Joshua M. Hare

Complications of transvenous right ventricular endomyocardial biopsy in adult patients with cardiomyopathy: A seven-year survey of 546 consecutive diagnostic procedures in a tertiary referral center

To determine the incidence, nature and subsequent management of complications occurring during right ventricular endomyocardial biopsy in patients with cardiomyopathy, all events occurring during 546 procedures in 464 consecutive patients were prospectively recorded. The internal jugular vein was the primary site of introduction in 96% of cases. A total of 33 complications (6%) occurred: 15 (2.7%) during catheter insertion including 12 arterial punctures (2%), 2 vasovagal reactions (0.4%) and 1 episode of prolonged bleeding (0.2%), all without sequelae; 18 (3.3%) during biopsy included 6 arrhythmias (1.1%), 5 conduction abnormalities (1%), 4 possible perforations (0.7%) and 3 definite perforations (0.5%) (pericardial fluid). Two (0.4%) of the three patients with a perforation died. There was no secular trend in the complication rate, nor were complications associated with specific clinical or hemodynamic characteristics. It is concluded that the overall rate of endomyocardial biopsy complications (6%) is low, but mortality may occur.

Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy

Current treatments for ischemic cardiomyopathy are aimed toward minimizing the deleterious consequences of diseased myocardium. The possibility of treating heart failure by generating new myocardium and vascular tissue has been an impetus toward recent stem cell research. Mesenchymal stem cells (MSC), also referred to as marrow stromal cells, differentiate into a wide variety of lineages, including myocardial and endothelial cells. The multi–lineage potential of MSCs, their ability to elude detection by the host immune system, and their relative ease of expansion in culture make MSCs a very promising source of stem cells for transplantation. In addition, emerging experimental results with MSCs offer novel mechanistic insights into cardiac regenerative therapy in general. Here we review the characterization of MSCs, animal and human trials studying MSCs in cardiomyogenesis and vasculogenesis in postinfarct myocardium, routes of delivery, and potential mechanisms of stem cell repair.

Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of Obesity

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob, db/db, and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.

Nitroso–Redox Interactions in the Cardiovascular System

ormal cardiovascular performance requires exquisitebalancing of many complex biochemical processes.Perturbation of this balance may lead to myocardial dysfunc-tion or may be a secondary result of structural heart diseasesuch as myocardial infarction (MI) or cardiomyopathic pro-cesses. Altered signaling systems in turn contribute to theprogression of myocardial dysfunction. The roles of reactiveoxygen species (ROS) and reactive nitrogen species (RNS) innormal and failing myocardium and vasculature have beenthe subject of intense investigation and continue to engenderconsiderabledebate.Adisturbanceintheoxidation–reductionstate of the cell, in which ROS production exceeds antioxi-dant defenses, is called oxidative stress. By analogy, nitrosa-tive stress is an impairment in nitric oxide (NO) signalingcaused by increased amounts of RNS, which may be causedby or associated with a disturbance in the redox state. Thisreview addresses the role of the redox state and nitroso–redoxbalance in determining cardiovascular function in health anddisease.

Stem Cell Therapy for Cardiac Repair Ready for the Next Step

Coronary heart disease and heart failure continue to be significant burdens to healthcare systems in the Western world. In the United States alone, there are 7.1 million survivors of myocardial infarction (MI) and 4.9 million people living with congestive heart failure (CHF).1 Despite recent advances in medical and device therapy for heart failure, the incidence, hospitalization, and mortality rates continue to rise. After receiving a diagnosis of CHF, 1 in 5 patients will be dead within 12 months.1 Therefore, any new treatment modality that benefits heart failure patients has the potential to result in a dramatic improvement in health outcomes and substantial cost savings for the community.nnResponse by Oettgen p 352 nnThe possibility of using stem cell–based therapies for people suffering an acute MI or living with CHF has captured the imagination of both the medical and popular communities. Since early reports in animal models >10 years ago,2,3 the stem cell field has made enormous advances in moving toward clinically applicable treatment options, and we now stand at the dawn of a new therapeutic era. An abundance of preclinical data demonstrate safety, feasibility, and efficacy, justifying the current entry into clinical trials of stem cell therapy in humans.4–8 This position, however, is extremely controversial, with some arguing that trials are premature because mechanistic insights are insufficiently addressed.9,10 Here, we argue that properly conducted rigorous clinical trials are a key and appropriate next step not only to start the long process of therapeutic development but also as an essential component in the process of understanding the scientific underpinnings of cardiac regeneration and its therapeutic utilization. The field of regenerative medicine will advance through the parallel conduct of in vitro/animal model studies and clinical trials, the latter frequently guiding the former.nnThe publication of Menasche et …

Cardiomyocyte Regeneration: A Consensus Statement

Cell therapy is an exciting option for repairing the injured heart, one that has attracted considerable interest over the past 15 years. Consensus exists that the injection/infusion or tissue-based implantation of various cell types may exert therapeutic effects,1–3 and there is general agreement that additional molecular, translational, and clinical studies are required to define the optimal cell source, method of delivery, and underlying mechanism(s) of action.nnOne of the remaining questions in this field pertains to cardiomyocyte turnover under normal and diseased conditions and its contribution to the beneficial effects of cell therapy. Although results published in the literature have not been consistent, we believe that the time is ripe to formulate a consensus for many of the pertinent questions.nnIt is important to emphasize that the focus of this consensus statement is on cardiomyocyte renewal; it is not on cell therapy in general. Although we touch on some aspects of therapeutic strategies based on delivery of exogenous cells, our intent here is to define areas of agreement and areas requiring further elucidation related to the regenerative potential of the myocardium itself.nnWe have included references to the scientific literature throughout the document. Although it is impossible for us to include all publications in this expansive field, representative studies that corroborate statements herein have been cited.nn1. Definition of cardiomyocyte renewal.n In this consensus statement, the term cardiomyocyte renewal is defined as the ability to replace lost cardiomyocytes by new ones. It is distinct from the turnover of cardiac proteins or the generation of polyploid cardiomyocytes (ie, those harboring >2 sets of chromosomes), either by nuclear division giving rise to multinucleation or by duplication of DNA without nuclear division resulting in polyploid nuclei.nn2. Naturally occurring cardiomyocyte renewal and proliferation.n 1. During normal mammalian developmentn 1. Growth of the heart during …

Influence of dilated cardiomyopathy, myocarditis and cardiac transplantation on the relation between plasma atrial natriuretic factor and atrial pressures☆

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative Automated Assessment of Myocardial Perfusion at Cardiac Catheterization

Perfusion assessed in the cardiac catheterization laboratory predicts outcomes after myocardial infarction. The aim of this study was to investigate a novel method of assessing perfusion using digital subtraction angiography to generate a time-density curve (TDC) of myocardial blush, incorporating epicardial and myocardial perfusion. Seven pigs underwent temporary occlusion of the left anterior descending coronary artery for 60 minutes. Angiography was performed in the same projections before, during, and after occlusion. Perfusion parameters were obtained from the TDC and compared with Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade. In addition, safety and feasibility were tested in 8 patients after primary percutaneous coronary intervention. The contrast density differential between the proximal artery and the myocardium derived from the TDC correlated well with TIMI myocardial perfusion grade (R = 0.54, p <0.001). The arterial transit time derived from the TDC correlated with TIMI frame count (R = 0.435, p = 0.011). Using a cutoff of 2.4, the density/time ratio, a ratio of density differential to transit time, had sensitivity and specificity of 100% for coronary arterial occlusion. The positive and negative predictive values were 100%. The generation of a TDC was safe and feasible in 7 patients after acute myocardial infarctions, but the correlation between TDC-derived parameters and TIMI parameters did not reach statistical significance. In conclusion, this novel method of digital subtraction angiography with rapid, automated, quantitative assessment of myocardial perfusion in the cardiac catheterization laboratory correlates well with established angiographic measures of perfusion. Further studies to assess the prognostic value of this technique are warranted.