What is the optimal revascularization technique for isolated disease of the left anterior descending artery: minimally invasive direct coronary artery bypass or percutaneous coronary intervention?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was, 'What is the optimal revascularization technique for isolated disease of the left anterior descending artery (LAD) in terms of patient survival, morbidity such as myocardial infarction (MI) and need for repeat target vessel revascularization: minimally invasive direct coronary artery bypass graft (MIDCAB) or percutaneous coronary intervention (PCI)?' Altogether 504 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. Outcome parameters that were used in the assessment include the incidence of major adverse cardiovascular or cerebral events (MACCEs), mortality and the rate of repeat target vessel revascularization. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. One meta-analysis showed no significant difference in terms of individual incidences of MI, stroke or mortality, but when considered as a composite MACCE outcome, this was found to be significantly lower in the MIDCAB group. Moreover, further meta-analytical data have revealed a 5-fold increase in the need for repeat revascularization with PCI, with some centres reporting rates of up to 34%. However, retrospective data have shown that average length of hospital stay was longer in the MIDCAB group (7.4 ± 3.2 vs 3.4 ± 3.5 days; P < 0.001). We conclude that there are obvious proven benefits with MIDCAB, namely in terms of a reduced need for repeat target vessel revascularization and incidence of MACCE, and one study has even shown that there is a long-term survival benefit in 'real-world' clinical practice. However, given that there is a lack of well-powered randomized controlled trial and long-term follow-up data to prove a mortality benefit in support of MIDCAB, patients requiring revascularization of isolated proximal LAD stenosis and being considered for percutaneous coronary intervention should be discussed in a multidisciplinary team setting prior to intervention.

Impact of European Society of Cardiology and European Association for Cardiothoracic Surgery Guidelines on Myocardial Revascularization on the activity of percutaneous coronary intervention and coronary artery bypass graft surgery for stable coronary artery disease.

OBJECTIVE: Joint guidelines on myocardial revascularization were published by the European Society of Cardiology and European Association for Cardiothoracic Surgery: Patients with left main stem, proximal left anterior descending, or 3-vessel disease should be discussed with a surgeon before revascularization, and ad hoc percutaneous coronary intervention has no elective indication in these categories. We assess the impact of the guidelines on referral patterns to a cardiac surgery service at a large-volume cardiac center in the United Kingdom. METHODS: Joint guidelines were published in August 2010. All patients with severe disease undergoing percutaneous coronary intervention at one institution were identified 6 months before (January to June 2010) and 6 months after (January to June 2011) their introduction. Decision-making and surgical referral were determined from minutes of multidisciplinary meeting. RESULTS: A total of 197 patients underwent elective percutaneous coronary intervention pre-guidelines, of whom 62 had severe disease. Only 6 patients (9%) were discussed at a multidisciplinary meeting before intervention. After introduction of the guidelines, elective percutaneous coronary interventions were performed in 164 patients, of whom 42 had surgical disease. Only 8 patients (17%) were discussed at a multidisciplinary meeting before intervention (P = not significant). Follow-up was a median of 480 (380-514) days for the pre-guideline group and 104 (31-183) days for the post-guideline group. Ad hoc percutaneous coronary intervention in surgical disease occurred in 8 patients (14%) pre-guidelines and was unchanged for 9 patients (26%) post-guidelines (P = not significant). CONCLUSIONS: Despite recommendation by both cardiology and cardiac surgical bodies and widespread publicity, a significant number of patients in this single-center study are not receiving optimal treatment recommended by these guidelines.

Adult progenitor cell transplantation influences contractile performance and calcium handling of recipient cardiomyocytes.

Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either 10(7) green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 x 10(6) GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, Ca(2+) handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the Ca(2+) transient observed in failing cardiomyocytes. The smaller and slower L-type Ca(2+) current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca(2+) sparks suggested a normalization of sarcoplasmic reticulum Ca(2+) leak after skeletal myoblast transplantation. The increased Ca(2+) wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation.

A gene expression profile of the myocardial response to clenbuterol.

Clenbuterol is currently being used as part of a clinical trial into a novel therapeutic approach for the treatment of end-stage heart failure. The purpose of this study was to determine the global pattern of myocardial gene expression in response to clenbuterol and to identify novel targets and pathways involved. Rats were treated with clenbuterol (n = 6) or saline (n = 6) for periods of 1, 3, 9, or 28 days. Rats treated for 28 days were also subject to continuous electrocardiogram analysis using implantable telemetry. RNA was extracted from rats at days 1 and 28 and used from microarray analysis, and further samples from rats at days 1, 3, 9, and 28 were used for analysis by real-time polymerase chain reaction. Clenbuterol treatment induced rapid development of cardiac hypertrophy with increased muscle mass at day 1 and elevated heart rate and QT interval throughout the 28-day period. Microarray analysis revealed a marked but largely transitory change in gene expression with 1,423 genes up-regulated and 964 genes down-regulated at day 1. Up-regulated genes revealed an unexpected association with angiogenesis and integrin-mediated cell adhesion and signaling. Moreover, direct treatment of endothelial cells cultured in vitro resulted in increased cell proliferation and tube formation. Our data show that clenbuterol treatment is associated with rapid cardiac hypertrophy and identify angiogenesis and integrin signaling as novel pathways of clenbuterol action. The data have implications both for our understanding of the physiologic hypertrophy induced by clenbuterol and for treatment of heart failure.

Prolonged mechanical unloading reduces myofilament sensitivity to calcium and sarcoplasmic reticulum calcium uptake leading to contractile dysfunction.

BACKGROUND: Prolonged unloading using left ventricular (LV) assist devices (LVADs) leads to unloading-induced atrophy with altered cardiomyocyte contractility. The causes for this time-dependent deterioration of myocardial function are unclear. Our aim was to determine the effects of prolonged mechanical unloading on cardiomyocyte function and, more specifically, on Ca(2+) cycling and myofilament sensitivity to Ca(2+). METHODS: LV unloading was induced by heterotopic abdominal transplantation (UN) in rats for 5 weeks. Recipient hearts were used as controls (REC). LV myocytes were isolated and cardiomyocyte area measured by planimetry, sarcomere length measured by Fourier analysis of digitized cardiomyocyte images, and cytoplasmic [Ca(2+)] monitored using Indo-1. Myofilament sensitivity to Ca(2+) was assessed as the slope of the linear relationship between Indo-1 ratio and sarcomere shortening during relaxation. RESULTS: UN cardiomyocyte area was smaller compared with REC (mean +/- SEM: UN 2,503 +/- 78 microm(2) [n = 132], REC 3,856 +/- 89 microm(2) [n = 116]; p < 0.001). UN cardiomyocytes had a smaller sarcomere shortening amplitude (UN 0.08 +/- 0.01 microm [n = 37], REC 0.11 +/- 0.01 microm [n = 38]; p < 0.01), despite normal Ca(2+) transient amplitude (UN 0.13 +/- 0.01 Indo-1 ratio units [n = 37], REC 0.11 +/- 0.01 Indo-1 ratio units [n = 38]; p = non-significant). Myofilament sensitivity to Ca(2+) was reduced in UN (UN 2.0 +/- 1.2 microm/ratio unit [n = 20], REC 3.7 +/- 0.4 microm/ratio unit [n = 22]; p < 0.01). Sarcoplasmic reticulum (SR) Ca(2+) uptake (assessed by 20 mmol/liter caffeine) was also reduced in UN (UN 84.3 +/- 0.79% relative contribution [n = 22], REC 89.8 +/- 0.67% relative contribution [n = 24]; p < 0.001). CONCLUSIONS: Prolonged myocardial unloading causes depressed contractility due to reduced SR Ca(2+) uptake and myofilament sensitivity to Ca(2+). These effects may be relevant with regard to myocardial performance after prolonged LVAD support.

Left ventricular assist device-induced molecular changes in the failing myocardium.

PURPOSE OF REVIEW: There is considerable increase in the use of left ventricular assist devices for the treatment of severe heart failure. Traditionally viewed as a bridge to transplantation and more recently as a destination therapy, left ventricular assist device support is now recognized to offer potential for myocardial recovery through reverse remodeling, a potential that is further enhanced by combination with pharmacologic therapy. In this study, we examine the molecular changes associated with left ventricular assist device support and how these may contribute to the recovery process. RECENT FINDINGS: Studies in both patients and experimental models have demonstrated that improved function is associated with alterations in several key pathways including cell survival, cytokine signaling, calcium handling, adrenergic receptor signaling, cytoskeletal and contractile proteins, energy metabolism, extracellular matrix, and endothelial and microvascular functions. Moreover, the unique research opportunities offered by left ventricular assist device analysis are beginning to distinguish changes associated with recovery from those of mechanical unloading alone and identify potential predictors and novel therapeutic targets capable of enhancing myocardial repair. SUMMARY: Significant progress has been made toward revealing molecular changes associated with myocardial recovery from heart failure. These studies also offer new insight into the pathogenesis of heart failure and point to novel therapeutic strategies.

Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure.

AIMS: Combined left ventricular assist device (LVAD) and pharmacological therapy has been proposed to favour myocardial recovery in patients with end-stage heart failure (HF). Clenbuterol (Clen), a beta(2)-adrenoceptor (beta(2)-AR) agonist, has been used as a part of this strategy. In this study, we investigated the direct effects of clenbuterol on unloaded myocardium in HF. METHODS AND RESULTS: Left coronary artery ligation or sham operation was performed in male Lewis rats. After 4-6 weeks, heterotopic abdominal transplantation of the failing hearts into normal recipients was performed to induce LV unloading (UN). Recipient rats were treated with saline (Sal) or clenbuterol (2 mg/kg/day) via osmotic minipumps (HF + UN + Sal or HF + UN + Clen) for 7 days. Non-transplanted HF animals were treated with Sal (Sham + Sal, HF + Sal) or clenbuterol (HF + Clen). LV myocytes were isolated and studied using optical, fluorescence, and electrophysiological techniques. Clenbuterol treatment improved in vivo LV function measured with echocardiography (LVEF (%): HF 35.9 +/- 2 [16], HF + Clen 52.1 +/- 1.4 [16]; P < 0.001; mean +/- SEM [n]). In combination with unloading, clenbuterol increased sarcomere shortening (amplitude (microm): HF + UN + Clen 0.1 +/- 0.01 [50], HF + UN + Sal 0.07 +/- 0.01 [38]; P < 0.001) by normalizing the depressed myofilament sensitivity to Ca(2+) (slope of the linear relationship between Ca(2+) transient and sarcomere shortening hysteresis loop during relaxation (microm/ratio unit): HF + UN + Clen 2.13 +/- 0.2 [52], HF + UN + Sal 1.42 +/- 0.13 [38]; P < 0.05). CONCLUSION: Clenbuterol treatment of failing rat hearts, alone or in combination with mechanical unloading, improves LV function at the whole-heart and cellular levels by affecting cell morphology, excitation-contraction coupling, and myofilament sensitivity to calcium. This study supports the use of this drug in the strategy to enhance recovery in HF patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvement in LV function.

Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle.

Clenbuterol (Clen), a beta(2)-agonist, is known to produce skeletal and myocardial hypertrophy. This compound has recently been used in combination with left ventricular assist devices for the treatment of end-stage heart failure to reverse or prevent the adverse effects of unloading-induced myocardial atrophy. However, the mechanisms of action of Clen on myocardial cells have not been fully elucidated. In an attempt to clarify this issue, we examined the effects of chronic administration of Clen on Ca(2+) handling and substrate preference in cardiac muscle. Rats were treated with either 2 mg x kg(-1) x day(-1) Clen or saline (Sal) for 4 wk with the use of osmotic minipumps. Ventricular myocytes were enzymatically dissociated. Cells were field stimulated at 0.5, 1, and 2 Hz, and cytoplasmic Ca(2+) transients were monitored with the use of the fluorescent indicator indo-1 acetoxymethyl ester. Two-dimensional surface area and action potentials in current clamp were also measured. We found that in the Clen group there was significant hypertrophy at the organ and cellular levels compared with Sal. In Clen myocytes, the amplitude of the indo-1 ratio transients was significantly increased. Sarcoplasmic reticulum Ca(2+) content, estimated by rapid application of 20 mM caffeine, was significantly increased in the Clen group. The action potential was prolonged in the Clen group compared with Sal. Carbohydrate contribution to the tricarboxylic cycle (Krebs cycle) flux was increased several times in the Clen group. This increase was associated with decreased expression of peroxisome proliferator-activated receptor-alpha. This study shows that chronic administration of Clen induces cellular hypertrophy and increases oxidative carbohydrate utilization together with an increase in sarcoplasmic reticulum Ca(2+) content, which results in increased amplitude of the Ca(2+) transients. These effects could be important when Clen is used in conjunction with left ventricular assist devices treatment.