced cardiomyopathy, is a distinctive reversible condition often affecting postmenopausal women after a stressful event. It is characterized by sudden temporary systolic dysfunction of the apical and/or mid-segments of the left ventricle. The underlying mechanisms have not yet been elucidated, but several hypotheses include catecholamine cardiotoxicity, microvascular dysfunction and coronary artery spasm. We conducted a retrospective descriptive study on patients with the discharge diagnosis of TTC from 2003 to 2012 at Danbury Hospital, Danbury, Conn., USA. A total of 78 patients met the Modified Mayo Criteria for the Diagnosis of TTC and were included in the study. Clinical characteristics at baseline, past surgical and medical history including psychiatric records were reviewed and recorded. The mean age was 70.5 ± 14 years, 87% (n = 68) were women, of which 11.7% (n = 8) were aged ≤55 years. Depression was present in 20.5% (n = 16) of the patients and anxiety in 30.8% (n = 24). Twenty-one patients (27.3%) reported a preceding emotional stressful event and 31 (40.3%) had a preceding physical stressor. Fifty patients (64.1%) presented with chest pain, 28 (35.9%) had ST-segment elevation upon admission and 5 (6.3%) died during their hospital stay. TTC is becoming an increasingly recognized condition and clinicians should include it in the differential diagnosis of patients presenting with a suspected acute coronary syndrome. It is frequent in postmenopausal women with preceding physical or emotional stress and overall prognosis is good among patients who survive the initial acute phase of heart failure.

Feasibility of a Heart Failure Disease Management Program in Eastern Europe: Tbilisi, Georgia

Background— Little is known about the importation of a heart failure disease management program (HFDMP) into low- and middle-income countries. We examined the feasibility of importing a HFDMP into the country of Georgia, located in the Caucuses. Methods and Results— Patients with ejection fraction ⩽40% were enrolled into a prospective, observational study consisting of a new HFDMP staffed by local cardiologists. Medications, emergency department use, hospital admissions, and mortality were assessed by interviews with patients or their families. Screening resulted in 400 patients who were followed for 10.2±3.5 months. &bgr;-Blocker prescriptions increased from 7.4–80.7% (P<0.001), angiotensin-converting enzyme inhibitor prescriptions increased from 18.4–92.6% (P<0.001), and mean systolic blood pressure declined from 145 to 114 mm Hg (P<0.001). Patients visiting the emergency department and hospitalizations were lowered by 40.7% and 52.5%, respectively, but were also influenced by the outbreak of war, during which 17.5% (n=70) of patients received follow-up in refugee tents. All-cause mortality extended to 7% of patients, with 12 of 28 deaths caused by war-related events. Conclusions— Importation of a Western HFDMP was demonstrated to be feasible, with a 5-fold increase in the use of recommended therapies, reduction of blood pressure, decrease of emergency department visits, and hospitalizations for heart failure. These measures could result in substantial cost savings in resource-limited settings, but assessment is complicated in unstable areas. Translating effective interventions to low- and middle-income countries requires sensitivity to regional cultures and flexibility to adapt both clinical goals and strategies to unexpected conditions.

Effects of combination of proliferative agents and erythropoietin on left ventricular remodeling post-myocardial infarction.

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post–myocardial infarction (MI) effects synergistically.

Eliminating Disparities in Hypertension Care for Hispanics and Blacks Using a Heart Failure Disease Management Program

Objectives: This study assessed if patients enrolled in a heart failure disease management program (HFDMP) reach the JNC VII target goals for blood pressure (BP) control, eliminate disparities in hypertension control by race/ ethnicity and the impact BP control has on survival. Methods: Patients (N = 898) with an ejection fraction <40% were enrolled into two HFDMPs and screened for hypertension, defined as BP > 130/80. Results: Mean baseline systolic BP (SBP) 132 ± 25.5 mm Hg and diastolic BP (DBP) 79 ± 16.8 mm Hg. Final mean SBP decreased to 129.6 mm Hg, DBP 77.6 mm Hg. Whites had the highest rate of achieving BP goals. Mortality reduction was associated with minority race, history of hypertension, increase ejection fraction and statin use. Conclusion: HFDMPs are an effective way to reduce BP in hypertensive patients. Disparities by race and ethnicity were not seen after adjustment for disease modifiers. There was no mortality difference in those who reached BP goal.