Thomas J. Kiernan

Circulating CD34+ Cell Subsets in Patients with Coronary Endothelial Dysfunction

Background Endothelial dysfunction is an early manifestation of atherosclerotic disease. Circulating cells that express CD34, including endothelial and hematopoietic progenitor cells, might play a part in the development and progression of atherosclerosis. The aim of this study was to evaluate the association between coronary endothelial dysfunction and concentrations of circulating CD34+ cell subsets.Methods Intracoronary acetylcholine challenge was used to test for coronary endothelial dysfunction in 57 consecutive patients scheduled to undergo diagnostic coronary angiography and with no signs of substantial obstructive lesions. Mononuclear cells were extracted from whole blood samples taken from all patients, analyzed by flow cytometry for CD14, CD34, CD133, CD45, and vascular endothelial growth factor receptor 2 (VEGFR2), and cultured for functional analysis.Results Compared with patients with normal coronary endothelial function, in those with coronary endothelial dysfunction, the number of circulating CD34+/CD45dim/VEGFR2− cells, CD34+/CD45dim/CD133+/VEGFR2− cells and colony-forming units were reduced. Concentrations of CD34+/CD45−/VEGFR2+ cells did not differ between groups.Conclusions Regulation of CD34+ cell subsets seems to differ between patients with coronary endothelial dysfunction and those with normal coronary endothelial function. Changes in specific circulating progenitor cell subsets might, therefore, be an early manifestation of atherosclerosis.

Circadian rhythm of appropriate implantable cardioverter defibrillator discharges in patients with hypertrophic cardiomyopathy.

Aims: To characterize the circadian pattern of implantable cardioverter defibrillators (ICD) discharges in patients with hypertrophic cardiomyopathy (HCM) without previous surgical myectomy or percutaneous alcohol septal ablation.

Effect of enhanced external counterpulsation on circulating CD34+ progenitor cell subsets

BACKGROUND Enhanced external counterpulsation (EECP) is associated with improvement in endothelial function, angina and quality of life in patients with symptomatic coronary artery disease, although the mechanisms underlying the observed clinical benefits are not completely clear. The purpose of this study was to examine the effects of EECP on circulating haematopoietic progenitor cells (HPCs) and endothelial progenitor cells (EPCs) in patients with refractory angina. We compared HPC and EPC counts between patients scheduled for EECP and patients with normal angiographic coronary arteries, with and without coronary endothelial dysfunction. We hypothesized that an increase in circulating bone marrow derived progenitor cells in response to EECP may be part of the mechanism of action of EECP. METHODS Thirteen consecutive patients scheduled to receive EECP treatment were prospectively enrolled. Clinical characteristics were recorded and venous blood (5 ml) was drawn on day 1, day 17, day 35 (final session) and one month post completion of EECP therapy. Buffy coat was extracted and HPCs and EPCs were counted by flow cytometry. RESULTS Median Canadian Cardiovascular Society (CCS) angina class decreased and Duke Activity Status Index (DASI) functional score increased significantly (both, p < 0.05) in response to EECP, an effect that was maintained at one month after termination of treatment. Flow cytometric analysis revealed an accompanying significant increase in CD34+, CD133+ and CD34+, CD133+ CPC counts over the course of treatment (p < 0.05). DASI scores correlated significantly with CD34+ (R = 0.38 p = 0.02), CD133+ (R = 0.5, p = 0.006) and CD34+, CD133+ (R = 0.47, p = 0.01) CPC counts. CONCLUSION This study shows that HPCs, but not EPCs are significantly increased in response to EECP treatment and correlate with reproducible measures of clinical improvement. These findings are the first to link the functional improvement observed with EECP treatment with increased circulating progenitor cells.

Nonrevascularizable coronary artery disease following coronary artery bypass graft surgery: a population-based study in Olmsted County, Minnesota.

AimsTherapeutic options for patients with recurrent cardiac ischemia after coronary artery bypass surgery may be limited and some patients may be considered nonrevascularizable. To further the understanding of this patient cohort, we performed a population-based study of post-coronary bypass patients who developed recurrent angina. Methods and resultsPatients who underwent coronary artery and bypass graft angiography at Mayo Clinic from 2001 to 2005 were identified. Medical records were reviewed to determine indication for angiography, and angiographic analysis was performed in all patients. Among 133 000 residents of Olmsted County, Minnesota, 347 post-bypass patients with angina underwent coronary angiography from 2001 to 2005. Of these, 177 patients received further revascularization (145 percutaneous coronary intervention and 32 redo coronary artery bypass grafting) and the remaining 170 patients were managed medically. Revascularization was not associated with improvement in all-cause or cardiac mortality. Multivariate analysis identified renal dysfunction, diabetes, and severe left ventricular dysfunction but not the lack of revascularization as predictors of mortality. ConclusionIn this population-based study, we identified a yearly incidence range of 17.9–33.2 patients with nonrevascularizable angina after coronary artery bypass grafting per 100 000 population. Further revascularization was not associated with improved mortality or morbidity. Attempts to develop therapeutics for this population must consider the incidence and outcomes of this cohort.

Dolasetron overdose resulting in prolonged QTc interval and severe hypotension: a case report and literature review

Dolasetron (Anzemet) overdose is uncommon, and, to our knowledge, this is the only case report of an intentional overdose. Dolasetron (dolasetron mesylate) is a selective 5-hydroxytryptamine 3 antagonist derived from pseudopelletierine, and is used in the prevention and treatment of nausea and vomiting. Transient and asymptomatic ECG changes, including QRS widening and PR and QTc prolongation, have been reported in therapeutic doses. The case of a 21-year-old woman who presented after an intentional overdose of 10×200 mg dolasetron tablets resulting in prolongation of the QTc interval and severe hypotension is reported here. Management of hypotension included intravenous fluid resuscitation and norepinephrine infusion with invasive monitoring in a high dependency unit. Sodium cardiac channel block contributes to cardiotoxicity observed in dolasetron overdose. Sodium bicarbonate was used in an attempt to reduce cardiac sodium channel block, although we observed no apparent benefit. As dolasetron becomes more commonly used in the outpatient setting, both doctors and patients need to be aware of the dangers of dolasetron in toxic doses. The pharmacology and toxicology of dolasetron are discussed.

Vasoprotective effects of human CD34+ cells: towards clinical applications

BackgroundThe development of cell-based therapeutics for humans requires preclinical testing in animal models. The use of autologous animal products fails to address the efficacy of similar products derived from humans. We used a novel immunodeficient rat carotid injury model in order to determine whether human cells could improve vascular remodelling following acute injury.MethodsHuman CD34+ cells were separated from peripheral buffy coats using automatic magnetic cell separation. Carotid arterial injury was performed in male Sprague-Dawley nude rats using a 2F Fogarty balloon catheter. Freshly harvested CD34+ cells or saline alone was administered locally for 20 minutes by endoluminal instillation. Structural and functional analysis of the arteries was performed 28 days later.ResultsMorphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 ± 0.18, and 1.71 ± 0.18 for CD34, and saline-treated vessels, respectively P < 0.05). Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 ± 10.2, and 36.8 ± 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05)ConclusionDelivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury. These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.

Vasculoprotective Effects of Erythropoietin New Developments and New Alternatives

The body of evidence demonstrating the vasculoprotective effects of direct cell-based therapies to inhibit the acute response to vascular injury continues to grow. Delivery of autologous circulation-derived cells capable of assuming an endothelial phenotype to an injured arterial segment results in early reendothelialization and normalization of vascular function.1–3 Current applications of this approach require cell isolation and modification in vitro, followed by direct delivery. However, novel approaches are being developed to avoid the inherent translational concerns of this strategy. Broadly, these new approaches include the mobilization and targeting of cell populations capable of augmenting reendothelialization of injured arteries while limiting neointimal formation. Multiple cytokines have been shown to mobilize cells capable of assuming an endothelial phenotype (broadly known as EPCs). These cytokines include VEGF, G-CSF, GM-CSF, and erythropoietin (Epo). The article by Urao et al4 in this issue of Circulation Research extends the observation that Epo can mobilize EPCs while demonstrating its ability to enhance reendothelialization and inhibit neointimal formation after vascular injury in an NO-dependent manner. Taken together, these findings extend our understanding of the role of Epo as a tissue protectant and apply it to the setting of acute vascular injury. The article by Urao tested the hypothesis that systemic delivery of recombinant human Epo would inhibit neointimal formation in a mouse carotid artery wire injury model.4 Epo (1000 IU/kg of body weight) was administered for 3 days beginning at the time of arterial injury. Morphometric analysis of serial arterial sections performed at 14 days after injury showed a 52% decrease in the neointimal area in the Epo-treated mice compared with the saline injected …

Medical Therapy for Chronic Refractory Angina

Medical therapy is the cornerstone of treatment for patients with chronic refractory angina, as it is across the entire spectrum of vascular disease. As part of a comprehensive risk modification program, including exercise, diet, and appropriate revascularization, optimal medical therapy offers significant benefit in reducing symptoms of ischemic heart disease and improving long-term prognosis. Indeed, current medical regimens, far superior to those offered only a decade ago, afford patients with refractory angina a marked survival benefit. Newer agents have demonstrated a marked symptomatic benefit, as well. This chapter will explore the importance of optimal medical therapy in improving prognosis, as well as details potential for imparting a much needed boost to quality of life and symptom amelioration.

THE UTILIZATION OF PTFE COVERED STENTS FOR THE TREATMENT OF RENAL ARTERY IN-STENT RESTENOSIS

Background: The optimal treatment for renal artery in-stent restenosis (RAISR) is not well established. Reintervention with balloon angioplasty, cutting-balloon, or additional bare-metal or drug-eluting stents can achieve immediate angiographic success. However, recurrent RA-ISR rates are high regardless of treatment strategy. Initial success with PTFE-covered stents, which may block in-growth of neointima, has led to expanded use for ISR.

PROGNOSTIC VALUE OF THE MAYO CLINIC RISK SCORE FOR CORONARY ARTERY REVASCULARIZATION USING THE AUSTRALASIAN SOCIETY OF CARDIAC AND THORACIC SURGEONS AND THE MELBOURNE INTERVENTIONAL GROUP REGISTRIES

Authors: Bryan P. Yan, Cheng-Hon Yap, Nick Andrianopoulos, Thomas J. Kiernan, Andrew E. Ajani, Julian A. Smith, David J. Clark, Stephen J. Duffy, Gilbert C. Shardey, Angela L. Brennan, Diem T. Dinh, Christopher M. Reid, Bernard J. Gersh, Australasian Society of Cardiac and Thoracic Surgeons and Melbourne Interventional Group, Chinese University of Hong Kong, Hong Kong, Hong Kong, Monash University, Melbourne, Australia