Mitral Valve Repair: What the ACORN Trial Taught Us

Progressive left ventricular remodeling is characterized by dilation of the left ventricle with a change in the heart from an elliptical shape to a more spherical shape. This change is part of the unfavorable natural history in patients with heart failure. The CorCap Cardiac Support Device (Acorn Cardiovascular, St. Paul, MN) is a mesh device that is implanted around the heart to reduce wall stress and the first therapy specifically designed to address left ventricular remodeling. The CorCap was studied in a large, prospective, randomized, multicentered trial. This study demonstrated safety and effectiveness of the CorCap in patients with advanced heart failure and remodeled ventricles. Moreover, it provided interesting insights into mitral valve surgery in patients with heart failure. These insights and a review of the ACORN (Assessment of a Cardiac Support Device [CSD] in Patients With Heart Failure) trial are discussed in this article.     

One-year clinical experience with the Acorn CorCap cardiac support device: results of a limited market release safety study in Italy and Sweden.

BACKGROUND: The Acorn CorCap cardiac support device (CSD) is a mesh-like device intended to provide end-diastolic support and reduce ventricular wall stress. Animal studies with the CorCap CSD have demonstrated beneficial reverse remodeling, and preliminary safety studies in patients with heart failure have shown that the device is safe and associated with improved left ventricular (LV) structure and function. The objective of the current study was to further evaluate the safety and efficacy of the CorCap CSD in patients with advanced heart failure. METHODS: Twenty-four patients with dilated cardiomyopathy, severe LV dysfunction, and advanced heart failure (NYHA class II-IV) were enrolled at four centers in Italy and Sweden. All patients underwent CorCap CSD implantation either alone (n = 3) or in combination with mitral valve repair/replacement (n = 13), coronary artery bypass surgery (n = 6), combined mitral valve repair/coronary artery bypass surgery (n = 1) or aneurysmectomy (n = 1). RESULTS: The LV end-diastolic diameter decreased from 69.3 +/- 7.2 to 60.1 +/- 9.0 mm at 3 months, 60.9 +/- 9.6 mm at 6 months, and 58.9 +/- 8.0 mm at 12 months (all p < 0.05). A trend toward an improved LV ejection fraction (28.8 +/- 10.5% at baseline and 32.4 +/- 12.7, 33.1 +/- 10.8, and 33.8 +/- 13.9% at 3, 6 and 12 months respectively) was also noted. The NYHA functional class, 6-min walking distance, and quality of life as measured using Uniscale were all improved. There were no differences in response among the patients submitted to the different types of concomitant surgery. CONCLUSIONS: In agreement with earlier safety studies, even the present investigation demonstrated improvements in cardiac structure and function as well as in patient functional status after Cor Cap CSD implantation. Randomized controlled trials are in progress.     

Global Left Ventricular Remodeling with the Acorn Cardiac Support Device: Hemodynamic and Angiographic Findings in Dogs with Heart Failure

Preventing progressive left ventricular (LV) remodeling is paramount in the treatment of heart failure. In recent years, several surgical approaches have been implemented with the objective of improving LV function through amelioration of progressive LV remodeling. These included surgical reduction of LV size, the so-called Batista procedure, dynamic cardiomyoplasty and mitral valve repair to limit or eliminate functional mitral regurgitation. While the Batista procedure and dynamic cardiomyoplasty have for all practical purposes been abandoned, the lessons learned from these procedures gave rise to a new generation of devices aimed at preventing progressive LV dilation and restoring LV shape by passive mechanical containment of the failing LV. One such device is the Acorn Cardiac Support Device (CSD) or the CorCap^TM. Studies in dogs with intracoronary microembolization-induced moderate and advanced heart failure have shown that long-term monotherapy with the CSD not only prevents progressive LV dilation but, in effect, partially reverses this phenotype. These studies have also shown that the CSD restores, albeit in part, progressive LV chamber sphericity and attenuates functional mitral regurgitation. These benefits were accompanied by improvement in global LV function along with improvements of remodeling at the cellular level. The findings were largely responsible for initiating safety and feasibility clinical trials with the CSD and ultimately, the initiation of the Acorn efficacy trial that was completed in 2004. This review will focus on studies conducted in dogs with heart failure and, specifically on hemodynamic, angiographic and echocardiographic results from these studies that provided support for the CSD as a successful technology targeting “reverse LV remodeling” for the treatment of heart failure.     

Left Ventricular Restoration Devices

Left ventricular (LV) remodeling results in continuous cardiac chamber enlargement and contractile dysfunction, perpetuating the syndrome of heart failure. With current exhaustion of the neurohormonal medical paradigm, surgical and device-based therapies have been increasingly investigated as a way to restore LV chamber architecture and function. Left ventricular restoration has been attempted with surgical procedures, such as partial left ventriculectomy, surgical ventricular restoration with or without revascularization, and devices, such as the Acorn CorCap, the Paracor HeartNet, and the Myocor Myosplint. Whereas all these techniques require surgical access, with or without cardiopulmonary bypass, a newer ventricular partitioning device (VPD) called Parachute, can be delivered percutaneously through the aortic valve. Designed to achieve LV restoration from within the ventricle, this VPD partitions the LV by isolating aneurysmal from normal myocardium thereby diminishing the functioning cavity. This review aims to critically appraise the above methods, with particular attention to device-based therapies.     

Left Ventricular Histomorphometric Findings in Dogs with Heart Failure Treated with the Acorn Cardiac Support Device

Progressive left ventricular (LV) dilation in the setting of heart failure is associated with increased mortality and morbidity. The Acorn Cardiac Support Device (CSD, Acorn Cardiovascular, Inc., St. Paul, MN) is a preformed polyester device that is surgically placed over the cardiac ventricles, anchored to the AV-groove and tailored anteriorly to fit snugly over the epicardial surface of the heart. The CSD was shown to prevent progressive LV enlargement and, indeed, reduce LV size and attenuate global LV remodeling in both animal models of experimentally-induced heart failure as well as in patients with advanced heart failure. This review will examine the CSD from two histologic perspectives namely, (1) the interaction of the CSD with the epicardial surface of the heart and (2) the effects of long-term therapy with the CSD on cellular remodeling. The review will be based on available pre-clinical data generated in dogs with coronary microembolization-induced heart failure that underwent long-term (3 and 6 months) monotherapy with the CSD. The data will show that long-term implantation leads to encapsulation of the CSD by connective tissue that matures with time and that does not invade the underlying myocardium. Furthermore that implantation of the CSD has no adverse impact on epicardial coronary vessel. At the cellular level, existing data will show that long-term monotherapy with the CSD is associated with reduced cardiomyocyte hypertrophy, reduced volume fraction of replacement and interstitial fibrosis, normalization of capillary density and oxygen diffusion distance and attenuation of cardiomyocyte apoptosis. The outcomes strongly argue in favor of a structural modification of the failing myocardium by CSD therapy that is consistent with “reverse cellular remodeling”.     

Reverse remodeling of the failing ventricle: surgical intervention with the Acorn Cardiac Support Device

Preclincial studies have shown that an innovative meshlike cardiac support device (CorCap, Acorn Cardiovascular, Inc., St. Paul, MN) can provide end diastolic support to reduce mechanical stress, improve function, and reverse cardiac remodeling. The CorCap device has been implanted worldwide in more than 130 patients with dilated cardiomyopathy (idiopathic or ischemic), with or without concomitant cardiac surgery. A series of 48 patients was implanted in initial safety and feasibility studies (33 received concomitant cardiac surgery, 15 patients received the CorCap device only). At implant, 33 patients were in New York Heart Association functional class III, 11 in class II, and four in class IV. There were no device-related intraoperative complications, deaths, or adverse events. Eight early and nine late deaths occurred during follow-up extending to 18-24 months. During follow-up, chamber dimensions decreased, and ejection fraction and New York Heart Association functional class improved. The CorCap device is correlated with improvements in patient functional status. Randomized clinical trials are underway in Europe, Australia, and North America.     

Diastolic ventricular support with cardiac support devices: an alternative approach to prevent adverse ventricular remodeling

Heart failure is a global epidemic with limited therapy. Abnormal left ventricular wall stress in the diseased myocardium results in a biochemical positive feedback loop that results in global ventricular remodeling and further deterioration of myocardial function. Mechanical myocardial restraints such as the Acorn CorCap and Paracor HeartNet ventricular restraints have attempted to minimize diastolic ventricular wall stress and limit adverse ventricular remodeling. Unfortunately, these therapies have not yielded viable clinical therapies for heart failure. Cellular and novel biopolymer-based therapies aimed at stabilizing pathologic myocardium hold promise for translation to clinical therapy in the future.     

Design and Features of the Acorn CorCap<Superscript>TM</Superscript> Cardiac Support Device: The Concept of Passive Mechanical Diastolic Support

The Laplace equation points to the importance of ventricular wall stress as a factor in heart failure development and progression. Based on animal and clinical experience with active and passive cardiomyoplasty, a synthetic passive constraint was proposed as a means of reducing excessive wall stress, and thus assuaging disease progression. The Acorn CorCap^TM CSD Cardiac Support Device was designed to provide passive diastolic support and serve as a constraint against chronic cardiac dilation in heart failure. Basic and uncomplicated in appearance, the device nevertheless incorporates numerous sophisticated structural and functional features intended maximize therapeutic value. The device is fabricated from medical grade multifilament polyester yarn, in a specific knit construction chosen to provide structural integrity, low physical profile, pliability for intimate contact with the epicardial surface, ease of manipulation during implantation, and anisotropic compliance characteristics to encourage beneficial reverse remodeling.     

Current and novel cardiac support therapies

Despite optimal medical therapy, many heart failure patients progress to end-stage disease associated with reduced quality of life and poor outcome. However, these patients can benefit from current novel cardiac support strategies, including ventricular assist devices (VADs), cardiac support devices (CSDs), and future cell- and/or matrix-based therapies. The most exciting goal in using VADs and CSDs is to achieve reverse remodeling, suppression of remodeling gene programs, and activation of myocardial recovery programs, which will improve left ventricular shape, size, and function. Long-term left VADs are effective, but recovery upon removal is uncommon. Passive CSDs (eg, Acorn devices) are very promising as long-term devices for therapy of end-stage heart failure and reversal of structural and biochemical remodeling. Expanding CSD use to include preventing progressive adverse left ventricular remodeling after ST-segment elevation myocardial infarction requires further study. The combination of cell- and/or matrix-based therapies with CSDs is under investigation.     

Socks for the dilated heart. Does passive cardiomyoplasty have a role in long-term care for heart failure patients?

Dynamic cardiomyoplasty has been performed in over 1000 patients worldwide but due to limited success the procedure was never been adopted as an alternative approach for the surgical therapy of heart failure. However, observations in these patients showed that the nonstimulated or fibrotic transformed latissimus dorsi by itself led to an improvement of heart failure symptoms. These findings stimulated animal experiments with so-called passive cardiomyoplasty devices. In several animal models, the progression of heart failure could be stopped, and even reversed remodeling could be demonstrated. Several different devices have been developed and tested in animal models. The Acorn CorCap has already passed a successful clinical feasibility study. However, the final evaluation of two multicenter trials has to be awaited to assess the future role of this device in the treatment of heart failure.     

Cardiac resynchronization therapy: a practical guide for device optimization, part I

This is the first part of a two-part series on strategies for optimizing the delivery of cardiac resynchronization therapy (CRT), focusing on device-related aspects. There is overwhelming evidence from prospective randomized controlled trials providing consistent and concordant support for CRT in patients with symptomatic heart failure and ventricular dyssynchrony. CRT has consistently improved quality of life, cardiac structure and function, and survival in the majority of patients enrolled in these trials. No longer a consideration for select individuals with heart failure, the 2005 American College of Cardiology/American Heart Association Guidelines for Managing Adults with Chronic Heart Failure now consider CRT a class IA recommendation for stage C patients (QRS duration > or = 120 milliseconds, left ventricular ejection fraction < or = 35%) who remain symptomatic despite optimal medical therapy. However, not everyone experiences clinical improvement from CRT. This article discusses measures that should be considered to ensure proper functioning of a CRT device. A subsequent article will present strategies to optimize patients' responses to CRT.     

Left Ventricular Size and Shape: Determinants of Mechanical Signal Transduction Pathways

Heart failure may be viewed as a progressive disorder that is impelled, at least in part, by progressive left ventricular (LV) remodeling. In the present discussion we will review the role of LV remodeling in the pathogenesis of heart failure, with a focus on the contribution that changes in LV size and shape play in the development and progression of the progression of heart failure. The clinical implication of this review is that existing neurohormonal strategies may not completely prevent disease progression in the failing heart, and that adjunctive strategies that are designed to specifically prevent and/or attenuate LV remodeling may play an important role in the clinical treatment of heart failure.     

Indications, technique and initial results of passive cardiomyoplasty

The cardiac support device (CSD, Acorn Cardiovasc. Inc.), a knitted polyester tissue, is surgically placed over the ventricles to prevent further dilatation of the heart. The aim of this study was to evaluate the feasibility and safety of CSD implantation in patients with advanced heart failure from cardiomyopathy of either idiopathic or ischemic origin. From April 1999, 23 patients received the CSD. In 8 patients the CSD implantation was the only surgical measure; in 12 patients a concomitant mitral valve repair was performed. In three more patients, the CSD implantation was combined with other surgical procedures. The CSD was placed while on bypass with the heart beating, attached to the AV groove and tailored anteriorly to snugly fit the ventricles. There were no intraoperative deaths or complications. Two patients died early postoperatively (4 d, 21 d); 1 late death occurred (44 d postop). The deaths were not considered to be device related. There were no CSD-related adverse events. Six months postoperatively all patients improved by at least one NYHA class. Echocardiography at 6 months revealed an increase in LVEF; the LVEDD decreased accordingly. Mitral valve regurgitation improved in all patients. These findings indicate that the CSD is safe, and improves heart failure symptoms and left ventricular function. Additional studies have to confirm these results.     

Predictors of remodeling in the CRT era: influence of mitral regurgitation, BNP, and gender

BackgroundWe analyzed quantitative echocardiographic data from a large heart failure cohort receiving medical and cardiac resynchronization therapy (CRT) to determine baseline predictors of progressive left ventricular (LV) enlargement.Methods and ResultsQuantitative echocardiograms were obtained at baseline and after 6 months in 776 outpatients with chronic heart failure who participated in MIRACLE (Multicenter InSync Randomized Clinical Evaluation) and MIRACLE-ICD (Multicenter InSync ICD Randomized Clinical Evaluation). We used multivariable regression to determine clinical, therapeutic, and echocardiographic characteristics that predicted a subsequent change in left ventricular end-diastolic volume (LVEDV). Over 6 months, LVEDV increased in 308 (40%) and decreased in 468 (60%) patients. Baseline mitral regurgitation and levels of plasma brain natriuretic peptide (BNP) independently predicted LV enlargement, whereas CRT predicted a decrease in LVEDV (all P < .01). In all models tested, male gender was an independent risk factor for progressive LV enlargement (P < .0001).ConclusionMen show more prominent LV dilation than women in chronic heart failure despite medical and device therapy. Rates of LV remodeling are influenced further by mitral regurgitation, plasma BNP, and CRT. Future studies should take these clinical factors into account when determining the influence of genetic factors and novel therapies on ventricular remodeling in chronic heart failure.     

Left atrial reverse remodeling in dogs with moderate and advanced heart failure treated with a passive mechanical containment device: an echocardiographic study

BackgroundAssessment of global left ventricular (LV) remodeling is important in evaluating the efficacy of pharmacologic and device therapies for the treatment of chronic heart failure (HF). The effects of pharmacologic or device therapies on global left atrial (LA) remodeling in HF, although also important, are not often examined. We showed that long-term therapy with the Acorn Cardiac Support Device (CSD), a passive mechanical ventricular containment device, prevents or reverses LV remodeling in dogs with HF. This study examined the effects of the CSD on global LA remodeling in dogs with moderate and advanced HF.Methods and ResultsStudies were performed in 24 dogs with coronary microembolization-induced HF. Of these, 12 had moderate HF (ejection fraction, EF 30% to 40%) and 12 advanced HF (EF ≤25%). In each group, the CSD was implanted in 6 dogs and the other 6 served as controls. Dogs were followed for 3 months in the moderate group and 6 months in the advanced HF group. LA maximal volume (LAVmax), LA volume at the onset of the p-wave (LAVp), LA minimal volume (LAVmin), LA active emptying volume (LAAEV), and LA active emptying fraction (LAAEF) were measured from 2-dimensional echocardiograms obtained before CSD implantation and at the end of the treatment period. Treatment effect (Δ) comparisons between CSD-treated dogs and controls showed that CSD therapy significantly decreased LA volumes (ΔLAVmax: 3.33 ± 0.70 vs. –2.87 ± 1.31 mL, P = .002; 7.77 ± 1.76 versus –0.37 ± 0.87 mL, P = .002) and improved LA function (ΔLAAEF: –6.00 ± 1.53 versus 1.85 ± 1.32%, P = .003; –2.39 ± 1.10 versus 3.13 ± 1.66%, P = .02) in the moderate HF and advanced HF groups, respectively.ConclusionsProgressive LA enlargement and LA functional deterioration occurs in untreated dogs with HF. Monotherapy with the CSD prevents LA enlargement and improves LA mechanical function in dogs with moderate and advanced HF indicating prevention or reversal of adverse LA remodeling.     

Upgrading to biventricular pacing for dilated cardiomyopathy following right ventricular pacing in a young patient

A 2-day-old male infant required a conventional VVI pacemaker for congenital atrioventricular block. Three years later, he developed progressive heart failure due to left ventricular (LV) dysfunction and mitral regurgitation despite optimized medical treatment, and a cardiac resynchronization therapy (CRT) device was implanted. This is the first Portuguese report of CRT in a pediatric patient. One-year echocardiographic follow-up showed that LV shortening fraction had improved and LV end-diastolic dimension and mitral regurgitation had decreased. New York Heart Association class had improved from III-IV to I at 1-year follow-up.     

Prevention and reversal of LV remodeling with neurohormonal inhibitors

Opinion statement Left ventricular (LV) remodeling refers to alterations in ventricular mass, chamber size, and shape that result from myocardial injury, pressure, or volume overload. Numerous studies have demonstrated that LV remodeling correlates with the incidence of heart failure and death, supporting a causative role for remodeling in heart failure progression. Heart failure trials have shown that neurohormonal antagonists, including angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic receptor blockers (β blockers), reduce remodeling in parallel with improved clinical outcomes. Existing data favor using angiotensin II type 1 (AT1) receptor antagonists (or “ARBs”), although their anti-remodeling effects are less well established. Recently, mineralocorticoid receptor antagonists have gained substantial interest based on favorable clinical trial results, although data regarding their effects on remodeling are limited. Thus, an optimal medical regimen to prevent or limit LV remodeling in patients with LV dysfunction should include both an ACE inhibitor and β-adrenergic receptor antagonist, irrespective of the degree of LV dysfunction and symptom status. For patients intolerant to ACE inhibitors, an AT1 receptor antagonist should be substituted. An aldosterone antagonist should be administered to patients with severe, New York Heart Association class III to IV heart failure who have normal or only mildly impaired renal function, or to those patients with depressed LV function following an acute myocardial infarction. Through the aggressive pharmacologic inhibition of both the renin-angiotensin-aldosterone and sympathetic nervous systems, progressive LV remodeling can be prevented or hindered, thereby favorably altering the natural history of the heart failure syndrome.     

Emerging role of pharmacogenomics in heart failure

PURPOSE OF REVIEW: The promise of pharmacogenomics is that it will one day result in targeted heart failure therapy that maximizes individual benefit and diminishes risk. Recent reports from the Beta Blocker Evaluation Survival and African American Heart Failure clinical trials provide a roadmap of how this promise may soon be realized. This review will discuss recent investigations of pharmacogenomics in heart failure, and the challenge of converting genomic heterogeneity into a usable clinical tool. RECENT FINDINGS: Genomic analysis from randomized clinical trials has been increasingly utilized to investigate genetic variables that affect drug response. Analysis from the Beta Blocker Evaluation Survival Trial, demonstrates the impact of beta-blockers on survival was primarily in patients with the beta-1 adrenergic receptor Arg389Arg genotype. The efficacy of angiotensin-converting enzyme inhibitors and the combination of isosorbide dinitrate and hydralazine differs in black and white heart failure cohorts. Initial reports from the African American Heart Failure Trial demonstrate the impact of aldosterone synthase polymorphism on left ventricle remodeling, outcomes and the impact of isosorbide dinitrate and hydralazine. Investigations from the African American Heart Failure Trial will continue to focus on determining the genomic bases for observed racial differences in therapeutic efficacy. An era of polygenic analysis, aided by Genome Wide Association Studies, should soon be upon us. SUMMARY: Modern clinical trials will increasingly have a pharmacogenetic component to allow more efficient targeting of therapeutics. Investigators are beginning to delineate the genomic basis for differences in drug efficacy between black and white heart failure cohorts. Pharmacogenomics will have an increasing role in the treatment of heart failure patients.     

Efficacy of the Acorn Cardiac Support Device in Animals with Heart Failure Secondary to High Rate Pacing

Aim: To utilise an ovine model of tachycardia induced progressive dilated cardiomyopathy and heart failure to investigate the efficacy of passive ventricular constraint with the Acorn cardiac support device as a heart failure treatment. Methods: (a) Moderate heart failure was produced in 16 sheep by pacing for 3 weeks. Half were implanted and half sham implanted with the CSD. Pacing continued at a higher rate for an additional 3 weeks. Cardiac function was assessed by echocardiography and manometry. (b) Moderate heart failure was produced (as above) in 27 sheep, 9 were implanted with CSD, pacing was restarted for 4 weeks, the initial CSD implants were terminated and another 9 animals were CSD implanted (severe heart failure), pacing was restarted in the remaining 18 animals for an additional 4 weeks (total 12 weeks) and then all animals were terminated. Cardiac function was assessed using echocardiography and treadmill exercise testing. Results: (a) After 6 weeks of rapid pacing CSD implant animals had significantly better cardiac function both when compared with pre implant values and with non-implanted animals at termination. (b) CSD implantation at both moderate and severe failure resulted in significant improvements in cardiac function both when compared with pre implant values and with non-implanted animals at termination. When compared to pre implant values the improvement was greatest in severe implant animals. Conclusion: In this ovine model of tachycardia induced progressive heart failure, CSD implantation in either moderate or severe heart failure resulted in improved cardiac function, reduced left ventricular volume and mitral regurgitation both when compared with function at time of implant and with non implanted control animals.