Management of heart failure

Management of heart failure requires a muitimodal approach. It involves a combination of lifestyle modifications, medications, and possibly the use of devices or surgery.

Diet and lifestyle measures

Patients with CHF are educated to undertake various non-pharmacological measures to improve symptoms and prognosis. Such measures include:^[1]

• Moderate physical activity, when symptoms are mild or moderate; or bed rest when symptoms are severe.
• If sleep apnea is identified, treat with CPAP, BiPAP, dental appliances or surgery. Sleep apnea is an under recognized risk factor for heart failure
• Weight reduction – through physical activity and dietary modification, as obesity is a risk factor for heart failure and left ventricular hypertrophy.
• Monitor weight - this is a parameter that can easily be measured at home. Rapid weight increase is generally due to fluid retention. Weight gain of more than 2 pounds is associated with admission to the hospital for heart failure^[2]
• Sodium restriction – excessive sodium intake may precipitate or exacerbate heart failure, thus a "no added salt" diet (60–100 mmol total daily intake) is recommended for patients with CHF. More severe restrictions may be required in severe CHF.

Fluid restriction

According to a review in 2009, there is apparently no evidence of benefit of fluid restriction in patients with clinically stable heart failure otherwise receiving optimal pharmacological treatment.^[3] The same review suggested that clinicians still choosing to restrict fluid intake for patients with HF should consider an individualized fluid prescription, potentially based on patient body weight, sodium intake, and likelihood of adherence.^[3]

Theoretically, patients with CHF have a diminished ability to excrete free water load. Hyponatremia frequently develops in decompensated heart failure due to the effects of excess circulating neuroendocrine hormones. While the activation of the renin-angiotensin-aldosterone axis due to decreased renal perfusion promotes both sodium and water retention, the activation of atrial natriuretic peptide due to atrial stretch favors sodium excretion, and the activation of antidiuretic hormone due to peripheral baroreceptors that sense hypotension as well as due to the activation of the sympathetic nervous system favors water retention alone, leading to disproportionately more water retention than sodium retention. The severity of the hyponatremia during an episode of decompensated heart failure can be predictive of mortality. Generally water intake should be limited to 1.5 L daily or less in patients with hyponatremia, though fluid restriction may be beneficial regardless in symptomatic reduction.

Pharmacological management

There is a significant evidence–practice gap in the treatment of CHF; particularly the underuse of ACE inhibitors and β-blockers and aldosterone antagonists which have been shown to provide mortality benefit.^[4] Treatment of CHF aims to relieve symptoms, to maintain a euvolemic state (normal fluid level in the circulatory system), and to improve prognosis by delaying progression of heart failure and reducing cardiovascular risk. Drugs used include: diuretic agents, vasodilator agents, positive inotropes, ACE inhibitors, beta blockers, and aldosterone antagonists (e.g.spironolactone). Some drugs which increase heart function, such as the positive inotrope Milrinone, lead to increased mortality, and are contraindicated.^[5][6]

Angiotensin-modulating agents

ACE inhibitor (ACE) therapy is recommended for all patients with systolic heart failure, irrespective of symptomatic severity or blood pressure.^[7][8][9] ACE inhibitors improve symptoms, decrease mortality and reduce ventricular hypertrophy. Angiotensin II receptor antagonist therapy (also referred to as AT₁-antagonists or angiotensin receptor blockers), particularly using candesartan, is an acceptable alternative if the patient is unable to tolerate ACEI therapy.^[10][11] ACEIs and ARBs decrease afterload by antagonizing the vasopressor effect of angiotensin, thereby decreasing the amount of work the heart must perform. It is also believed that angiotensin directly affects cardiac remodeling, and blocking its activity can thereby slow the deterioration of cardiac function.

Diuretics

Diuretic therapy is indicated for relief of congestive symptoms. Several classes are used, with combinations reserved for severe heart failure:^[1]

• Loop diuretics (e.g. furosemide, bumetanide) – most commonly used class in CHF, usually for moderate CHF.
• Thiazide diuretics (e.g. hydrochlorothiazide, chlorthalidone, chlorthiazide) – may be useful for mild CHF, but typically used in severe CHF in combination with loop diuretics, resulting in a synergistic effect.
• Potassium-sparing diuretics (e.g. amiloride) – used first-line use to correct hypokalaemia.
  • Spironolactone is used as add-on therapy to ACEI plus loop diuretic in severe CHF.
  • Eplerenone is specifically indicated for post-MI reduction of cardiovascular risk.

If a heart failure patient exhibits a resistance to or poor response to diuretic therapy, ultrafiltration or aquapheresis may be needed to achieve adequate control of fluid retention and congestion. The use of such mechanical methods of fluid removal can produce meaningful clinical benefits in patients with diuretic-resistant heart failure and may restore responsiveness to conventional doses of diuretics.⁹

Beta blockers

Until recently (within the last 20 years), β-blockers were contraindicated in CHF, owing to their negative inotropic effect and ability to produce bradycardia – effects which worsen heart failure. However, current guidelines recommend β-blocker therapy for patients with systolic heart failure due to left ventricular systolic dysfunction after stabilization with diuretic and ACEI therapy, irrespective of symptomatic severity or blood pressure.^[9] As with ACEI therapy, the addition of a β-blocker can decrease mortality and improve left ventricular function. Several β-blockers are specifically indicated for CHF including: bisoprolol, carvedilol, nebivolol and extended-release metoprolol. The antagonism of β₁ inotropic and chronotropic effects decreases the amount of work the heart must perform. It is also thought that catecholamines and other sympathomimetics have an effect on cardiac remodeling, and blocking their activity can slow the deterioration of cardiac function.

Positive inotropes

Digoxin (a mildly positive inotrope and negative chronotrope), once used as first-line therapy, is now reserved for control of ventricular rhythm in patients with atrial fibrillation; or where adequate control is not achieved with an ACEI, a beta blocker and a loop diuretic.^[9] There is no evidence that digoxin reduces mortality in CHF, although some studies suggest a decreased rate in hospital admissions.^[12] It is contraindicated in cardiac tamponade and restrictive cardiomyopathy.

The inotropic agent dobutamine is advised only in the short-term use of acutely decompensated heart failure, and has no other uses.^[9]

Phosphodiesterase inhibitors such as milrinone are sometimes utilized in severe cardiomyopathy. The mechanism of action is through inhibiting the breakdown and thereby increasing the concentration of cAMP similar to beta adrenoreceptor agonism, resulting in inotropic effects and modest diuretic effects.

Alternative vasodilators

The combination of isosorbide dinitrate/hydralazine is the only vasodilator regimen, other than ACE inhibitors or angiotensin II receptor antagonists, with proven survival benefits. This combination appears to be particularly beneficial in CHF patients with an African American background, who respond less effectively to ACEI therapy.^[13][14]

Aldosterone receptor antagonists

The RALES trial^[15] showed that the addition of spironolactone can improve mortality, particularly in severe cardiomyopathy (ejection fraction less than 25%.) The related drug eplerenone was shown in the EPHESUS trial^[16] to have a similar effect, and it is specifically labelled for use in decompensated heart failure complicating acute myocardial infarction. While the antagonism of aldosterone will decrease the effects of sodium and water retention, it is thought that the main mechanism of action is by antagonizing the deleterious effects of aldosterone on cardiac remodeling.

Recombinant neuroendocrine hormones

Nesiritide, a recombinant form of B-natriuretic peptide, is indicated for use in patients with acute decompensated heart failure who have dyspnea at rest. Nesiritide promotes diuresis and natriuresis, thereby ameliorating volume overload. It is thought that, while BNP is elevated in heart failure, the peptide that is produced is actually dysfunctional or non-functional and thereby ineffective.

Vasopressin receptor antagonists

Tolvaptan and conivaptan antagonize the effects of antidiuretic hormone (vasopressin), thereby promoting the specific excretion of free water, directly ameliorating the volume overloaded state, and counteracting the hyponatremia that occurs due to the release of neuroendocrine hormones in an attempt to counteract the effects of heart failure. The EVEREST trial, which utilized tolvaptan, showed that when used in combination with conventional therapy, many symptoms of acute decompensated heart failure were significantly improved compared to conventional therapy alone^[17] although they found no difference in mortality and morbidity when compared to conventional therapy.^[18]

Devices

Patients with NYHA class III or IV, left ventricular ejection fraction (LVEF) of 35% or less and a QRS interval of 120 ms or more may benefit from cardiac resynchronization therapy (CRT; pacing both the left and right ventricles), through implantation of a bi-ventricular pacemaker, or surgical remodeling of the heart. These treatment modalities may make the patient symptomatically better, improving quality of life and in some trials have been proven to reduce mortality.

The COMPANION trial demonstrated that CRT improved survival in individuals with NYHA class III or IV heart failure with a widened QRS complex on an electrocardiogram.^[19] The CARE-HF trial showed that patients receiving CRT and optimal medical therapy benefited from a 36% reduction in all cause mortality, and a reduction in cardiovascular-related hospitalization.^[20]

Patients with NYHA class II, III or IV, and LVEF of 35% (without a QRS requirement) may also benefit from an implantable cardioverter-defibrillator (ICD), a device that is proven to reduce all cause mortality by 23% compared to placebo in patients who were already optimally managed on drug therapy.^[21][22] Patients with severe cardiomyopathy are at high risk for sudden cardiac death due to ventricular dysrhythmias. Although ICDs deliver electrical shocks to resynchronize heart rhythm which are potentially destressing to the patient, they have not been shown to affect quality of life.^[23] The number of (appropriate and inappropriate) shocks seems to be associated to a worse outcome.^[24] Although they are expensive, ICDs are potentially cost-effective in this setting.^[25]

Another current treatment involves the use of left ventricular assist devices (LVADs). LVADs are battery-operated mechanical pump-type devices that are surgically implanted on the upper part of the abdomen. They take blood from the left ventricle and pump it through the aorta. LVADs are becoming more common and are often used by patients who have to wait for heart transplants.

Surgery

The final option, if other measures have failed, is heart transplantation or (temporary or prolonged) implantation of an artificial heart. These remain the recommended surgical treatment options. However, the limited number of hearts available for transplantation in a growing group of candidates, has led to the development of alternative surgical approaches to heart failure. These commonly involve surgical left ventricular remodeling. The aim of the procedures is to reduce the ventricle diameter (targeting Laplace's law and the disease mechanism of heart failure), improve its shape and/or remove non-viable tissue.^[26] These procedures can be performed together with coronary artery bypass surgery or mitral valve repair.

If heart failure ensues after a myocardial infarction due to scarring and aneurysm formation, reconstructive surgery may be an option. These aneurysms bulge with every contraction, making it inefficient. Cooley and coworkers reported the first surgical treatment of a left ventricular aneurysm in 1958.^[27] They used a linear closure after their excision. In the 1980s, Vincent Dor developed a method using a circular patch stitched to the inside of the ventricle (the endoventricular circular patch plasty or Dor procedure) to close the defect after excision.^[28] Dor's approach has been modified by others and is today the preferred method for surgical treatment of incorrectly contracting (dyskinetic) left ventricle tissue, although a linear closure technique combined with septoplasty might be equally effective.^[29][30] The multicenter RESTORE trial of 1198 participants demonstrated an increase in ejection fraction from about 30% to 40% with a concomitant shift in NYHA classes, with an early mortality of 5% and a 5-year survival of 70%.^[31] As of yet, it remains unknown if surgery is superior to optimal medical therapy. The STICH trial (Surgical Treatment for IschemiC Heart Failure) will examine the role of medical treatment, coronary artery bypass surgery and left ventricle remodeling surgery in heart failure patients. Results are expected to be published in 2009^{[dated info]} and 2011.^[32]

The Batista procedure was invented by Brazilian surgeon Randas Batista in 1994 for use in patients with non-ischemic dilated cardiomyopathy. It involves removal of a portion of viable tissue from the left ventricle to reduce its size (partial left ventriculectomy), with or without repair or replacement of the mitral valve.^[33] Although several studies showed benefits from this surgery, studies at the Cleveland Clinic concluded that this procedure was associated with a high early and late failure rate. At 3 years only 26 percent were event-free and survival rate was only 60 percent.^[34] Most hospitals have abandoned this operation and it is no longer included in heart failure guidelines.^[26]

Newer procedures under examination are based on the observation that the spherical configuration of the dilated heart reduces ejection fraction compared to the elliptical form. Mesh-like constraint devices such as the Acorn CorCap aim to improve contraction efficacy and prevent further remodeling. Clinical trials are underway.^[35] Another technique which aims to divide the spherical ventricle into two elliptical halves is used with the Myosplint device.^[36]

References

1. ^ ^{a b} Smith A, Aylward P, Campbell T, et al. Therapeutic Guidelines: Cardiovascular, 4th edition. North Melbourne: Therapeutic Guidelines; 2003. ISSN 1327-9513
2. ^ Chaudhry SI et al. (2007). "Patterns of Weight Change Preceding Hospitalization for Heart Failure". Circulation 116 (14): 1549–54. doi:10.1161/CIRCULATIONAHA.107.690768. PMC 2892745. PMID 17846286. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2892745. 
3. ^ ^{a b} Tai MK (October 2009). "[Evidence-based practice of fluid restriction in patients with heart failure]" (in Chinese). Hu Li Za Zhi 56 (5): 23–9. PMID 19760574. 
4. ^ Jackson S, Bereznicki L, Peterson G. Under-use of ACE-inhibitor and β-blocker therapies in congestive cardiac failure. Australian Pharmacist 2005;24(12):936.
5. ^ Packer M (1989). "Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure". Am. J. Cardiol. 63 (2): 41A–45A. doi:10.1016/0002-9149(89)90392-5. PMID 2642629. 
6. ^ Packer M, Carver JR, Rodeheffer RJ, et al. (1991). "Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group". N. Engl. J. Med. 325 (21): 1468–75. doi:10.1056/NEJM199111213252103. PMID 1944425. 
7. ^ Hunt SA, Abraham WT, Chin MH, et al. (2005). "ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult" (PDF). Circulation 112 (12): e154–235. doi:10.1161/CIRCULATIONAHA.105.167586. PMID 16160202. http://circ.ahajournals.org/cgi/reprint/112/12/e154.pdf. 
8. ^ Krum H, National Heart Foundation of Australia and Cardiac Society of Australia & New Zealand Chronic Heart Failure Clinical Practice Guidelines Writing Panel. (2001). "Guidelines for management of patients with chronic heart failure in Australia". Med J Aust 174 (9): 459–66. PMID 11386592. 
9. ^ ^{a b c d} National Institute for Clinical Excellence. Chronic heart failure: management of chronic heart failure in adults in primary and secondary care. Clinical Guideline 5. London: National Institute for Clinical Excellence; 2003 Jul. Available from:www.nice.org.uk/pdf/CG5NICEguideline.pdf
10. ^ Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigators and Committees. (2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial". Lancet 362 (9386): 772–6. doi:10.1016/S0140-6736(03)14284-5. PMID 13678870. 
11. ^ Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees. (2003). "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme". Lancet 362 (9386): 759–66. doi:10.1016/S0140-6736(03)14282-1. PMID 13678868. 
12. ^ Haji SA, Movahed A (2000). "Update on digoxin therapy in congestive heart failure". American Family Physician 62 (2): 409–16. PMID 10929703. 
13. ^ Exner DV, Dries DL, Domanski MJ, Cohn JN (2001). "Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction". N Engl J Med. 344 (18): 1351–7. doi:10.1056/NEJM200105033441802. PMID 11333991. 
14. ^ Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; African-American Heart Failure Trial Investigators. (2004). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". N Engl J Med 351 (20): 2049–57. doi:10.1056/NEJMoa042934. PMID 15533851. 
15. ^ Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999). "The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure". N Engl J Med. 341 (10): 709–717. doi:10.1056/NEJM199909023411001. PMID 10471456. 
16. ^ Pitt B, Williams G, Remme W, Martinez F, Lopez-Sendon J, Zannad F, Neaton J, Roniker B, Hurley S, Burns D, Bittman R, Kleiman J. (2001). "The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study". Cardiovasc Drugs Ther 15 (1): 79–87. doi:10.1023/A:1011119003788. PMID 11504167. 
17. ^ Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. (2007). "Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials". JAMA 297 (12): 1332–1343. doi:10.1001/jama.297.12.1332. PMID 17384438. 
18. ^ Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. (2007). "Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial". JAMA 297 (12): 1319–1331. doi:10.1001/jama.297.12.1319. PMID 17384437. 
19. ^ Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. (2004). "Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure". N Engl J Med 350 (21): 2140–50. doi:10.1056/NEJMoa032423. PMID 15152059. 
20. ^ Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. (2005). "The effect of cardiac resynchronization on morbidity and mortality in heart failure". N Engl J Med 352 (15): 1539–49. doi:10.1056/NEJMoa050496. PMID 15753115. 
21. ^ Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. (2005). "Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure". N Engl J Med 352 (3): 225–237. doi:10.1056/NEJMoa043399. PMID 15659722. 
22. ^ Moss AJ, Zareba W, Hall WJ, et al. (March 2002). "Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction". N. Engl. J. Med. 346 (12): 877–83. doi:10.1056/NEJMoa013474. PMID 11907286. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11907286&promo=ONFLNS19. 
23. ^ Mark DB, Anstrom KJ, Sun JL, Clapp-Channing NE, Tsiatis AA, Davidson-Ray L, Lee KL, Bardy GH; Sudden Cardiac Death in Heart Failure Trial Investigators (September 2008). "Quality of life with defibrillator therapy or amiodarone in heart failure". N. Engl. J. Med. 359 (10): 999–1008. doi:10.1056/NEJMoa0706719. PMC 2823628. PMID 18768943. http://content.nejm.org/cgi/content/abstract/359/10/999. 
24. ^ Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, Reddy RK, Marchlinski FE, Yee R, Guarnieri T, Talajic M, Wilber DJ, Fishbein DP, Packer DL, Mark DB, Lee KL, Bardy GH; Sudden Cardiac Death in Heart Failure Trial Investigators (September 2008). "Prognostic Importance of Defibrillator Shocks in Patients with Heart Failure". N. Engl. J. Med. 359 (10): 1009–1017. doi:10.1056/NEJMoa071098. PMC 2922510. PMID 18768944. http://content.nejm.org/cgi/content/abstract/359/10/1009. 
25. ^ Sanders GD, Hlatky MA, Owens DK (October 2005). "Cost-effectiveness of implantable cardioverter-defibrillators". N. Engl. J. Med. 353 (14): 1471–80. doi:10.1056/NEJMsa051989. PMID 16207849. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=16207849&promo=ONFLNS19. 
26. ^ ^{a b} Tønnessen T, Knudsen CW (August 2005). "Surgical left ventricular remodeling in heart failure". Eur. J. Heart Fail. 7 (5): 704–9. doi:10.1016/j.ejheart.2005.07.005. PMID 16087128. 
27. ^ Cooley DA, Collins HA, Morris GC, Chapman DW (May 1958). "Ventricular aneurysm after myocardial infarction; surgical excision with use of temporary cardiopulmonary bypass". J Am Med Assoc 167 (5): 557–60. PMID 13538738. 
28. ^ Dor V (September 2001). "The endoventricular circular patch plasty ("Dor procedure") in ischemic akinetic dilated ventricles". Heart Fail Rev 6 (3): 187–93. doi:10.1023/A:1011477132227. PMID 11391036. http://www.kluweronline.com/art.pdf?issn=1382-4147&volume=6&page=187. 
29. ^ Lundblad R, Abdelnoor M, Svennevig JL (September 2004). "Surgery for left ventricular aneurysm: early and late survival after simple linear repair and endoventricular patch plasty". J. Thorac. Cardiovasc. Surg. 128 (3): 449–56. doi:10.1016/j.jtcvs.2004.04.017. PMID 15354107. http://linkinghub.elsevier.com/retrieve/pii/S0022522304006427. 
30. ^ Mickleborough LL, Carson S, Ivanov J (April 2001). "Repair of dyskinetic or akinetic left ventricular aneurysm: results obtained with a modified linear closure". J. Thorac. Cardiovasc. Surg. 121 (4): 675–82. doi:10.1067/mtc.2001.112633. PMID 11279407. http://linkinghub.elsevier.com/retrieve/pii/S0022-5223(01)49811-4. 
31. ^ Athanasuleas CL, Buckberg GD, Stanley AW, et al. (October 2004). "Surgical ventricular restoration in the treatment of congestive heart failure due to post-infarction ventricular dilation". J. Am. Coll. Cardiol. 44 (7): 1439–45. doi:10.1016/j.jacc.2004.07.017. PMID 15464325. http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(04)01443-3. 
32. ^ Velazquez EJ, Lee KL, O'Connor CM, et al. (December 2007). "The rationale and design of the Surgical Treatment for Ischemic Heart Failure (STICH) trial". J. Thorac. Cardiovasc. Surg. 134 (6): 1540–7. doi:10.1016/j.jtcvs.2007.05.069. PMID 18023680. http://linkinghub.elsevier.com/retrieve/pii/S0022-5223(07)01391-8. 
33. ^ "Pioneers of heart surgery". NOVA Online: Cut to the heart. http://www.pbs.org/wgbh/nova/heart/pioneers.html. Retrieved 2007-11-07. 
34. ^ Franco-Cereceda A, McCarthy PM, Blackstone EH, et al. (May 2001). "Partial left ventriculectomy for dilated cardiomyopathy: is this an alternative to transplantation?". J. Thorac. Cardiovasc. Surg. 121 (5): 879–93. doi:10.1067/mtc.2001.113598. PMID 11326231. http://linkinghub.elsevier.com/retrieve/pii/S0022-5223(01)37736-X. 
35. ^ Oz MC, Konertz WF, Kleber FX, et al. (October 2003). "Global surgical experience with the Acorn cardiac support device". J. Thorac. Cardiovasc. Surg. 126 (4): 983–91. doi:10.1016/S0022-5223(03)00049-7. PMID 14566236. http://linkinghub.elsevier.com/retrieve/pii/S0022522303000497. 
36. ^ Schenk S, Reichenspurner H, Boehm DH, et al. (June 2002). "Myosplint implant and shape-change procedure: intra- and peri-operative safety and feasibility". J. Heart Lung Transplant. 21 (6): 680–6. doi:10.1016/S1053-2498(01)00773-2. PMID 12057702.