Septal Ablation Versus Surgical Myomectomy for Hypertrophic Obstructive Cardiomyopathy.

PURPOSE OF REVIEW: Patients with hypertrophic cardiomyopathy (HCM) who have left ventricular outflow tract obstruction (LVOTO) often experience severe symptoms and functional limitation. Relief of LVOTO can be achieved by two invasive interventions, i.e., surgery myectomy and alcohol septal ablation (ASA), leading in experienced hands to a dramatic improvement in clinical status. Despite extensive research, however, the choice of the best option in individual patients remains challenging and poses numerous clinical dilemmas. RECENT FINDINGS: Invasive strategies have been recently incorporated in recommendations for the diagnosis and treatment of HCM on both sides of the Atlantic. These guidelines are based on a bulk of well-designed but retrospective studies as well as on expert opinions. Evidence now exists that adequate evaluation and management of HCM requires a multidisciplinary team capable of choosing the best available options. Management of LVOTO still varies largely based on local expertise and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, the concept of a "HCM heart team" is coming of age.

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World.

Twelve years after cardiologists and cardiac surgeons from all over the world issued the 'Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa', calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and RHD, and to periodically review progress made and challenges that remain, RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide. Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.

Expression of the familial cardiac valvular dystrophy gene, filamin-A, during heart morphogenesis.

Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease.

Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes.

Clenbuterol, a compound classified as a beta2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca2+ transients, and L-type Ca2+ current and compared these effects to two other clinically used beta2-AR agonists: fenoterol and salbutamol. Clenbuterol (30 microM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca2+ transient amplitude and L-type Ca2+ current. Selective beta1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol (P < 0.05). Incubation with 2 microg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 microM clenbuterol. In addition, overexpression of inhibitory G protein (Gi) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the Gi protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through Gi, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

Pharmacological inhibition of AMP-deaminase in rat cardiac myocytes.

Because mutation of AMP deaminase 1 gene leading to reduced AMP deaminase activity may result in protection of cardiac function in patients with heart disease, inhibitors of AMP deaminase (AMPD) may have therapeutic applications. This study evaluated the effect of a specific inhibitor of AMP deaminase 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo [4,5-d][1,3]diazepin-8-ol (AMPDI) on the isolated human enzyme and on nucleotide catabolism in rat cardiomyocytes. AMPDI effectively inhibited isolated human AMPD with an IC(50) = 0.5 micro M. AMPDI was much less effective with isolated cardiomyocytes (IC(50) = 0.5 mM). AMPDI is a very effective inhibitor of AMPD that despite lower efficiency in the cell system examined could be useful for in vivo studies.

Specialist surgery in the developing world: luxury or necessity?

Patients suffering from conditions requiring specialist intervention cannot obtain treatment when facilities do not exist locally. Specialist visiting teams in a number of surgical disciplines have attempted to address these issues in collaboration with local clinicians. These interventions require careful planning and communication to achieve optimum results. Several teams have been successful in building long-term relationships that have lead to important clinical developments in the local country.

Stimulatory effects of atorvastatin on extracellular nucleotide degradation in human endothelial cells.

Endothelial degradation of extracellular nucleotides is known to be an important mechanism in regulation of thrombosis, inflammation and immune response. It is possible that this pathway is a target for pleiotropic drugs such as atorvastatin. We studied therefore the effect of atorvastatin on extracellular nucleotide degradation in human endothelial cells. Atorvastatin treatment of human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC-1) resulted in significant increase in ATP breakdown and adenosine formation both if analysed in intact cell studies and as enzyme activity in cell lysates. We conclude that one of the beneficial effects of atorvastatin may include acceleration of extracellular nucleotide breakdown. This will attenuate nucleotide mediated pro-inflammatory effect and stimulate protective mechanisms of adenosine.

Differences in activities of the enzymes of nucleotide metabolism and its implications for cardiac xenotransplantation.

Xenotransplantation is one be possible solution for a severe shortage of human organs available for transplantation. However, only a few studies addressed metabolic compatibility of transplanted animal organs. Our aim was to compare activities of adenosine metabolizing enzymes in the heart of different species that are relevant to clinical or experimental xenotransplantation. We noted fundamental differences: ecto-5' nucleotidease (E5' N) activity was 4-fold lower in pig and baboon hearts compared to the human hearts while mouse activity was compatible with human and rat activity was three times higher than human. There also were significant differences in AMP-deaminase (AMPD), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities. We conclude that differences in nucleotide metabolism may contribute to organ dysfunction after xenotransplantation.

The effect of N-methyl-2-pyridone-5-carboxamide--A nicotinamide catabolite on poly ADP-rybosylation and oxidative stress injury in endothelial cells.

This study evaluated the effect of nicotinamide (NA) and its endogenous metabolite 2PY (N-methyl-2-pyridone-5-carboxamide) on the activity of poly (ADP-ribose) polymerase (PARP) and on peroxynitrite-induced injury in endothelial cells. 2PY and NA inhibited isolated PARP with half-maximal constants of 0.53 mM and 0.025 mM, respectively. Exposure to peroxynitrite caused a decrease of the NAD pool in cultured endothelial cells to below 10% of initial level. Addition of 2PY or NA provided partial protection from peroxynitrite-induced NAD depletion, with NA being more effective. 2PY and NA also provide protection from ATP depletion. We conclude that NA as well as 2PY protect from oxidative stress injury in endothelial cells by inhibition of PARP and protection from NAD depletion. This, in turn, protects energetics, allowing maintaining cellular ATP.

Purine metabolism in pigs and humans and its implications for xenotransplantation.

We compared concentrations of nucleotide substrates and activities of enzymes of nucleotide metabolism in pig and human blood, heart, and kidney. The most important difference was lower ecto-5-nucleotidase (ESN) activity in both pig hearts and kidney. Furthermore, higher hypoxanthine, inosine, adenine, and uracil, but lower uridine and uric acid concentrations were observed in pig blood as compared to human. A twofold increase in UTP concentration has been observed in pig hearts following 4 h perfusion with human blood. Purine metabolism is an important target for genetic and pharmacological manipulation during xenotransplantations.

Exposure to human blood inactivates swine endothelial ecto-5'-nucleotidase.

Ecto-5'-nucleotidase (E5'N) is an extracellular enzyme forming anti-inflammatory and immunosuppressive adenosine. We evaluated whether confrontation of pig heart and endothelial cells with human blood changes the activity of E5'N. Pig hearts were perfused ex vivo with fresh human blood for 4 h. Pig aortic endothelial cells (PAEC) were incubated in vitro with human plasma for 3 h. Ex vivo perfusion of pig heart with fresh human blood resulted in a decrease in E5'N activity to 62% and 61% of initial in wild-type and transgenic pig hearts, respectively. PAEC activity of E5'N decreased to 71% and 50% of initial after 3 h exposure to heat-inactivated and active complement human plasma, respectively, while it remained constant in controls. Pig heart activity of E5'N decreased following exposure to human blood, which may affect adenosine production and exacerbate hyperacute and vascular rejection.

Prevention of adriamycin induced heart failure by an increase in endogenous adenosine production.

Adenosine (Ado) triggers several protective mechanisms that may attenuate development of heart failure, both locally and systemically. We developed a procedure allowing sustained increase in endogenous Ado production by the combined application of Ado metabolism inhibitors and nucleotide precursors. We found that our procedure attenuate the development of heart failure induced by adriamycin.

Lidoflazine combined with nucleotide precursors increases ATP content and adenosine production in cardiomyocytes.

We have previously identified that the nucleoside transport blocker dipyridamole increases adenosine production but may cause depletion of the nucleotide pool in cardiomyocytes during extended exposure and that this effect was abolished by co-administration of adenine and ribose. The present study aimed to establish whether lidoflazine, a newer generation of nucleoside transport inhibitor with calcium antagonist properties, would cause a similar effect. We conclude that lidoflazine did not affect the nucleotide pool while the combined application of lidoflazine with precursors of nucleotide resynthesis increased ATP concentration and further enhanced adenosine production.

Expression of human ecto 5' nucleotidase in pig endothelial cells and its implication for adenosine production and xenotransplantation.

Human endothelial activity of ecto-5'-nucleotidase (E5'N) is several times higher than in pig endothelial cells. This may have implication for xenotransplantation due to the role this enzyme plays in conversion of pro-inflammatory and pro-aggreggatory nucleotides into anti-inflammatory and antiaggregatory adenosine. We have shown in this study that human E5'N can be functionally expressed in pig endothelial cells leading to increased adenosine production from both extracellular AMP and ATP. We suggest that E5'N expression in transgenic pigs for xenotransplantation may help to prolong graft survival.

AMPD1 C34T mutation selectively affects AMP-deaminase activity in the human heart.

Possession of the nonsense mutation in AMPD 1 C34T gene has been linked to improved survival in patients with heart failure, possibly by promoting the formation of adenosine. This mutation is known to decrease the activity of AMP-deaminase in skeletal muscle. We have found that the AMPD1 mutation decreases the activity of AMP-deaminase in the heart without changing the activity of any other enzymes of adenine nucleotide metabolism. Protective mechanism of this mutation may be thus induced by local cardiac metabolic changes.

Primary lung carcinoma after heart or lung transplantation: management and outcome.

OBJECTIVE: We sought to examine our management and outcome of lung carcinoma occurring after thoracic organ transplantation. METHODS: We performed a retrospective review of cases of primary lung carcinoma diagnosed between 1990 and 2000 in patients who have previously undergone thoracic transplantation at our institution. RESULTS: Seventeen patients were identified (1 lung and 16 heart transplants). Median time from transplantation to diagnosis of lung carcinoma was 89 months (range, 46-138 months). Predominant presentation was as an incidental finding at chest radiography (13/17). All patients had smoked cigarettes before transplantation, with 5 continuing to smoke after transplantation. Histologic types were squamous (n = 11), adenocarcinoma (n = 3), small cell (n = 2), and undifferentiated (n = 1). Revised International Union Against Cancer (UICC) clinical stage at the time of diagnosis was stage I or II in 11 of 17 patients. Of these, 9 underwent surgical resection; 2 patients unfit for surgical intervention had radiotherapy. Surgical procedures were lobectomy (n = 5), wedge excision (n = 3), and no resection (n = 1). Median survival after diagnosis was 12 months for all patients and 24 months if the tumor was resected. Six patients who had surgical resection subsequently died (survival of 2, 9, 21, 21, 36, and 67 months); 2 remain alive after 12 and 54 months, respectively. CONCLUSIONS: When possible, surgical intervention should be undertaken for early stage lung cancer occurring after thoracic transplantation because medium-term survival is achievable. Sublobar excisions and definitive radiotherapy should be considered if comorbidity prevents optimal surgical treatment.

Biological mechanisms influencing the function of the aortic root.

Optimal function of the aortic root relies upon the ability of its component structures to move in a coordinated fashion. Some of the cells that make up the structures of the aortic root have been shown to contain nerves, receptors, and contractile elements. The ability to contract or relax may contribute to the successful function of the valve by allowing it to move in a coordinated manner in response to biological stimuli. It is known that cusp tissue receives primary, sensory, and autonomic nerves, suggesting a role for neuronal regulation of cusp function. In addition, cusp tissue has been shown to express a wide variety of receptors and to contract to a range of common vasoactive agents. The cells that constitute the valve have also shown secretory and proliferative responses. The biological signals that mediate the cross-talk between the different parts of the root have not been established. This review will examine the mechanisms that have been documented to be present and to assess their potential contribution in affecting aortic valve function.

Role of endogenous endothelin on coronary reflow after cardioplegic arrest.

OBJECTIVE: Endothelin plays a role in the regulation of basal coronary tone. We hypothesized that low coronary reflow and reduced cardiac function after prolonged ischemia may be due to increased release of endogenous endothelin. METHODS: Using an isolated perfused rat heart, we examined the effect of the addition of various endothelin antagonists during reperfusion after 4 hours of cardioplegic arrest at 4 degrees C. Hearts were freeze-clamped at the end of reperfusion for analysis of high-energy phosphate levels. Results are expressed as the percentages of preischemic values. RESULTS: The addition of bosentan or Ro61-0612 (nonselective endothelin antagonists) resulted in a significant increase in the recovery of coronary flow after 30 minutes of reperfusion (100.9% vs 85.3% [P =.03] and 122.4% vs 83.7% [P <.001], respectively, versus controls). The addition of PD155080 (endothelin A antagonist) had a similar effect (129.5% vs 91.4%, P =.008). BQ788 (endothelin B antagonist) and phosphoramidon (endothelin-converting enzyme inhibitor) had no effect. Myocardial adenosine triphosphate levels were significantly (12.1%) higher after reperfusion with Ro61-0612 (18.1 +/- 0.4 micromol/g vs 16.2 +/- 0.5 micromol/g, P =.01). There was no difference in the recovery of cardiac mechanical function with any of the antagonists studied. CONCLUSION: These results suggest that endogenous endothelin plays a role in low coronary reflow after prolonged cardioplegic arrest but does not impair recovery of myocardial function.

Subjective patient outcomes following coronary artery bypass using the radial artery: results of a cross-sectional survey of harvest site complications and quality of life.

OBJECTIVES: To assess patient-based outcomes following radial artery harvesting for coronary artery bypass surgery (CABG). METHODS: A cross-sectional telephone survey of 127 patients who underwent radial artery grafting was undertaken. The parameters assessed included symptoms related to the radial artery harvest site (functional impairment, sensory symptoms, and wound infection) and health related quality of life. RESULTS: A high percentage of patients (67.7%) reported altered sensation, in the hand, in particular around the thenar eminence, in the forearm, or in relation to the incision; this was self-limiting and clinically insignificant in the vast majority of patients. Twelve patients reported residual insignificant symptoms after a median follow-up of 17.5 months. Four patients reported a subjective decrease in grip strength. Patients reported a good quality of life, and there was no association between this and the presence or absence of symptoms related to radial artery harvest. Some patients volunteered a 'preference' for the radial artery harvest site when compared with concomitantly harvested long saphenous vein (LSV), and there was a lower wound infection rate at radial artery harvest sites compared with vein harvest sites (6 vs. 15%). CONCLUSIONS: Sensory symptoms following radial artery procurement occur more frequently than previously reported, but are largely self-limiting and are usually clinically insignificant. Patients appear to have a good quality of life following CABG using the radial artery. Radial artery harvest may be associated with lower wound infection rates and greater patient satisfaction than LSV harvest, however, the presence of residual sensory symptoms may be of relevance when obtaining informed consent.

Overexpression of connexin 43 in skeletal myoblasts: Relevance to cell transplantation to the heart.

OBJECTIVE: Skeletal myoblast transplantation is a promising strategy for treating end-stage heart failure. One potential problem in the development of functional, synchronously contracting grafts is the degree of intercellular communication between grafted myoblasts and host cardiomyocytes. Thus it is expected that enhancement of intercellular gap junction formation would result in improved efficiency of skeletal myoblast transplantation. In this study we investigated whether myoblasts overexpressing connexin 43, a major cardiac gap junction protein, would enhance this intercellular communication. METHODS AND RESULTS: L6 rat skeletal myoblast cell lines overexpressing connexin 43 were generated by means of gene transfection and clonal selection. Connexin 43 overexpression of these myoblasts, which continued both in undifferentiated and differentiated states (up to 17-fold greater protein level in comparison with control-transfected myoblasts, as measured with Western blotting), was observed on cell surfaces where gap junctions should exist. Both dye microinjection and scrape loading with fluorescent dyes showed enhancement in intercellular dye transfer between connexin 43-transfected myoblasts compared with that found in control-transfected cells. Morphologically, these myoblasts fused and differentiated into multinucleated myotubes more rapidly, demonstrating a higher level of cellular creatine kinase activity as a marker of myogenic differentiation throughout the culture period compared with that of control-transfected myoblasts. CONCLUSIONS: We have generated connexin 43-overexpressing skeletal myoblast cell lines that resulted in improved formation of functional intercellular gap junctions, which could be relevant to synchronous contraction of grafted myoblasts in the heart. In addition, these cells demonstrated more rapid differentiation, which would also be advantageous in a graft for transplantation to the heart.