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Reviews

Alternatives to transplantation in the surgical therapy for heart failure

Heart Surgery Section, Department of Surgical Sciences, University of Parma Medical School, Italy

Received 20 May 2008; received in revised form 10 October 2008; accepted 7 November 2008.

^_* Corresponding author. Address: Sezione di Cardiochirurgia, Università degli Studi di Parma, Via A. Gramsci 14, 43100 Parma, Italy. Tel.: +39 0 521 703270; fax: +39 0 521 293196. (Email: francesconicolini{at}libero.it).

	Abstract

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Despite considerable improvements in the medical treatment of heart failure (HF), the gold standard for the treatment of these patients remains heart transplantation. Nevertheless, in consideration of the shortage of organ donors, this procedure can be offered only to a small percentage of patients who could benefit from a new heart. A number of innovative approaches are being investigated in terms of improved survival and quality of life in patients refractory to medical therapy and excluded from cardiac transplantation lists. These procedures include the optimization of medical therapy, coronary artery bypass surgery and valve surgery in high-risk patients, ventricular restoration techniques, and the implantation of ventricular assist devices as destination therapy. Future therapies for HF could include stem cell therapy, associated with standard revascularization techniques or with other procedures such as ventricular assist devices implantation or ventricular restoration techniques, allowing the potential differentiation of implanted stem cells in a resting and unloaded heart. The modern approach to surgical treatment of HF is multidisciplinary, given that the number of alternative available options to heart transplantation requires a close collaboration between both cardiologists and cardiac surgeons in treating patients with end-stage HF who are not candidates for transplant.

Key Words: Heart failure • Surgery • Cardiomyopathy

	1. Introduction

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Cardiovascular disease is the leading cause of death in the USA and western countries with ischemic heart disease accounting for the majority of these deaths. Improvements in the medical and surgical treatment of acute coronary syndromes are leading to an increasing number of patients surviving with their disease and evolving toward heart failure. It is estimated that approximately 5 million Americans currently live with heart failure (HF) and an additional 500,000 patients are newly diagnosed each year [1].

Many diseases can lead to end-stage HF, including ischemic cardiomyopathy, dilated idiopathic cardiomyopathy, valvular disease, and metabolic and inflammatory disorders. The pathological end point for most of these diseases is cardiac remodelling, characterized by myocyte hypertrophy and chamber dilatation, leading to a more spherical shape of left ventricle and to a reduced pump function.

Although the New York Heart Association (NYHA) classification is usually used to define symptoms and functional limitations of patients, recent guidelines of the American College of Cardiology and the American Heart Association describe in more detail four stages of HF based on evolution, progression and consequent structural deterioration [2]. There are many independent predictors of prognosis but NYHA class and left ventricular ejection fraction remain the two most important predictors of survival in HF [3].

Despite considerable improvements in the medical treatment of HF, the gold standard for the treatment of these patients remains heart transplantation. Nevertheless, this procedure can be offered only to a small percentage of patients who could benefit from a new heart, due to limited donor organ availability. So a number of innovative surgical approaches are being investigated in terms of improved survival and quality of life in patients refractory to medical therapy and excluded from cardiac transplantation lists.

	2. Medical therapy

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
After myocardial injury has resulted in structural heart disease, the aim of HF treatment is to lower mortality, to reduce disease evolution and to avoid worsening of quality of life. Many pharmacological therapies exist as a first line strategy to limit manifestations of congestive HF.

Diuretic therapy is one of the cornerstones in the treatment of HF. It decreases ventricular diastolic pressure, with consequent reduction in ventricular wall stress and optimization of subendocardial perfusion. Two potassium sparing diuretics, spironolactone and eplerenone, have been studied in prospective randomized trials, showing that their beneficial effects are related to their aldosterone antagonism rather than their diuretic pharmacologic effects. The RALES (Randomized Evaluation Aldactone Evaluation Study) trial [4] and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trial [5] have demonstrated a significant decrease in the risk of death in the setting of chronic dilated cardiomyopathy and in patients with post acute myocardial infarction cardiomyopathy, respectively.

The rennin–angiotensin system plays a critical role in the pathogenesis of HF. Angiotensin-converting enzyme (ACE) inhibitors decrease the conversion of angiotensin I to angiotensin II and counteract the effects of angiotensin II on peripheral resistance, sodium retention and neurohormonal pathways involved in the pathogenesis of HF. Moreover, angiotensin-converting enzyme inhibitors decrease the breakdown of bradykinin, promoting natriuresis and vasodilation. In several large clinical heart failure trials ACE inhibitors have been shown to improve symptoms and functional capacity while decreasing the rate of hospitalizations and mortality. ACE inhibitors are indicated in patients who experienced HF after acute myocardial infarction, and have been shown to improve survival and reduce reinfarctions and hospitalizations in these patients [6–9].

Beta-blockers are another key point of medical therapy for HF. They counteract the excessive sympathetic nervous system activity in chronic HF [10], leading to a decrease of the rate of hospitalizations. Beta-adrenergic antagonists decrease myocardial oxygen consumption and improve symptoms, exercise tolerance, hemodynamics and perhaps mortality in HF patients. Lechat et al. reviewed 18 clinical trials showing that beta-blockers reduced the risk of mortality or hospitalization for HF by 37% [11]. It is well known, however, that caution is mandatory when starting beta-blocker therapy in chronic HF, in consideration of the potential acute reduction in left ventricular systolic function resulting in worsening of clinical status. In the setting of acute decompensated HF, it seems appropriate first to start angiotensin-converting enzyme inhibitor therapy to obtain hemodynamic stability through vasodilation and then to initiate beta-blocker therapy once the patient becomes compensated and paucisymptomatic [12]. The choice of beta-blocker to use in the therapy of chronic HF has been debated and should be driven by its proven effectiveness in a clinical trial and by other patient-specific issues: clinical benefits are also found in several types of beta-adrenergic blockers, including metoprolol and carvedilol [13,14].

Angiotensin receptor blockers antagonize the effect of angiotensin II at the level of the angiotensin II receptors providing a more complete block of the rennin–angiotensin system than angiotensin-converting enzyme inhibitors. They are better tolerated since they do not cause bradykinin potentiation-related cough and angioedema. Several studies comparing angiotensin receptor blockers and angiotensin-converting enzyme inhibitors have shown no difference in mortality or need for repeat hospitalization [1].

Digoxin, a cardiac glycoside, is second line therapy for the management of HF [1]. Treatment with digoxin results in fewer hospitalizations and improvement of symptoms but does not confer a survival benefit [15]. Recent work suggests that the benefit of digoxin in chronic HF is related to neurohormonal effects enhancing autonomic dysregulation such as inhibition of sympathetic outflow from the central nervous system, decrease of plasmatic levels of norepinephrine and increase of parasympathetic activity [16].

Combination therapy with hydralazine and isosorbide dinitrate can be considered for patients with HF and NYHA class III or IV symptoms, already treated with rennin–angiotensin system antagonists and beta-blockers [17].

There has been growing interest in the potential therapeutic benefits of statins in HF [18]. Their potential therapeutic role comes from their antiatherogenic properties and their ability to improve endothelial function and plaque stabilization, which could reduce the risk of acute coronary events on the failing ventricle. A recently published prospective randomized study of statins in HF patients did not demonstrate improved clinical outcomes after treatment with 10 mg daily of rosuvastatin when compared with placebo [19]. Until further information becomes available, the benefits observed for statins in other populations do not seem to apply to patients with HF.

	3. Coronary artery bypass grafting

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Coronary artery bypass grafting (CABG) may potentially improve the outcome of patients with ischemic left ventricular dysfunction [20]. The Veteran Affairs Cooperative Study of Surgery [21] and the Coronary Artery Surgery Study [22] have demonstrated a significantly higher survival rate in the subset of patients with reduced left ventricular ejection fraction after CABG, versus those who were randomized to medical therapy. Recent studies have confirmed that CABG in patients with severely depressed left ventricular function gave a satisfactory survival rate, approaching that of cardiac transplantation [23,24].

Selection of patients for high-risk myocardial revascularization involves considerations about potential systemic comorbidities like chronic pulmonary disease, renal failure requiring dialysis, cancer or severe advanced diabetes, even though the most important factor probably is the presence of myocardial viability [25,26]. Myocardial dysfunction in patients affected by ischemic cardiomyopathy depends on impaired blood flow leading to oxygen supply/demand imbalance. This condition can result in myocardial stunning and/or hibernation, reversible after CABG, or scarring [27]. Myocardial stunning follows an acute episode of cardiac ischemia and leads to reversible reduced systolic and diastolic function. Hibernation was described in the late 1980s and it is characterized by decreased myocardial function concomitant with a reduction in blood supply. The identification of viable myocardium usually allows confirmation of contractile reserve, preserved metabolic activity and myocyte membrane integrity and is associated with convincing improvements in left ventricular function after coronary revascularization [28].

The techniques employed to identify the presence of hibernation include positron emission tomography (PET) with fluorodeoxyglucose (FDG), which is limited by its high costs and availability [29]. Myocardial viability can be demonstrated by dobutamine stress echocardiography and by its predictive biphasic response, characterized by an initial improvement in myocardial contractility at low doses of dobutamine infusion, followed by a decrease at high doses [30]. Nevertheless, the most promising imaging technique seems to be magnetic resonance with gadolinium enhancement [31], because it can reveal scar or viable muscle [32].

Both hibernating and stunned myocardium contribute to progressive systolic dysfunction, remodelling, and the development of HF. Rahimtoola et al. [33] have recently suggested a unifying concept of hibernation and remodelling with emphasis on the importance of early revascularization. In fact, remodelling appears to progress over time and the ability to reverse the process may also be time-sensitive.

Heart surgeons have evolved their practice to gain the greatest benefit from surgical revascularization in these high-risk patients. Attention to intraoperative myocardial protection appears mandatory and the use of antegrade and retrograde normothermic blood cardioplegia should be encouraged [34]. Advances in surgical management also include a wider use of the intra-aortic balloon pump and the administration of non-β receptor agonist inotropes such as levosimendan, which seems to be a valid pharmacological strategy increasing the likelihood of a good outcome [35,36].

Off-pump coronary artery bypass grafting (OPCABG) has become another option in the treatment of patients with coronary artery disease, especially those with associated systemic disease and functional impairment of various organs. Avoiding the potential damaging effect of cardiopulmonary bypass, this procedure has been considered for patients with poor left ventricular ejection fraction [37,38]. Several studies have shown that beating heart revascularization allows reduced perioperative blood loss and perioperative myocardial injury and lower operative mortality when compared to conventional grafting [39,40], even if to date no randomized trial results between on- and off-pump surgery in these high-risk patients have been published. The greatest concern in OPCABG surgery is hemodynamic deterioration during displacement of the heart. Displacement of the beating heart may well be tolerated in patients with good ventricular function, but hemodynamic compromise occurs more often in patients with severe ventricular dysfunction, producing less favorable operative exposure, safety and subsequently incomplete revascularization. A recent study published by Kleisli et al. has confirmed that complete revascularization improves long-term cardiac survival [41]: in consideration of these findings it appears mandatory to perform a rigorous selection of potential candidates for this technique, particularly in the setting of ischemic cardiomyopathy.

Hausmann et al. studied patients with end-stage ischemic cardiomyopathy and severely depressed left ventricular function in order to identify differential indications for CABG versus cardiac transplantation [42]. The study group consisted of 225 patients, potential candidates to cardiac transplantation, who underwent high-risk CABG because of viable myocardium detected preoperatively with myocardial thallium scintigraphy and echocardiography. In this group, operative mortality was 7.1% with an actuarial survival at 6 years of 78.9%. The authors compared this study group to 231 patients affected by ischemic dilated cardiomyopathy who underwent cardiac transplantation at the same institution in the same period. The authors reported an operative mortality of 18.2% with an actuarial survival of 68.9% at 6 years and stressed the observation that the detection of a viable area of 20% of more of the total heart mass is a good predictor for a satisfactory outcome after CABG.

There is a general agreement about the management of patients affected by ischemic dilated cardiomyopathy presenting documented contractile reserve and graftable target vessels. In the absence of significant right ventricular dysfunction, pulmonary hypertension and marked left ventricular dilation they can be considered good candidates for CABG rather than heart transplantation.

	4. Aortic valve surgery

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Aortic diseases frequently cause evolving HF. It is well known that aortic stenosis can lead to left ventricle pressure overload and subsequent compensatory hypertrophy. In absence of surgery, uncorrected pressure overload can lead to progressive and irreversible systolic and diastolic dysfunction and to the onset of symptoms of HF. The natural history of aortic stenosis confirms that the presence of dyspnea is the most important risk factor for death, with a mean survival rate of 50% at 2 years [43].

Surgery is a feasible option in the setting of severe aortic valve stenosis with clinical symptoms of HF, although preoperative decision-making is controversial and based on the detection of reversible left ventricular dysfunction [44]. The results are particularly uncertain among patients with severe aortic stenosis, reduced left ventricular ejection fraction and low transvalvular mean gradient, due to increased perioperative risk and reduced late outcome. Left ventricular dysfunction may be secondary to long-standing severe aortic stenosis with superimposed myocardial fibrosis, extensive coronary artery disease, or prior myocardial infarction. In this situation, the left ventricular dysfunction is not likely to improve after aortic valve replacement. Preoperative evaluation with dobutamine echocardiography allows the identification of patients who could potentially benefit from high-risk aortic valve replacement, mainly in cases of coexistence of severe aortic valve stenosis, depressed left ventricular ejection fraction and low transvalvular gradients [45]. If preoperative evaluation shows that ventricular dysfunction depends on valvular pathology and not on ischemic or restrictive cardiomyopathy, aortic valve replacement can be offered to these patients in consideration of the potential ventricular recovery after surgery. This strategy has been confirmed by recent series published in the literature [45–50], showing that aortic valve replacement can be performed in the setting of depressed left ventricular function with acceptable operative mortality and significant improvement in the quality of life of survivors.

Aortic regurgitation can initially cause a compensatory ventricular eccentric hypertrophy evolving into progressive myocardial fibrosis and cardiac dysfunction with the onset of symptoms of heart failure. It is well known that the natural history of these severely symptomatic patients affected by aortic insufficiency with depressed left ventricular dysfunction is very poor, and there is also evidence that medical therapy is not effective in reversing cardiac dysfunction [51]. It is recommended that patients with aortic regurgitation and in NYHA functional class III or IV with preserved left ventricular function, and those pauci- or asymptomatic patients with progressive left ventricular dilatation and/or mild to moderate left ventricular dysfunction, should undergo aortic valve surgery. No recommendations have been reported in current guidelines for aortic valve replacement in patients classified in NYHA class III or IV, affected by significant aortic regurgitation and severely depressed left ventricular function [52]. In this setting the best treatment is still a matter of debate, and no prospective studies comparing medical therapy versus aortic valve replacement versus heart transplantation have been published. In a recent study from Cleveland Clinic, Bhudia et al. have reviewed their experience in the treatment of patients affected by chronic aortic regurgitation and severe left ventricle dysfunction. They conclude that improved modern medical management based on angiotensin-converting enzyme inhibitors and beta-blockers has neutralized the high risk of severe left ventricle dysfunction [53] and that ‘aortic valve surgery for chronic aortic regurgitation and cardiomyopathy is no longer a high-risk procedure for which transplantation is the best option’ [54].

Earlier surgery, before the onset of left ventricular dysfunction, appears mandatory in order to improve survival in these high-risk patients [55], because the occurrence of symptoms and left ventricle structural changes lead to significantly increased morbidity and mortality.

	5. Mitral valve surgery

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Functional mitral regurgitation of varying severity commonly occurs in patients with end-stage cardiomyopathy, regardless of etiology. Patients affected by functional mitral regurgitation are a heterogeneous group and mechanisms such as annular dilation, decreased systolic annular contraction, left ventricle dilation and displacement of papillary muscles can play a role in the genesis of functional mitral regurgitation in the setting of dilated cardiomyopathy. Carpentier [56] described a functional classification of leaflet motion abnormalities. In type I dysfunction, mitral leaflet motion is unrestricted and mitral valve insufficiency depends on posterior annular dilation. Type IIIb dysfunction is caused by displacement of papillary muscles associated with left ventricle dilation, determining tenting of mitral leaflets and restricting their coaptation. Alterations in the left ventricular shape strengthen mitral regurgitation and mitral insufficiency increases ventricular dilatation and dysfunction: in this vicious cycle both these factors contribute to increasing volume overload and left ventricular wall stress [57]. Therefore functional mitral regurgitation is an independent risk factor for cardiovascular morbidity and mortality, because it worsens symptoms and prognosis in patients affected by left ventricular dysfunction [58].

Mitral valve surgery in patients with HF has gained a general consensus because the rationale for repair or replacement is to allow for left ventricular unloading and to promote myocardial remodelling. Historically, the surgical solution to mitral valve insufficiency has been the complete replacement with a mechanical or biologic prosthesis; it is well known, however, that this procedure, associated with the removal of subvalvular apparatus, leads to very high mortality rates. In the setting of severe left ventricular dysfunction and mitral regurgitation, mitral valve surgery has demonstrated to offer symptomatic improvements and survival benefit [59]. Moreover several studies have demonstrated that the preservation of the annulo-papillary muscle continuity obtained with mitral valve repair preserves systolic and diastolic left ventricular function, and improves left ventricle geometry and wall stress [57,60,61].

These issues provided the rationale for the series of results concerning patients affected by dilated cardiomyopathy and secondary mitral regurgitation, who underwent mitral valve repair [62,63]. In this series, mean NYHA functional class improved from 3.9 to 2.0 and actuarial survival was 82% at 1 year and 72% at 2 years. These authors were the first to describe the technique of remodelling mitral annuloplasty using a flexible posterior ring. In most instances, functional mitral regurgitation determines a central jet that can be treated with the reduction ring annuloplasty technique. Mitral valve annuloplasty can also be performed with partial rigid rings or complete rigid rings; however, differences in ring design have not yet demonstrated significant differences in clinical outcome [64]. In the presence of leaflet pathology, triangular or quadrangular resections, chordal shortening and edge-to-edge repair (Alfieri correction) [65] have been successfully used with the aim of preserving the mitral valve apparatus. Several reports concerning a series of patients who underwent mitral valve repair in the setting of dilated cardiomyopathy are summarized in Table 1 [65–71].

In consideration of these findings, other groups have developed several surgical strategies for the treatment of mitral regurgitation secondary to ischemic cardiomyopathy: the first is based on the relocation of posterior papillary muscle tip to treat type IIIb leaflet motion abnormalities [72]. This procedure is based on the observation that the displacement of the posterior papillary muscle tip after posterolateral ischemia is the main mechanism of ischemic mitral regurgitation [73]. The second procedure consists of the cutting of second-order chordae tendineae to the anterior leaflet that has been shown to improve coaptation and reduce mitral valve regurgitation [74].

In conclusion, the correction of functional mitral valve regurgitation with annuloplasty alone results in partial reversal of left ventricular remodelling. The long-term benefit of this procedure has yet to be demonstrated by randomized trials comparing optimal medical management with mitral valve surgery.

	6. Ventricular restoration techniques

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Long-term prognosis after an episode of myocardial infarction depends on changes in left ventricular shape and contractile function. It is well known that the ventricle remodels from its normal elliptic shape to a spherical shape as a consequence of a transmural myocardial infarction. However, in the era of early reperfusion strategies, namely thrombolysis and/or primary angioplasty, the principal macroscopic finding is the endocardial necrosis that leads to left ventricular wall akinesis and not to a true thinned, dyskinetic left ventricular aneurysm. In fact surgical ventricular restoration is based on the concept of the ‘wavefront phenomenon’ [75]. Following this concept, the irreversible ischemic injury occurs first in the subendocardial myocardium layer. If perfusion is restored before ischemic myocardium evolves towards a transmural infarction, the viable subepicardial tissue creates an akinetic zone determining impairment in segmental contraction. This geometrical change derived from ventricular remodelling, in turn, leads to symptoms associated with HF and is a risk factor for decreased survival [76]. Moreover, increased left ventricular volume and wall motion abnormalities are responsible for augmented myocardial oxygen demands and impaired left ventricular function. According to Laplace's law, which could be roughly applied as explanation for the progressive left ventricular dilation, surgical intervention improves myocardial blood supply and left ventricular wall stress reducing left ventricular radius/volume ratio. In fact, left ventricular volume reduction surgery was the consequence of treatment of left ventricular aneurysms reported by Cooley et al. [77], Jatene [78] and Dor [79].

Although surgical approaches continue to improve, the goal of ventricular remodelling techniques is still to reduce left ventricle chamber volume and to restore its normal elliptical geometry, excluding akinetic or dyskinetic scar tissue. Fundamental concepts have been learned about volume reduction surgery through clinical experience with partial left ventriculectomy promoted by Batista et al. [80]. This technique was based on the resection of a portion of left ventricular lateral wall without any consideration of regional dysfunction, with the aim of reducing volume, wall stress and improving left ventricular ejection fraction as opposed to improving overall pump function. This procedure was largely abandoned after the publication of reports showing disappointing results in terms of low event free survival rates at 1 and 3 years and redevelopment of left ventricular dilation requiring rescue assist device implantation [81].

Surgical ventricular restoration is now generally performed by placing a patch at the same level of a purse-string suture positioned at the transition zone of myocardial asinergy. The operation can be completed by coronary revascularization and/or mitral valve repair or replacement, as indicated by the Berlin Heart Center group. The aim of this approach is to obtain a reduction in the longitudinal axis of left ventricle with a return to an elliptical shape determined by the position of the new apex. Enhancing the partial effects of the coronary revascularization and of mitral valve repair, left ventricular restoration improves the left ventricle performance because it allows septal scar exclusion and the reorganization of the left ventricle wall, suppressing the wall tension of myocardial remote areas and improving contraction of these areas. Moreover, the patch avoids a too large reduction of volume and maintains a reasonable physiological diastolic volume. Analysis of results published by Berlin Heart Center in Berlin [82] showed improvement in left ventricular wall thickness and contraction after months of left ventricular assistance, allowing weaning idiopathic cardiomyopathy patients from assistance (bridge to recovery). Similar management may be possible in ischemic cardiomyopathy, where left ventricular wall consists of scar areas and dilated, living perfused myocardium portions.

The efficacy of surgical ventricular restoration has been documented by the Reconstructive Endoventricular Surgery returning Torsion Original Radius Elliptical shape to the left ventricle (RESTORE) group [83]. The investigators showed that, after ventricular restoration performed using the Dor technique in 1198 post-infarction patients, there was an increase in left ventricle ejection fraction from 29.6% to 39.5% and a reduction in left ventricular end-systolic volume index from 80 ± 51 ml/m² to 57 ± 34 ml/m². Moreover, overall 30-day mortality was 5.5%, a considerable improvement in postoperative NYHA functional class was detected and 5-year survival resulted 69 ± 3% [84].

The international STICH trial (Surgical Treatment for Ischemic Heart Failure) was set up to obtain a randomized evaluation of the optimal management of patients with HF who also have artery disease that is amenable to revascularization [85]. This trial started in 2002 at 100 centers. It involved patients with ejection fraction less than 35%, and aimed to compare ventricular restoration and coronary artery bypass grafting and medical therapy and to define the role of each therapeutic approach in the palliation of HF. The STICH trial is expected to reveal some important findings with respect to the management of high-risk patients. Surgical coronary revascularization is expected to confer a significant reduction in mortality when compared with medical therapy, and ventricular restoration is also expected to improve hospitalization-free survival when compared with coronary artery bypass surgery alone.

	7. Dynamic cardiac myoplasty

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
The intention of this surgical strategy was to re-power the failing heart using autologous skeletal muscle. Latissimus dorsi is mobilized on its neurovascular pedicle and brought into the chest through a small thoracotomy and wrapped around the heart to deliver increased muscle bulk in order to improve ventricular contraction and systolic function. The muscle is paced in order to synchronize the skeletal wrap contraction with cardiac contraction.

Despite promising animal work, improvement in systolic function in patients has been inconsistent [86]. This procedure is rarely undertaken now.

	8. New devices for ventricular reshaping

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Some researchers have tested new prosthetic devices to reverse ventricular dilation secondary to cardiomyopathy.

The most studied product is the CorCap^TM cardiac device (Acorn Cardiovascular), which is a mesh-like polyester fabric, compliant, biocompatible support that is sewn circumferentially around both ventricles with the aim of limiting and reversing ventricular remodelling associated with HF thereby reducing wall tension [87]. Its use is based theoretically on the observations made in patients who underwent dynamic cardiomyoplasty with latissimus dorsi wrapping, in whom beneficial effects seemed to be attributable only to passive containment of ventricular dilatation. Early clinical reports have shown a decrease in ventricular chamber dimensions and improvement in symptoms and left ventricle ejection fraction [88]. The results of the Acorn Pivotal Trial including patients with NYHA classes III–IV and dilated cardiomyopathy were recently presented. They revealed that patients receiving the cardiac support device benefited from considerable improvement in quality of life and had fewer major cardiac procedures (left ventricular assist device implantation, heart transplantation) and significant greater reduction in left ventricular volumes, compared to the control group [89]. A recent paper published by Starling et al. has demonstrated sustained benefits of the CorCap cardiac support device on left ventricular remodelling, confirming a long-term beneficial impact on left ventricular size and shape in patients with heart failure [90]. Although the beneficial effects of passive containment surgery in patients affected by heart failure who underwent mitral valve surgery have been shown in the Acorn clinical trial [91], a recent case-control study has shown that the implantation of this device in patients with longstanding aortic regurgitation and severely dilated left ventricle does not seem to influence reverse remodelling or to improve left ventricular function [92]. This procedure is now undertaken in a few heart surgery centers in the world.

The Myosplint (Myocor Inc., Maple Grove, MN) is another device implanted with the aim of reducing wall stress using the Laplace principle and improving ventricular function. The operation is based on the reduction of the ventricular diameter by a series of buttons placed across the left ventricle perpendicular to its long axis. This technique has the effect of creating a symmetric bilobular section of the ventricle reducing its internal radius. After the successful results obtained from an animal model [93], the largest clinical series published by Fukamachi and McCarthy [94] consisted of 21 patients in whom the authors reported a significant improvement in symptoms and reduction of ventricular volumes. Moreover, no device-related failure was detected at 6-month follow-up. The procedure is rarely undertaken now: then the results obtained by this small number of patients do not permit conclusions regarding safety and efficacy of this device on the ventricular reshaping.

	9. Cardiac resynchronization therapy

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Clinical and laboratory variables predicting mortality in advanced HF include wide QRS complex as evidence of electrical dyssynchrony [95]. This type of conduction disorder is usually associated with delayed depolarization and contraction of the left ventricular free lateral wall, whereas the interventricular septum contracts normally resulting in paradoxical septal motion. HF patients frequently have altered electrical depolarization leading to further mechanical cardiac pump failure.

One of the most recent advances in HF management is the concept of biventricular pacing in which both the ventricles are resynchronized to contract simultaneously. The transvenous approach is the most commonly used and is achieved by using a special delivery sheath to allow cannulation of the coronary sinus to permit delivery of pacing leads into the epicardial vein serving the left ventricular free wall. The surgical approach is performed by placement of the left ventricle lead under direct vision and is used when transvenous approach fails.

Several studies have examined the short-term effects of biventricular pacing in patients with severe HF and electrical dyssynchrony, demonstrating hemodynamic benefits, and improved quality of life, 6 min walk test, and peak VO2 [96,97]. Large randomized clinical trials have subsequently confirmed both morbidity and mortality benefits of cardiac resynchronization therapy [98–101].

The ACC/AHA heart failure guidelines (2005) recommend cardiac resynchronization therapy (class I indication) in patients with all the following characteristics, unless contraindicated, (level of evidence: A): NYHA functional class III or ambulatory class IV symptoms despite recommended, optimal medical therapy, LVEF 35%, and cardiac dyssynchrony, which is currently defined as a QRS duration >120 ms [102].

	10. Ventricular assist devices

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
Many devices have been developed as replacement therapy, either as a pump or as a stable electrical system, with the aim of supporting the failing heart in critically ill patients with end-stage HF. Depending on the particular device used, both the right and left ventricle can be assisted with the same concept: blood is removed from the failing ventricle into a pump and delivered to either aorta or pulmonary artery. VADs can also be categorized by implantation site (intracorporeal, paracorporeal or extracorporeal) or by mechanism of action (pulsatile or continuous flow devices).

Pulsatile devices were the first generation of pumps introduced clinically: they have a large size, multiple moving parts and can be implanted intracorporeally or paracorporeally. The second generation continuous flow pumps are miniaturized and have a single moving part: they permit intracorporeal placement in consideration of their small size. A third generation of blood pumps with mechanical noncontact magnetic bearings are in preclinical studies or have recently been used.

VADs have been used in three clinical situations: as bridge to transplantation, when clinical status of patients who are listed for transplantation is deteriorating rapidly before a suitable donor heart becomes available; as bridge to recovery, in patients who are expected to recover left ventricular function: (e.g. postcardiotomy shock and fulminant myocarditis); or as alternative to heart transplantation, in patients not considered candidates for this procedure (‘destination’ therapy).

10.1 Bridge to transplantation
VADs can also be used under circumstances where clinical status of patients who are listed for transplantation is deteriorating rapidly (bridge to transplant). Typically, patients are those with large myocardial infarctions, those with myocarditis and most commonly, patients with chronic end-stage HF. This scenario is the most common indication for use of LVADs. Survival to transplantation is excellent in patients supported with a VAD [103]; and most of these devices allow these patients to be discharged from hospital and obtain a more stable hemodynamic condition before heart transplantation [104]. Several devices have been tested and validated for use as bridge to transplantation including the Novacor LVAS (World Heart Corporation) [105], the HeartMate VE (Thoratec Corporation) [106] and the Thoratec paracorporeal and intracorporeal devices [107]. Newer devices used as bridge to transplantation include intracorporeal devices as the axial flow pumps HeartMate II [108], Jarvik 2000 [109], Micro-Med DeBakey VAD [110] and the novel magnetically suspended axial flow INCOR (Berlin Heart AG, Berlin, Germany) LVAD [111] and extracorporeal systems as Levitronix CentriMag maglev pump [112]. These pumps are small and generate flows of more than to 5 l/min. These devices produce a non-pulsatile flow and have potential advantages of improved durability, simple management and silent functioning.

10.2 Bridge to recovery
VADs have been successfully used in patients who are expected to recover sufficient myocardial function. The first condition is related to patients with compromised left ventricular function who have undergone long operations. Because of the severity of the postoperative circulatory shock, short-term mechanical support as bridge to recovery is often needed. An additional indication for VAD implantation as a bridge to recovery is post acute myocardial infarction shock, when traditional inotropic support and intra-aortic balloon pump counterpulsation appear insufficient for a good hemodynamic status and too weak to reverse the stunning of damaged myocardium. Patients affected by fulminant myocarditis with severe hemodynamic compromise recover fully in the majority of cases after VAD implantation. Finally, the last ‘bridge to recovery’ indication is the transient support of the right ventricle failure following LVAD therapy of after heart transplantation. In these cases RVAD support for a few days is sufficient to reduce pulmonary pressures and to improve right ventricular function.

Abiomed BVS is one of the devices employed as short-term bridge to recovery. This device, not widely used in Europe, is simple to use, able to support both ventricles and useful for inter-hospital transfer [113]. Other newer devices have been used for ‘rescue’ therapy. The Tandem Heart Percutaneous VAD [114] is a continuous flow centrifugal assist device with an inflow cannula inserted percutaneously through the femoral vein and advanced across the intra-atrial septum into the left atrium. The extracorporeal pump receives blood from left atrium and returns it to femoral artery via outflow cannula. It provides a satisfactory hemodynamic short-term support for patients affected by post-cardiotomy shock and for patients undergoing high-risk coronary percutaneous procedures. Nevertheless, this device has not demonstrated significant survival improvement in comparison with IABP. Another device used in the setting of severe ventricular dysfunction and cardiogenic shock following percutaneous procedures or post-cardiac surgery is the Impella (Impella Technologies of Abiomed Corporation) [115]. This system uses a microaxial pump mounted on a 9 F catheter, inserted directly in the heart chambers or percutaneously through the femoral artery and positioned under radioscopy across the aortic valve to unload the failing left ventricle. This device has the potential for being used also as a bridge to heart transplantation or to another permanent destination support device. The Levitronix CentriMag circulatory support system, a centrifugal pump with a magnetically levitated rotor, has been successfully used as a bridge to decision and as a bridge to another more permanent device in patients with refractory acute cardiogenic shock and multisystem organ failure [116,117].

10.3 Destination therapy
VADs are selectively deployed as ‘destination’ therapy as alternative to heart transplantation in patients not considered candidates for this procedure. To date, the HeartMate XVE has been approved for this purpose, but several newer devices are being evaluated for destination therapy. Results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study have been widely discussed. It is the only prospective, randomized study comparing maximum medical therapy to implantation of an early generation of HeartMate VAD in a group of extremely ill patients with end-stage heart disease not eligible for transplantation [118]. Survival of VAD and medical patients at 1 year was 52% versus 25% and at 2 years 23% versus 8%. In addition, VAD patients had improvement in quality of life compared to the medically treated cohort. Recent modifications of the technique and in perioperative care have decreased the high VAD-related morbidity and mortality reported in the REMATCH trial, including the high incidence of septic complications and their limited long-term reliability [119]. The axial flow pumps HeartMate II [119], Jarvik 2000 [109], DeBakey VAD [120] and the VentrAssist left ventricular assist system (Ventracor) [121] are the subjects of ongoing clinical evaluation to test their use as heart failure destination therapy.

10.4 Pediatric myocardial mechanical support
Mechanical circulatory support systems for children with advanced heart failure are now available. ECMO [122] and extracorporeal centrifugal pumps [123] have been widely used in this setting with good results, even if their application is limited by the requirement for continuous intensive care and short time reliability. The use of the Thoratec and the MicroMed DeBakey VAD is limited to children weighing more than 15–20 kg [124,125]. Only the pediatric Berlin Heart Excor and the Medos HIA systems have been reported to be successful in children. Both systems consist of a paracorporeal, pneumatic compressor-operated diaphragm pump with valves. Application of the Medos VAD has been reported in small series of children with shorter support times [126,127]. More data are available for the Berlin Heart Excor [128–130]. This device enables long-term circulatory support, allowing the necessary time to obtain organ function restoration, extubation, mobilization and oral feeding of children. Recently, the VentrAssist (Ventracor Ltd., Chatswood, Australia) VAD has been used in pediatric patients with end-stage heart failure [131]. This device, a relatively small, continuous flow, third-generation left ventricular assist device, has been implanted in three patients enabling each of them to be discharged home with survival time more than 1 year. A larger patient cohort has been required in order to confirm safety and efficacy of this device.

10.5 Complications of VADs
Implantation of a mechanical support with a VAD is associated with significant mortality and morbidity: the most frequent early complications remain perioperative bleeding and right ventricular failure. The former is often the result of a prolonged heart operation and is related to perioperative coagulopathy and platelet dysfunction induced by the extracorporeal circulation. Moreover bleeding is increased by routine use of anticoagulant and antiplatelet drugs in these patients affected by heart failure associated with frequent hepatic dysfunction secondary to right heart failure. This latter complication, present in patients who underwent LVAD implantation, occurs in 30% of patients and its etiology is still a matter of debate. Elevated pulmonary vascular resistance induced by cardiopulmonary bypass, changes in interventricular dependence, right coronary ischemia, and other causes have been put forward to explain this catastrophic complication, associated with a very high mortality [132]. Late complications of VADs implantation are device-related infection and limited reliability. Driveline infections can be successfully eradicated with wound treatment and antibiotics administration while device infection often requires device exchange or heart transplantation. Device reliability is variable depending on the characteristics of mechanical support device: the first generation of large pulsatile pumps perform well for 1–3 years only, due to the presence of several moving parts and the strain of mechanical bearings over time. The recent miniaturized axial flow pumps continue to work in humans for a duration of as long as 5.5 years [133]. The third generation of maglev pumps allow suspension of a moving element without any mechanical contact, thus eliminating wear that will take place at the contact surface, and heat generation. Nevertheless, durability and stability of the sensors and control system could be a problem in the sophisticated and expensive maglev system. All the equipment operates in the biological environment with a body temperature of 37 °C and with high humidity: these conditions can affect electronic performance and sealing of body fluid entering the package and can lead to an increase in the probability of failures. A simple maglev system is required for making a long-life device. Nevertheless, INCOR VAD has demonstrated to be effective for more than 4 years, showing the feasibility of long-term assistance with a continuous pump [134].

	11. Total artificial heart

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
The most radical therapy for the treatment of end-stage heart disease also includes the complete orthotopic replacement of the heart with a total artificial heart (TAH). Two devices have been used: the CardioWest pneumatic TAH (TAH-t; SynCardia, Inc., Tucson, AZ, USA) and the hydraulic AbioCor Implantable Replacement Heart (IRH) (ABIOMED, Danvers, MA, USA). The CardioWest pneumatic TAH has been approved as a temporary device for bridge to cardiac transplantation. It is an orthotopic pneumatic biventricular device that replaces the ventricles, all four valves and the proximal portion of each great vessel. Its main limitations remain the external power source and a large control console which is not portable thereby restricting patients to a hospital setting.

More than 700 CardioWest TAH-ts have been implanted worldwide. Several reports have suggested that CardioWest TAH-t safety is comparable to currently used biventricular assist devices and LVADs [135,136]. Risk factor profiles for LVADs are right ventricular failure, and markers of multiple organ failure such as need for mechanical ventilation, elevated total bilirubin serum levels, and serum creatinine. Extracorporeal BiVADs have been associated with increased risk with increased age, previous mediastinal operation, elevated blood urea nitrogen, elevated bilirubin levels, and mechanical ventilation before implantation. Recently, Copeland et al. have reported their study on risk factor analysis for bridge to transplantation with the CardioWest TAH-t [137]. By multivariate analysis, none of the previously reported risk factors related to VADs implantation influenced survival of patients bridged with the CardioWest. The authors concluded that this device can fill ‘a therapeutic gap that is not covered by LVADs or extracorporeal BiVADs’.

The AbioCor TAH was designed as a completely implantable device intended exclusively as an alternative to transplantation. Its design permits its complete implantation in the body and thus, patients are not tethered to a large air-pumping console nor do they have transcutaneous wires or tubes. The system is powered by a small external battery that transmits power across the skin wirelessly. The initial clinical experience suggests that the AbioCor TAH might be effective as destination therapy in patients with biventricular end-stage congestive heart failure [138–140] even if further investigation is warranted. The company is proceeding with the development of a second generation of AbioCor that will be smaller and designed to perform well over 5 years.

	12. Cellular transplantation

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
A recent concept in the treatment of end-stage heart failure is the potential use of stem cells to improve cardiac function. Cellular transplantation is based on the theory that a progenitor stem cell can differentiate into cardiac myocytes and endothelial cells and subsequently replace damaged myocardium [141]. In the field of heart surgery, multiple cell types are currently being studied. These include skeletal myoblasts, bone marrow stem cells (mesenchymal and hematopoietic), adipocytes, and endothelial progenitor cells; all as adjuvant therapy at the time of coronary artery bypass grafting in patients with ischemic cardiomyopathy.

Initial cell-based cardiac therapeutic studies used satellite cells isolated from skeletal muscle [142]. Skeletal myoblasts were also the first cell candidate to be used in a clinical setting for the treatment of heart disease. These cells can grow easily in vitro, have high resistance to ischemia induced apoptosis and are progenitors able to differentiate into multinucleated myotubes only, without the potential risk of tumor formation [143]. The skeletal muscle is able to regenerate itself after injury because it contains satellite cells or myoblasts with the capacity to differentiate into functional skeletal muscle. Results from experimental studies have shown that the satellite cells were able to differentiate into muscle cells but they did not become cardiomyocytes [144]. In fact these cells did not couple electrophysiologically with the host myocardium, because skeletal myoblasts are not able to express the cardiac specific gap junction proteins N-cadherin and connexin 43.

To date, clinical trials have been performed in individual centers with limited patient numbers. In a recent phase I clinical trial based on the use of autologous skeletal myoblasts during coronary artery revascularization, Menasché et al. reported better results with the adjuvant cellular therapy in terms of increased NYHA functional class (mean preoperative NYHA 2.7 vs 1.6 postoperatively) and improvement of left ventricular ejection fraction (24% to 32%) [145]. One major safety concern is that myoblast grafts may represent an arrhythmogenic substrate [146], probably due to the absence of electromechanical coupling. In fact, in the first clinical trial published by Menasché et al., four of the 10 patients undergoing CABG and myoblast injections sustained ventricular tachycardia and required the implantation of a cardioverter-defibrillator [145]. Other phase I clinical studies have reported the use of skeletal myoblasts for the treatment of heart disease with an agreement concerning improvements of regional wall motion and global left ventricular ejection fraction (Table 2 ). The low number of patients, however, associated with the absence of control groups and the confounding effect of concomitant revascularization mean that further studies are necessary for definitive conclusions about the efficacy of this procedure.

	13. Conclusions

Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 
The modern approach to surgical treatment of HF is multidisciplinary, given that mandatory multiorgan attention is required in the perioperative period, to ensure early good outcome in these high-risk patients. Future therapies for HF could include stem cell therapy associated with other procedures such as ventricular assist devices implantation or ventricular restoration techniques, allowing the potential differentiation of implanted stem cells in a resting and unloaded heart. More questions remain unanswered in the growing field of stem cell therapy, including optimal cell type, optimal cell quantity and density, identification of correct patients, best method of delivery, detection of stem cell homing, engraftment and survival, definitive elucidations on safety with regard to arrhythmogenic and tumorigenic potentials.

The number of alternative available options to heart transplantation suggests however that there should be close collaboration between both cardiologists and cardiac surgeons in treating patients with end-stage HF who are not candidates for transplant.

	Acknowledgments

 
We thank Lois Clegg, English Language Teacher, University Medical School of Parma, for her assistance in the revision of the manuscript.

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Top Abstract 1. Introduction 2. Medical therapy 3. Coronary artery bypass... 4. Aortic valve surgery 5. Mitral valve surgery 6. Ventricular restoration... 7. Dynamic cardiac myoplasty 8. New devices for... 9. Cardiac resynchronization... 10. Ventricular assist devices 11. Total artificial heart 12. Cellular transplantation 13. Conclusions References

 

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