Surgical management of congestive heart failure: translational research to clinical application – the future is bright!

It is clearly established that morbidity and mortality from congestive heart failure (CHF) is related to the irreversible progression of left ventricular (LV) dysfunction. Regardless of the etiology of CHF, the associated deterioration in LV diastolic compliance and systolic function results in impaired ventricular filling and decreased tissue perfusion leading to the progression of the symptoms of fatigue, dyspnea on exertion and peripheral edema [1]. The management options for CHF range from medical therapy, to conventional surgical procedures aimed at alleviating the cause of CHF, to cardiac augmentation procedures and total cardiac transplantation [1].

With the introduction of more effective antiarrhythmic agents and afterload reducing agents to the drug armamentarium, the currently available pharmacologic therapy for CHF is of proven, but limited, efficacy in reducing symptoms and long-term mortality [2]. A Survival Trial of Amiodarone Therapy in Congestive Heart Failure (STAT-CHF trial) found no difference in survival among heart failure patients with asymptomatic ventricular arrhythmias who received amiodarone therapy or placebo [3].

The conventional surgical options for the management of CHF are directed at the underlying pathophysiology of the disease; Coronary artery bypass grafting (CABG), mitral valve repair or replacement and LV aneurysm resection or remodeling are all attempts to reverse or slow down the progressive LV dilatation and failure. The Duke Cardiovascular Disease Databank followed more than 1400 patients with CHF and compared CABG to medical therapy [4]. The study reported favorable event-free survival for CABG over medical therapy after 30 days to over 10 years. The 10-year adjusted survival in the CABG cohort was 42 compared with only 13% for nonsurgically treated patients [4]. In patients with ischemic or nonischemic CHF, the associated or functional mitral regurgitation (MR) worsens both symptoms and prognosis. In these instances, surgical approaches including mitral valve repair with an annuloplasty ring and valve replacement with preservation of the subvalvular apparatus may alleviate these symptoms or delay their progression.

In one series, Rothenburger et al. reported 31 patients with MR and ejection fraction below 30% who underwent isolated repair or replacement with complete preservation of the subvalvular apparatus [5]. They reported comparable results between the two groups with 1-, 2- and 5-year survival rates of 91, 84 and 74%, respectively [5]. These results clearly demonstrate that preserving the mitral valve apparatus results in improved ventricular geometry, decreased wall stress and improved systolic and diastolic function. Understanding the interdependence of ventricular function and geometry and the mitral annulopapillary muscle continuity have led to the belief that restoring a more functional, elliptical shape to a dilated, sphere-shaped LV would further reduce wall stress and improve ventricular function. This concept of ‘surgical ventricular restoration’ (SVR), pioneered by Dor et al., was evaluated in more than 1100 patients in the Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV (RESTORE) study [6]. The data demonstrated that reducing the LV end-systolic volume index (LVESVI) by 35% led to a corresponding 30–35% improvement in LV ejection fraction. Whereas 67% of the patients were in New York Heart Association (NYHA) class III or IV preoperatively, only 15% remained in class III or IV and 85% were in class I or II after surgery. The overall 5-year survival was 68% and the 5-year freedom from hospitalization for CHF was 78%. Many of the patients enrolled in the RESTORE study had concomitant procedures (95% had concomitant CABG and 22% had concomitant MV Repair), which may have accounted for the improved outcomes, given the previous trials mentioned [6]. Consequently, and in order to determine the improvement in LV function due to SVR alone or SVR in combination with CABG, the Surgical Treatment for Ischemic Heart Failure (STICH) trial was initiated in 2002. The STICH trial will likely identify the patients who will benefit from CABG, SVR, both procedures or from medical therapy alone [7].

In the absence of identifiable causes for CHF or with untreatable causes such as nonbypassable coronary artery disease, therapy is aimed at prevention of sudden cardiac death in the form of automated implantable cardioverter defibrillator (AICD) therapy. The Sudden Cardiac Death in Heart Failure trial (SCD-HEFT) looked at amiodarone therapy versus placebo or AICD therapy [8]. There was no difference in mortality between the amiodarone and placebo groups but a 23 % relative risk reduction in all-cause mortality with AICD therapy [8].

It is clearly established that the irreversibly injured myocardium lacks the ability to regenerate and is replaced by noncontractile, nonconducting fibrous scar [9]. Newer surgical therapies are aimed at augmenting the depressed systolic function of the injured myocardium [1]. These modalities range from cardiac resynchronization therapy, to mechanical ventricular assist devices (VADs), to generating functional neomyocardium using growth factors (or cellular cardiomyoplasty) [10]. It is estimated that up to 30% of patients with CHF experience significant ventricular dysynchrony secondary to intraventricular conduction delays. Cardiac resynchronization therapy (CRT) has been shown, in a meta-analysis, to substantially reduce all-cause mortality and major morbidity and improve quality of life [11]. Eight randomized trials looking at 3380 patients, observed a total of 524 deaths. Follow-up ranged from 1 month to a mean of 29.4 months. CRT reduced mortality (odds ratio: 0.72; 95% confidence interval: 0.59–0.88), reduced hospitalization for worsening heart failure (odds ratio: 0.55; 95% confidence interval: 0.44–0.68) and improved quality of life as measured by the Minnesota Living with Heart Failure Questionnaire [11].

The concept of dynamic cardiomyoplasty (DC), now of historic interest only, had focused on providing skeletal muscle support, in the form of a latissimus dorsi muscle (LDM) flap, to aid the failing ventricle [12]. As originally studied, the LDM flap is wrapped around the ventricle in order to provide mechanical and structural support. The LDM was then trained by increasing electrical stimulation by a myocardial burst stimulator to condition the previously fatigable, type II, skeletal muscle fiber into a nonfatigable, type I, contractile tissue. A review of the 10-year experience in the USA reported over a decade ago (1996) demonstrated a significant increase in LV ejection fraction (25 vs 30%) and LV Stroke Work Index (LVSWI; 26.1 vs 34.3 g/m/beat) after 6 months [13]. Although DC did not translate into a measurable survival benefit when studied in patients with end stage heart disease, this concept has inspired several investigators to look at similar methods of structural support or physiologic augmentation that are still under investigation.

Another form of ventricular support that is currently in clinical use is ‘artificial ventricular’ chambers ranging from pulsatile LV assist devices (LVADs) such as the electric HeartMate™, XVE™ and Novacor™ devices to continuous flow devices such as the Thoratec HeartMate II. The first-generation devices are currently being used primarily as bridge-to-transplantation and bridge-to-recovery and have been explored for use as destination therapy with favorable results. The ‘second-generation’ HeartMate II continues to be investigated, for destination therapy in lieu of transplantation and the device is expected to be approved by the US FDA. Patients placed on LVAD support as a bridge-to-transplantation have excellent survival to transplantation and also post-transplant survival equal to that seen with nonbridged patients [14]. The bridge-to-recovery strategies have also been in place for quite a long time, especially for post-cardiotomy shock and fulminant myocarditis patients. Whereas the role for LVADs as a bridge-to-transplantation has been established, the data supporting their role as permanent therapy in nontransplant candidates is still limited. The Investigation of Nontransplant-Eligible Patients Who Are Inotrope Dependent (INTrEPID) trial was a prospective, nonrandomized clinical trial comparing LVAD with optimal medical therapy (OMT) [15]. A total of 55 patients with NYHA functional class IV symptoms who failed weaning from inotropic support were offered a Novacor LVAD. The Novacor-treated patients had superior survival rates at 6 months (46 vs 22%; p = 0.03) and 12 months (27 vs 11%; p = 0.02). A total of 85% of the LVAD-treated patients had minimal or no heart-failure symptoms. Five Novacor^® patients and one OMT patient improved sufficiently while on therapy to qualify for cardiac transplantation [15]. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial have also demonstrated that implantation of the HeartMate XVE LVAD, as destination therapy, can provide survival superior to any known medical treatment in patients with end-stage heart failure who are ineligible for transplantation [16]. The 1-year survival after LVAD implantation was 56% (compared with 25% in the optimal medical therapy group) [16]. Unfortunately, the current pulsatile, volume-displacement devices have limitations, including the large pump size, the limited long-term mechanical durability and infections, that have reduced widespread adoption of this technology. Continuous-flow pumps are newer types of LVADs developed to overcome some of these limitations. In a prospective, multicenter study, 133 patients with end-stage heart failure who were on a waiting list for heart transplantation underwent implantation of a HeartMate II continuous-flow pump [17]. The median duration of support was 126 days (range: 1–600). The survival rate during support was 75% at 6 months and 68% at 12 months. At 3 months, therapy was associated with significant improvement in functional status and quality of life [17].

An alternative approach to mechanically assisting or replacing a damaged, dysfunctional ventricle is to generate a ‘new’ functional ventricle [9]. As a terminally differentiated cell, the mature cardiomyocyte has withdrawn from the cell cycle and lacks the ability to repair and proliferate. Researchers have employed strategies to induce the formation of functional neomyocardium using cells already present in the ventricle by inducing the regeneration-potential of cardiomyocytes or transforming scar tissue into vascularized myocytes using various growth factors such as basic fibroblast growth factor (bFGF), VEGF and transforming growth factor β-1 [9,18]. Other strategies focus on restoring regional blood flow by transmyocardial revascularization using laser- or needle-created channels to induce an inflammatory response that leads to the subsequent increase in regional blood flow. Both of these approaches are aimed at salvaging any viable, functional myocardium [19]. A third group of strategies focus on transplanting exogenous cells into an injured area to regenerate new, functional, myocardium. Many cell sources have been identified including fetal, myoblast cell-line and stem cell (satellite cell and stromal cell) lines. Since fetal cell lines may need immunosuppression and research in this area may be conceived by some as (un)ethical and since myoblast cell lines may have some tumor growth potential in the donor pool of cells, two alternative autologous cell sources have been studied extensively: the skeletal muscle satellite cell and the bone marrow stromal cell [20]. Menasche et al. reported the first human autologous myoblast transplantation in a patient undergoing concomitant CABG [21]. Transthoracic echocardiography and positron emission tomography demonstrated improved regional function and viability after skeletal myoblast implantation. Patel et al. performed a prospective, randomized study of CD34⁺ adult, autologous, stem cell implantation, as an adjuvant to CABG, in patients with ischemic cardiomyopathy [22]. Compared with control, there was a significant improvement in cardiac function at 6 months (46.1 vs 36.2%; p < 0.001).

At present, the main replacement therapy for CHF is the biologic replacement through cardiac allograft transplantation; however, this mode of therapy necessitates immunosuppression and frequent monitoring of the allograft function for rejection. It has been estimated that the half-life of a cardiac allograft is 10 years, with acute rejection, nonspecific graft failure and accelerated graft coronary artery disease being the main causes of death in this patient population and remain to be the Achilles’ Heel of heart transplantation [23]. Unfortunately, of the 40,000 patients per year in the USA who die of end-stage heart disease, and that could have been treated with a transplant, only 2500 actually receive grafts due to the poor supply of donor hearts [23]. Measures to increase the availability of donor hearts, such as improving graft preservation, prolonging the organ ischemia time and development of isolated perfused working heart models during transportation to the recipient centers, have all contributed, and continue to be explored as venues, to increase the number of heart transplants performed worldwide.

It is the hope of the authors that this brief editorial would provide the reader with a glimpse of the bright future of the surgical options for the management of CHF and end stage heart disease. This is indeed a growing area of clinical applications that will no doubt create a major impact on the long-term outcome of patients who have been historically perceived as doomed and unsalvageable. The surgical management of CHF is here to stay and the future remains very promising.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.