Mechanical unloading and [beta]2-adrenoceptor stimulation for the treatment of heart failure

Background & Introduction: Heart transplantation is the most effective treatment for end-stage heart failure (HF) but is hindered due to an inadequateavailability of donor organs. Left ventricular assist devices (LVADs) have beenshown to be a suitable alternative and primarily used as a ?bridge to transplantation? wherein the failing heart can be supported by mechanical circulatoryassistance until a suitable donor organ becomes available. In 4-9% of patients,the LVAD also acts as ?bridge to recovery?, since it induces substantial functional improvement that allows LVAD explantation, without the need of transplantation. The rate for explantation of the LVAD remains low and the functional improvement observed, a transient phenomenon. LVADs cause mechanical unloading, which produces functional, structural, signalling and molecularchanges in HF. Development of myocardial unloading-induced atrophy, time-dependent myocyte contractile dysfunction and excitation-contraction (EC)coupling changes may have detrimental consequences.However, when mechanical unloading is combined with pharmacological therapy, including the ?2-AR agonist clenbuterol, an improved ?bridge to recovery? rate of 75% can be achieved. The effects of clenbuterol on functional,structural, signalling and molecular changes in a normal and failing hearts,during mechanical unloading, are unknown. This thesis investigates some ofthe key effects of mechanical unloading and ?2-AR agonist stimulation withclenbuterol for HF treatment, based on the following hypotheses which havebeen individually addressed in Chapters 3, 4 and 5 respectively.? Chronic administration of clenbuterol alters myocardial structure andfunction and affects calcium handling in normal rat hearts.? Mechanical left ventricular unloading and the consequent left ventricular atrophy results in altered whole-heart and cellular function in non-failing/normal rat hearts.? Clenbuterol treatment during mechanical unloading of a normal rat heartnormalises whole-heart and cellular function. ? Clenbuterol has an additional benefit when combined with mechanicalunloading in the treatment of failing rat hearts.Methods: Clenbuterol was administered by osmotic minipumps. Mechanical un-loading was achieved by heterotopic abdominal heart transplantation. Heartfailure was induced by left coronary artery ligation in rats. In-vivo whole heartfunction was assessed by echocardiography and ex-vivo function by pressure-volume relationship. Only LV myocytes were isolated and studied using optical, fluorescence and electrophysiological techniques. Calcium handling protein expression was assessed by Western blotting. Theory and methodologyof the single-cell studies is outlined, together with validation experiments andthe necessary assumptions.Results: Data obtained and their interpretations are presented in three chaptersaccording to the proposed hypotheses. The results show that clenbuterol with,without mechanical unloading, or on its own can affect both whole-heart andcellular function in normal hearts. The treatment of failing hearts with clenbuterol, alone or in combination with mechanical unloading, improves LV function at whole-heart and cellular level by effects on cell morphology, EC couplingand myofilament sensitivity to calcium. The details of individual experimentsand their interpretation are discussed in the respective chapter.General Discussion: This thesis supports the use of clenbuterol in the strategy toimprove recovery in HF patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvementin LV function. The questions remaining unanswered are discussed and possible future experiments that could be performed to address them are described.Imperial Users onl

Mechanical unloading and β2-adrenoceptor stimulation for the treatment of heart failure

Background & Introduction: Heart transplantation is the most effective treatment for end-stage heart failure (HF) but is hindered due to an inadequate availability of donor organs. Left ventricular assist devices (LVADs) have been shown to be a suitable alternative and primarily used as a ‘bridge to transplantation’ wherein the failing heart can be supported by mechanical circulatory assistance until a suitable donor organ becomes available. In 4-9% of patients, the LVAD also acts as ‘bridge to recovery’, since it induces substantial functional improvement that allows LVAD explantation, without the need of transplantation. The rate for explantation of the LVAD remains low and the functional improvement observed, a transient phenomenon. LVADs cause mechanical unloading, which produces functional, structural, signalling and molecular changes in HF. Development of myocardial unloading-induced atrophy, time- dependent myocyte contractile dysfunction and excitation-contraction (EC) coupling changes may have detrimental consequences. However, when mechanical unloading is combined with pharmacological therapy, including the β2-AR agonist clenbuterol, an improved ‘bridge to recovery’ rate of 75% can be achieved. The effects of clenbuterol on functional, structural, signalling and molecular changes in a normal and failing hearts, during mechanical unloading, are unknown. This thesis investigates some of the key effects of mechanical unloading and β2-AR agonist stimulation with clenbuterol for HF treatment, based on the following hypotheses which have been individually addressed in Chapters 3, 4 and 5 respectively. • Chronic administration of clenbuterol alters myocardial structure and function and affects calcium handling in normal rat hearts. • Mechanical left ventricular unloading and the consequent left ventricular atrophy results in altered whole-heart and cellular function in non- failing/normal rat hearts. • Clenbuterol treatment during mechanical unloading of a normal rat heart normalises whole-heart and cellular function. • Clenbuterol has an additional benefit when combined with mechanical unloading in the treatment of failing rat hearts. Methods: Clenbuterol was administered by osmotic minipumps. Mechanical un- loading was achieved by heterotopic abdominal heart transplantation. Heart failure was induced by left coronary artery ligation in rats. In-vivo whole heart function was assessed by echocardiography and ex-vivo function by pressure- volume relationship. Only LV myocytes were isolated and studied using optical, fluorescence and electrophysiological techniques. Calcium handling protein expression was assessed by Western blotting. Theory and methodology of the single-cell studies is outlined, together with validation experiments and the necessary assumptions. Results: Data obtained and their interpretations are presented in three chapters according to the proposed hypotheses. The results show that clenbuterol with, without mechanical unloading, or on its own can affect both whole-heart and cellular function in normal hearts. The treatment of failing hearts with clenbuterol, alone or in combination with mechanical unloading, improves LV function at whole-heart and cellular level by effects on cell morphology, EC coupling and myofilament sensitivity to calcium. The details of individual experiments and their interpretation are discussed in the respective chapter. General Discussion: This thesis supports the use of clenbuterol in the strategy to improve 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. The questions remaining unanswered are discussed and possible future experiments that could be performed to address them are described

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 b 2 -adrenoceptor (b 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 þ UN þ Sal or HF þ UN þ Clen) for 7 days. Non-transplanted HF animals were treated with Sal (Sham þ Sal, HF þ Sal) or clenbuterol (HF þ Clen). LV myocytes were isolated and studied using optical, fluorescence, and electrophysiological techniques. 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

Mechanical unloading and β2-adrenoceptor stimulation for the treatment of heart failure

Background ;Introduction: Heart transplantation is the most effective treatment for end-stage heart failure (HF) but is hindered due to an inadequate availability of donor organs. Left ventricular assist devices (LVADs) have been shown to be a suitable alternative and primarily used as a ‘bridge to transplantation’ wherein the failing heart can be supported by mechanical circulatory assistance until a suitable donor organ becomes available. In 4-9% of patients, the LVAD also acts as ‘bridge to recovery’, since it induces substantial functional improvement that allows LVAD explantation, without the need of transplantation. The rate for explantation of the LVAD remains low and the functional improvement observed, a transient phenomenon. LVADs cause mechanical unloading, which produces functional, structural, signalling and molecular changes in HF. Development of myocardial unloading-induced atrophy, time- dependent myocyte contractile dysfunction and excitation-contraction (EC) coupling changes may have detrimental consequences. However, when mechanical unloading is combined with pharmacological therapy, including the β2-AR agonist clenbuterol, an improved ‘bridge to recovery’ rate of 75% can be achieved. The effects of clenbuterol on functional, structural, signalling and molecular changes in a normal and failing hearts, during mechanical unloading, are unknown. This thesis investigates some of the key effects of mechanical unloading and β2-AR agonist stimulation with clenbuterol for HF treatment, based on the following hypotheses which have been individually addressed in Chapters 3, 4 and 5 respectively. • Chronic administration of clenbuterol alters myocardial structure and function and affects calcium handling in normal rat hearts. • Mechanical left ventricular unloading and the consequent left ventricular atrophy results in altered whole-heart and cellular function in non- failing/normal rat hearts. • Clenbuterol treatment during mechanical unloading of a normal rat heart normalises whole-heart and cellular function. • Clenbuterol has an additional benefit when combined with mechanical unloading in the treatment of failing rat hearts. Methods: Clenbuterol was administered by osmotic minipumps. Mechanical un- loading was achieved by heterotopic abdominal heart transplantation. Heart failure was induced by left coronary artery ligation in rats. In-vivo whole heart function was assessed by echocardiography and ex-vivo function by pressure- volume relationship. Only LV myocytes were isolated and studied using optical, fluorescence and electrophysiological techniques. Calcium handling protein expression was assessed by Western blotting. Theory and methodology of the single-cell studies is outlined, together with validation experiments and the necessary assumptions. Results: Data obtained and their interpretations are presented in three chapters according to the proposed hypotheses. The results show that clenbuterol with, without mechanical unloading, or on its own can affect both whole-heart and cellular function in normal hearts. The treatment of failing hearts with clenbuterol, alone or in combination with mechanical unloading, improves LV function at whole-heart and cellular level by effects on cell morphology, EC coupling and myofilament sensitivity to calcium. The details of individual experiments and their interpretation are discussed in the respective chapter. General Discussion: This thesis supports the use of clenbuterol in the strategy to improve 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. The questions remaining unanswered are discussed and possible future experiments that could be performed to address them are described.EThOS - Electronic Theses Online ServiceBritish Heart Foundation, The Magdi Yacoub Institute and the Wellcome TrustGBUnited Kingdo

Mechanical unloading and β2-adrenoceptor stimulation for the treatment of heart failure

Background ;Introduction: Heart transplantation is the most effective treatment for end-stage heart failure (HF) but is hindered due to an inadequate availability of donor organs. Left ventricular assist devices (LVADs) have been shown to be a suitable alternative and primarily used as a ‘bridge to transplantation’ wherein the failing heart can be supported by mechanical circulatory assistance until a suitable donor organ becomes available. In 4-9% of patients, the LVAD also acts as ‘bridge to recovery’, since it induces substantial functional improvement that allows LVAD explantation, without the need of transplantation. The rate for explantation of the LVAD remains low and the functional improvement observed, a transient phenomenon. LVADs cause mechanical unloading, which produces functional, structural, signalling and molecular changes in HF. Development of myocardial unloading-induced atrophy, time- dependent myocyte contractile dysfunction and excitation-contraction (EC) coupling changes may have detrimental consequences. However, when mechanical unloading is combined with pharmacological therapy, including the β2-AR agonist clenbuterol, an improved ‘bridge to recovery’ rate of 75% can be achieved. The effects of clenbuterol on functional, structural, signalling and molecular changes in a normal and failing hearts, during mechanical unloading, are unknown. This thesis investigates some of the key effects of mechanical unloading and β2-AR agonist stimulation with clenbuterol for HF treatment, based on the following hypotheses which have been individually addressed in Chapters 3, 4 and 5 respectively. • Chronic administration of clenbuterol alters myocardial structure and function and affects calcium handling in normal rat hearts. • Mechanical left ventricular unloading and the consequent left ventricular atrophy results in altered whole-heart and cellular function in non- failing/normal rat hearts. • Clenbuterol treatment during mechanical unloading of a normal rat heart normalises whole-heart and cellular function. • Clenbuterol has an additional benefit when combined with mechanical unloading in the treatment of failing rat hearts. Methods: Clenbuterol was administered by osmotic minipumps. Mechanical un- loading was achieved by heterotopic abdominal heart transplantation. Heart failure was induced by left coronary artery ligation in rats. In-vivo whole heart function was assessed by echocardiography and ex-vivo function by pressure- volume relationship. Only LV myocytes were isolated and studied using optical, fluorescence and electrophysiological techniques. Calcium handling protein expression was assessed by Western blotting. Theory and methodology of the single-cell studies is outlined, together with validation experiments and the necessary assumptions. Results: Data obtained and their interpretations are presented in three chapters according to the proposed hypotheses. The results show that clenbuterol with, without mechanical unloading, or on its own can affect both whole-heart and cellular function in normal hearts. The treatment of failing hearts with clenbuterol, alone or in combination with mechanical unloading, improves LV function at whole-heart and cellular level by effects on cell morphology, EC coupling and myofilament sensitivity to calcium. The details of individual experiments and their interpretation are discussed in the respective chapter. General Discussion: This thesis supports the use of clenbuterol in the strategy to improve 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. The questions remaining unanswered are discussed and possible future experiments that could be performed to address them are described.EThOS - Electronic Theses Online ServiceBritish Heart Foundation, The Magdi Yacoub Institute and the Wellcome TrustGBUnited Kingdo

Robotic mitral valve surgery

Totally endoscopic robotic mitral valve repair is the least invasive surgical therapy for mitral valve disease. Robotic mitral valve surgery demonstrates faster recovery with shorter hospital stays, less morbidity, and equivalent mortality and mid-term durability compared to sternotomy. In this review, we will explore the advantages and disadvantages of robotic mitral valve surgery and consider important technical details of both operative set-up and mitral valve repair techniques. The number of robotic cardiac surgical procedures being performed globally is expected to continue to rise as experience grows with robotic techniques and increasing numbers of cardiac surgeons become proficient with this innovative technology. This will be facilitated by the introduction of newer robotic systems and increasing patient demand

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 107 green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 × 106 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, Ca2+ 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 Ca2+ transient observed in failing cardiomyocytes. The smaller and slower L-type Ca2+ current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca2+ sparks suggested a normalization of sarcoplasmic reticulum Ca2+ leak after skeletal myoblast transplantation. The increased Ca2+ 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