Echocardiographic Assessment of Treatment for Systolic Congestive Heart Failure

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9 Echocardiographic Assessment of Treatment for Systolic Congestive Heart Failure

Rory B. Weiner, Judy Hung

Introduction

The echocardiographic assessment of heart failure (HF) yields important diagnostic and prognostic information. Once diagnosed, numerous medical and device therapies exist to reduce symptoms and mortality in patients with congestive HF secondary to systolic dysfunction. These therapies can also produce favorable changes in left ventricular (LV) structure and function. Additionally, novel therapies are under investigation. The echocardiographic assessment of systolic HF and review of the established and developing treatment options for systolic HF are the focus of this chapter.

Echocardiographic Assessment of Systolic HF

• Echocardiography is an appropriate diagnostic test to investigate symptoms and signs of suspected HF.1 Echocardiography is also appropriate for guiding therapeutic decisions in HF patients and evaluating changes in clinical status.1 In addition to diagnosis, results from an echocardiogram (i.e., left ventricular ejection fraction [LVEF]) can provide important prognostic information.2
• In addition to LVEF, other echocardiographic parameters provide prognostic information. Specifically, in a study of cardiac mortality in HF patients with LVEF less than 40%, a restrictive transmitral flow pattern (Figure 9-1) by Doppler echocardiography was the best clinical predictor of cardiac death. Relative risk for cardiac death was estimated as 4.1 at 1 year and 8.6 at 2 years in the restrictive group compared with the nonrestrictive group.3 Several other markers of LV size and function (i.e., end-diastolic and end-systolic volume, myocardial performance index) and diastolic properties of the LV (i.e., pseudo-normal mitral inflow pattern) predict adverse prognosis in systolic HF.
• Three-dimensional (3D) echocardiography is a newer modality for measurement of LV volumes and LVEF. Studies have demonstrated that LV volumes measured by 3D echocardiography compare favorably with cardiac magnetic resonance imaging as a reference standard.4
• Novel echocardiographic measures of regional LV function, such as global longitudinal strain by speckle tracking echocardiography, may have superior prognostic value in HF patients over traditional measures of global function such as LVEF.5 Longitudinal and circumferential strain rates were independent predictors of outcome in myocardial infarction patients with LV dysfunction and/or HF.6 The effect of HF therapies on these novel echocardiographic measures represents an important area of ongoing investigation.
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Figure 9-1 Echocardiograhic example of a restrictive transmitral Doppler pattern (deceleration time < 150 ms).

Medications

Several classes of medications are approved for symptom relief and mortality benefit in systolic HF. These medications are summarized below.

Beta Blockers

• Once thought to be detrimental, several beta-adrenergic blocking agents (beta blockers) are known to provide mortality benefits for systolic HF.
• Bisoprolol, carvedilol, and metoprolol are the beta blockers for which studies have documented mortality benefits in systolic HF.
• Improvement in LVEF with carvedilol in systolic HF results from decreased heart rate, improved chamber contractility, and afterload reduction.7

Key Points

• Large mortality trials of beta blockers in systolic HF are highlighted in Table 9-1. Beta blockers are essential first-line therapy in patients with HF and LV systolic dysfunction. Beta blockers are typically started at low doses and titrated to target doses.
• In the MDC trial, beta blockers produced favorable LV remodeling, with a larger increase in LVEF compared to placebo (13.0% vs. 6.0%, p < 0.0001). In general, treatment with beta blockers improves systolic function (increase in LVEF of 5% to 10%) and reduces symptoms.

TABLE 9-1 LARGE MORTALITY TRIALS OF BETA BLOCKERS IN SYSTOLIC CONGESTIVE HF

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Angiotensin-Converting Enzyme (ACE) Inhibitors

• Neurohormonal blockade of the renin-angiotensin-aldosterone system with ACE inhibitors has proven mortality benefit in systolic HF.
• Although ACE inhibitors have vasodilator properties, the main mechanism of benefit in HF patients is the prevention of angiotensin II–mediated LV remodeling. ACE inhibitors are first-line therapy for all patients with systolic HF.

Key Points

• Large mortality trials of ACE inhibitors in systolic HF are highlighted in Table 9-2.
• ACE inhibitors reduce ventricular size, increase the LVEF modestly, and reduce symptoms. In the CONSENSUS trial, treatment with enalapril resulted in reduction in LV size. Furthermore, captopril has been shown to attenuate LV dilatation after anterior myocardial infarction.8

TABLE 9-2 LARGE MORTALITY TRIALS OF ACE INHIBITORS IN SYSTOLIC CONGESTIVE HF

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Angiotensin II Receptor Blockers (ARBs)

• ACE inhibitors do not completely inhibit renin-angiotensin activation, suggesting that alternative or additional strategies for inhibition (e.g., ARBs) may be useful. Since ARBs are generally more expensive, they are most commonly used as an alternative to ACE inhibitors in patients in whom a cough develops as the result of ACE inhibitor therapy.

Key Points

• Large mortality trials of ARBs in systolic HF are highlighted in Table 9-3.
• ARBs can be used in addition to ACE inhibitors in patients with persistent symptoms despite an optimal dose of ACE inhibitor and beta-blocker. However, the risk of adverse effects (e.g., hyperkalemia, increase in serum creatinine, or hypotension) may be increased.
• The Valsartan Heart Failure Trial (Val-HeFT) echocardiographic substudy of 5010 patients with moderate HF demonstrated that valsartan therapy, taken with either an ACE inhibitor or a beta blocker, reversed LV remodeling (decrease in LV end-diastolic dimension and increase in LVEF).9

TABLE 9-3 LARGE MORTALITY TRIALS OF ARBS IN SYSTOLIC CONGESTIVE HF

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Aldosterone Antagonists

• Aldosterone antagonists can be used as an adjunct for further neurohormonal blockade in patients with systolic HF.

Key Points

• In the RALES trial, there was a 30% decrease in mortality when spironolactone was added to the therapeutic regimen for patients with New York Heart Association (NYHA) class III/IV HF and LVEF ≤ 35%. Spironolactone may exhibit this clinical benefit as a result of improvement in LV volumes and function.10
• In the EPHESUS trial, the addition of eplerenone to optimal medical therapy in patients with HF caused by acute myocardial infarction (LVEF ≤ 40%) resulted in a 15% decrease in mortality.11
• Recently, the addition of spironolactone in NYHA class I/II HF resulted in beneficial effects on LV remodeling and diastolic function. Specifically, in the spironolactone group, LVEF increased significantly from 35% to 39%, with a decrease in LV end-diastolic and end-systolic volumes and myocardial mass and an improvement in LV diastolic filling pattern.12

Hydralazine and Isosorbide Dinitrate

• In African American patients, the response to ACE inhibitors may not be as strong, and hydralazine and isosorbide dinitrate may have an expanded role in this patient group.
• In the A-HeFT trial, a 40% decrease in mortality was observed in African Americans with NYHA class III/IV HF when isosorbide dinitrate and hydralazine were added to standard treatment.13

Diuretics

• Diuretics are used for the relief of dyspnea and fluid retention but do not modify the course of the disease in systolic HF.

Digoxin

• In a trial of systolic HF patients in sinus rhythm, digoxin (added to a diuretic and ACE inhibitor) had no effect on mortality but reduced the risk of hospitalization for HF.

Implantable Cardioverter-Defibrillator (ICD)

• About one half of the deaths in patients with systolic HF are attributed to ventricular arrhythmias. An ICD reduces the risk of sudden cardiac death in patients with LV systolic dysfunction. The benefit of ICD therapy may not be apparent until 1 year or more after implantation of the device.

Key Points

• For primary prevention, the current indications for ICD implantation are:

• LVEF ≤ 35% despite optimal medical therapy
• NYHA functional class II or III
• Expected survival of at least 1 year with a reasonable quality of life and functional status12

• For secondary prevention, an ICD is indicated for any patient who survives an unprovoked episode of ventricular fibrillation or sustained ventricular tachycardia.14
• The benefit of ICDs is documented for ischemic and nonischemic cardiomyopathies. Following myocardial infarction, early (<40 days) implantation of an ICD does not improve survival.14

Cardiac Resynchronization Therapy (CRT)

• Intraventricular conduction delay (IVCD), identified by a 12-lead electrocardiogram QRS interval ≥ 120 ms, occurs in up to one third of patients with systolic HF. IVCD is associated with dyssynchronous LV contraction, leading to impaired emptying and possibly mitral regurgitation (MR).
• CRT may improve cardiac performance by increasing stroke volume and producing reverse remodeling, a process characterized by a reduction in LV volumes leading to improved systolic and diastolic function.15 CRT has also demonstrated a reduction in functional MR.16
• In randomized trials of severe systolic HF, CRT resulted in a reduction in symptoms and improved functional capacity, a reduction in the number of hospitalizations for worsening HF, and increased survival.17
• Current guidelines recommend CRT in patients with NYHA functional class III/IV HF, LVEF ≤ 35%, sinus rhythm, and a QRS duration ≥ 120 ms.14

Key Points

• In the MADIT-CRT trial,18 CRT in addition to an ICD in patients with NYHA functional class I/II, LVEF ≤ 30%, and QRS duration ≥ 130 ms resulted in improved LV function and reduced risk of worsening HF, compared to those who received an ICD alone. These effects were most pronounced in patients with a QRS complex ≥ 150 ms.
• In the RethinQ trial,19 CRT was not shown to increase the primary outcome measure of peak oxygen consumption in patients with NYHA class III symptoms and a narrow (< 120 ms) QRS interval and echocardiographic evidence of dyssynchrony (opposing wall delay > 65 ms; see below).
• Several echocardiographic parameters have been investigated as measures of mechanical dyssynchrony. These involve M-mode measurements as well as tissue Doppler imaging (TDI) for measurement of longitudinal tissue velocity or deformation (strain) of the myocardium. Several of the well-studied parameters of intraventricular dyssynchrony are described here:

• M-mode echocardiography: Septal-posterior wall motion delay (SPWMD), the time difference between peak inward motion of the ventricular septum and the posterior wall, can be obtained from parasternal short axis M-mode images (Figure 9-2A). An initial study showed SPWMD ≥ 130 ms predicted reduction in LV-end systolic volume index greater than 15% with a sensitivity of 100% and specificity of 63% in 20 patients after 1 month of CRT, and predicted improvement in LVEF greater than 5% and better prognosis at 6 months after CRT.20 However, this parameter was feasible in only one half of patients, and in follow-up reports SPWMD did not predict outcome after CRT.21
• TDI: The standard deviation of time to peak systolic velocity among 12 basal segments and mid-LV segments (Ts-SD) has been proposed as a dyssynchrony index.22 Ts-SD greater than 32.6 ms predicted reverse remodeling 3 months after CRT with a sensitivity and specificity of 100% in the initial 30 patients.22 A Ts-SD greater than 31.4 ms had a sensitivity of 96% and specificity of 78% in a subsequent 54 patients.23 Ts-SD was shown to correlate better with reverse remodeling after CRT compared to other dyssynchrony parameters.
• TDI: A basal septal-lateral delay greater than 60 ms in time to peak systolic velocity predicted a short-term improvement in LVEF,24 and a similar dyssynchrony index (maximum difference in opposing basal segment delay greater than 65 ms; Figure 9-2B) predicted reverse remodeling at 6 months after CRT.25

• Interventricular dyssynchrony can also be evaluated to assess coordinated ventricular contraction. It is measured by the preejection period difference between pulsed wave Doppler flow in the aorta and pulmonary artery. This measure correlates with QRS duration and typically exceeds 40 ms in patients with a QRS greater than 150 ms. The CARE-HF research group found that a cutoff value of 49.2 ms separated event-free curves after CRT.26
• Although numerous echocardiographic parameters of mechanical dyssynchrony have been proposed, no large prospective trial to date has proven the clinical utility of these indices for selecting patients for CRT.
• In the prospective, multicenter PROSPECT trial, 12 echocardiographic parameters of mechanical dyssynchrony were tested to predict CRT response.27 Indicators of positive CRT response were improved clinical composite score and 15% reduction in LV end-systolic volume at 6 months. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting LV end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%.
• At present, no single echocardiographic parameter beyond current guidelines (e.g., LVEF) can be recommended to improve patient selection for CRT. However, ongoing efforts to reduce variability in technical and interpretative factors may improve the predictive powers of these or other newer echocardiographic parameters.
• CRT has been shown to reduce functional MR by producing favorable changes in mitral valve geometry and closing forces on the mitral valve. Specifically, tethering is reduced through reversal of LV remodeling and increasing the systolic duration of peak transmitral closing forces, consistent with improved coordination of LV force generation.28
• Potential future directions include the use of real-time 3D echocardiography and 3D speckle tracking echocardiography to assess mechanical dyssynchrony and the site of latest mechanical activation.
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Figure 9-2 A, M-mode echocardiography with color-coded tissue velocity. Left panel: Timing of ventricular septal (VS) wall motion is difficult to define because of its severe hypokinesis and the lack of distinct peaks. Right panel: Color coding of tissue velocity helps to identify the exact wall motion timing as the transition point of blue to red color for the septal wall (arrows) and red to blue color for the posterior wall (PW; arrowheads). B, Color-coded tissue Doppler study from three standard apical views of a patient who responded to resynchronization therapy. Time-velocity curves from representative basal or mid-LV levels are shown. Maximum opposing wall delay was seen in the apical long-axis view (140 ms between septum and PW), consistent with significant dyssynchrony (≥ 65 ms).

(A, Reprinted with permission from Anderson LJ, Miyazaki C, Sutherland GR, Oh JK. Patient selection and echocardiographic assessment of dyssynchrony in cardiac resynchronization therapy. Circulation. 2008;117:2009-2023. B, Reprinted with permission from Gorcsan J 3rd, Abraham T, Agler DA, et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr. 2008;3:191-213.)

Novel Devices

MR Reduction and Direct Ventricular Remodeling

• Chronic ischemic MR results from ischemic ventricular distortion with papillarly muscle (PM) displacement and restricted mitral leaflet closure resulting from tethering. The mitral leaflets are structurally normal. Functional MR is a more general term to describe MR resulting from ischemic disease or cardiomyopathy. Ischemic MR occurs in up to 30% of patients with postinfarct CHF, and increasing MR severity is associated with a progressively worse 5-year survival rate.29
• Restrictive annuloplasty (Figure 9-3), combined with coronary artery bypass grafting (CABG), is currently the most commonly performed surgical procedure to treat ischemic MR, although its impact on late survival and functional class is unproven. Alternative methods for ischemic MR reduction, via percutaneous or surgical approaches, are currently under investigation.30
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Figure 9-3 A, Schematic representation of the position of a mitral annuloplasty ring. B, Left panel: two-dimensional transesophageal image following mitral ring annuloplasty (arrows). Right panel: 3D transesophageal echocardiographic image showing mitral valve with ring annuloplasty (arrows) as viewed from left atrium.

(Reprinted with permission from www.nature.com/…/v13/n10/images/nm1645-F4.jpg.)

Key Points

• Direct remodeling of the PMs is a potential therapeutic target to reduce ischemic MR. Surgical approaches (both experimentally and in human patients) that reposition the PMs to reduce tethering of the mitral leaflets have been developed in small case series (Figure 9-4A).
• The Coapsys device (Myocor Inc.) was designed to treat mitral annular dilatation and PM displacement using two epicardial pads that are approximated through an internal cord (Figure 9-4B and 9-4C). It has the advantage that it can be placed on a beating heart without cardiopulmonary bypass. One-year follow-up of the first 11 patients with a Coapsys device and off-pump CABG showed effective ischemic MR and NYHA class improvement. Preoperative MR grade 2.9 ± 0.5 was reduced to grade 1.1 ± 0.8 at 1-year follow-up (p < 0.05). The RESTOR-MV trial (Randomized Evaluation of a Surgical Treatment for Off-pump Repair of the Mitral Valve) demonstrated a greater decrease in LV end-diastolic dimension and improved survival at 2 years of follow-up with the Coapsys device.31
• PM remodeling techniques remain investigational or alternative surgical approaches at the present time.
• Alfieri edge-to-edge mitral valve repair has been applied percutaneously with a clip device (MitraClip; Evalve Inc.). Results from the EVEREST II trial show that the novel MitraClip device may lead to fewer early adverse events than traditional valve repair or replacement, with “noninferior” efficacy out to 1 year.32

• EVEREST II enrolled a highly selected group of 279 patients with significant MR (3+ to 4+); 27% of patients had ischemic MR and 73% had degenerative MR. Patients were randomized 2 : 1 to the MitraClip procedure or to surgical repair or replacement at the surgeon’s discretion.
• The primary safety endpoint (a combination of adverse events including death, major stroke, reoperation, urgent/emergent surgery, myocardial infarction, renal failure, blood transfusions, and others) in the per-protocol analysis significantly favored the percutaneous procedure at 30 days, with less than 10% of patients experiencing a major adverse event, as compared with 57% of the patients treated surgically (p < 0.0001). Need for blood transfusions was the main driver of the safety endpoint, with a difference of 8.8% versus 53.2%.
• For the primary efficacy endpoint in the per-protocol analysis, the overall clinical success rate was numerically higher in the surgery group, at 87.8% compared with 72.4%, but this difference, statistically, met the pre-specified noninferiority hypothesis. However, MR reduction was greater in the surgical group.
• Percutaneous coronary sinus-based mitral valve repair remains under study. In the AMADEUS trial of patients with dilated cardiomyopathy, acute MR reduction (grade 3.0 ± 0.6 to 2.0 ± 0.8, p < 0.0001) and permanent implantation were achieved in 30 of 43 patients in whom an attempt was made.33
• Cardiac support devices that reduce ventricular wall stress and promote beneficial reverse remodeling have been proposed as an adjunct to mitral valve surgery. The Acorn CorCap (Acorn Cardiovascular, St. Paul, MN; Figure 9-5), an LV passive restraint device, was studied in 193 patients in the ACORN study.34

• MR grade was not reduced further by the use of the CorCap device; however, addition of the CorCap device led to greater decreases in LV end-diastolic volume and LV end-systolic volume, and a more elliptical LV shape. These changes were maintained at 3 years of follow-up.
• Direct ventricular remodeling was evaluated in the STITCH trial to address the question of whether surgical ventricular reconstruction (SVR) added to CABG would decrease the rate of death or hospitalization for cardiac causes, as compared with CABG alone.35

• Adding SVR reduced ventricular volumes, but this anatomic change was not associated with a greater improvement in symptoms or exercise tolerance or with a reduction in the rate of death or hospitalization for cardiac causes.
• The “Batista operation” (partial left ventriculectomy) showed initial promise as a method to achieve direct ventricular reverse remodeling; however, follow-up studies showed early and late failures of this technique and therefore it is not a recommended treatment.
image image image

Figure 9-4 A, PM approximation by passing a single U-shaped suture reinforced by two patches of autologous pericardium through the bodies of the posterior and anterior PMs. B, The Coapsys device (Myocor Inc., Maple Grove, MN) was designed to treat mitral annular dilatation and PM displacement. The device consists of epicardial posterior and anterior pads connected by a flexible subvalvular chord. The two pads are located on the epicardial surface of the heart with the load-bearing subvalvular chord passing through the LV. When the device is tightened under echocardiographic guidance, the annular head increases coaptation and the papillary head repositions the PMs. C, Preoperative (left panel) and postoperative (right panel) echocardiographic views after application of the Coapsys device.

(A, Reprinted with permission from Rama A, Praschker L, Barreda E, Gandjbakhch I. Papillary muscle approximation for functional ischemic mitral regurgitation. Ann Thorac Surg. 2007;84:2130-2131. B, Reprinted with permission from Fukamachi K, Inoue M, Popović ZB, et al. Off-pump mitral valve repair using the Coapsys device: a pilot study in a pacing-induced mitral regurgitation model. Ann Thorac Surg. 2004;77:688-692. C, Reprinted with permission from Grossi EA, Woo YJ, Schwartz CF, et al. Comparison of Coapsys annuloplasty and internal reduction mitral annuloplasty in the randomized treatment of functional ischemic mitral regurgitation: impact on the left ventricle. J Thorac Cardiovasc Surg. 2006;131:1095-1098.)

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Figure 9-5 Schematic representation of the Acorn CorCap LV passive restraint device.

(Reprinted with permission from www.vingmed.se.)

References

1 Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate use criteria for echocardiography. J Am Coll Cardiol. 2011;57:1126-1166.

This document identifies common clinical scenarios in cardiovascular disease and indicates the appropriateness of using echocardiography for diagnosis, treatment, or management. The use of echocardiography is rated as either appropriate, uncertain, or inappropriate.

2 Rihal CS, Nishimura RA, Hatle LK, Bailey KR, Tajik AJ. Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy: Relation to symptoms and prognosis. Circulation. 1994;90:2772-2779.

This study reports that, in patients with a clinical diagnosis of cardiomyopathy, LVEF was independently predictive of subsequent mortality. Markers of diastolic function correlated with congestive symptoms.

3 Xie GY, Berk MR, Smith MD, Gurley JC, DeMaria AN. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol. 1994;24:132-139.

This study documented that a restrictive transmitral flow pattern by Doppler echocardiography was a predictor of cardiac mortality in patients with congestive HF. Results from this study provided the foundation for making transmitral flow velocity a routine measurement in clinical echocardiography.

4 Sugeng L, Mor-Avi V, Weinert L, et al. Quantitative assessment of left ventricular size and function: Side-by-side comparison of real-time three-dimensional echocardiography and computed tomography with magnetic resonance reference. Circulation. 2006;114:654-661.

3D echocardiography is emerging as a technique to improve quantification of LV geometry and function, and this study is one of the initial clinical studies to show strong correlations between the reference standard of cardiac magnetic resonance imaging with 3D echocardiography (with regard to measurement of LV volumes and LVEF).

5 Nahum J, Bensaid A, Dussault C, et al. Impact of longitudinal myocardial deformation on the prognosis of chronic heart failure patients. Circ Cardiovasc Imaging. 2010;3:249-256.

This study of symptomatic HF patients demonstrated that global longitudinal strain measured by speckle tracking echocardiography was superior to LVEF in predicting major adverse cardiac events. Results from this study indicate that novel echocardiographic measurements may have prognostic significance in HF patients.

6 Hung CL, Verma A, Uno H, et al. Longitudinal and circumferential strain rate, left ventricular remodeling, and prognosis after myocardial infarction. J Am Coll Cardiol. 2010;56:1812-1822.

Participants of the VALIANT (Valsartan in Acute Myocardial Infarction Trial) were studied, and both longitudinal and circumferential strain rates were independent predictors of clinical outcomes after myocardial infarction. Circumferential strain rate was also predictive of ventricular remodeling, indicating that preserved circumferential function may limit ventricular enlargement after myocardial infarction.

7 Maurer MS, Sackner-Bernstein JD, El-Khoury Rumbarger L, Yushak M, King DL, Burkhoff D. Mechanisms underlying improvements in ejection fraction with carvedilol in heart failure. Circ Heart Fail. 2009;2:189-196.

This study used 3D echocardiography to investigate the mechanisms resulting in improved LVEF with chronic beta blocker therapy. In addition to a reduction in heart rate, positive inotropic effects and afterload reduction were shown to contribute to reverse remodeling with carvedilol treatment.

8 Pfeffer MA, Lamas GA, Vaughan DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988;319:80-86.

This double-blind, placebo-controlled study documented that ventricular enlargement after anterior myocardial infarction is progressive, although captopril can prevent ventricular dilatation. Captopril was also shown to reduce filling pressures and improve exercise tolerance.

9 Wong M, Staszewsky L, Latini R, et al. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002;40:970-975.

In this echocardiographic substudy of the large Val-HeFT trial, the addition of an angiotensin receptor blocker to prescribed HF therapy resulted in more favorable cardiac remodeling. The exception was patients already receiving an ACE inhibitor and beta blocker, in whom there was no difference in LV size and function between the angiotensin receptor blocker and placebo groups.

10 Cicoira M, Zanolla L, Rossi A, et al. Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol. 2002;40:304-310.

In an effort to understand the mechanism behind the clinical benefit of spironolactone in HF patients, this study demonstrated that the medication improved LV volumes and function. Exercise tolerance (assessed by cardiopulmonary exercise testing) was also improved.

11 Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.

12 Vizzardi E, D’Aloia A, Giubbini R, et al. Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure. Am J Cardiol. 2010;106:1292-1296.

The benefits of spironolactone in HF were initially demonstrated in patients with NYHA class III/IV symptoms. This study evaluated NYHA class I or II symptoms and demonstrated improvements in LV volumes as well as measures of systolic and diastolic function.

13 Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057.

14 Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:e391-e479.

This practice guideline serves as an evidence-based document summarizing the recommendations for care of HF patients. Behavioral, medical, and device-based therapies are addressed.

15 St. John Sutton MG, Keane MG. Reverse remodeling in heart failure with cardiac resynchronization therapy. Heart. 2007;93:167-171.

This review summarizes the role of CRT in the treatment of systolic HF, with a focus on the beneficial effects of CRT on producing favorable changes in LV size and function.

16 St. John Sutton MG, Plappert T, Hilpisch KE, et al. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: Quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation. 2006;113:266-272.

In this substudy of the MIRACLE trial, CRT was shown to reduce LV volumes and increase ejection fraction. A reduction in MR was also observed. Findings were more pronounced in patients with nonischemic cardiomyopathy as compared to ischemic cardiomyopathy.

17 Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549.

In this groundbreaking randomized trial, CRT improved symptoms and quality of life in NYHA class III/IV HF patients, as well as producing a reduction in mortality.

18 Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361:1329-1338.

In this trial of relatively asymptomatic patients (NYHA class I/II), CRT decreased the risk of HF events. This trial supports the recommendation to expand CRT to less symptomatic HF patients with reduced systolic function and a wide QRS complex on electrocardiogram.

19 Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med. 2007;357:2461-2471.

Since a subset of HF patients have evidence of mechanical dyssynchrony despite a narrow QRS complex, this trial sought to examine the effect of CRT in such patients. However, CRT did not improve peak oxygen consumption in HF patients with a narrow QRS.

20 Pitzalis MV, Iacoviello M, Romito R, et al. Ventricular asynchrony predicts a better outcome in patients with chronic heart failure receiving cardiac resynchronization therapy. J Am Coll Cardiol. 2005;45:65-69.

In an effort to predict response to CRT, this study investigated the M-mode echocardiographic parameter defining the time difference between peak inward motion of the ventricular septum and the posterior wall (SPWMD). This parameter predicted response to CRT in this study of 60 patients.

21 Marcus GM, Rose E, Viloria EM, et al. Septal to posterior wall motion delay fails to predict reverse remodeling or clinical improvement in patients undergoing cardiac resynchronization therapy. J Am Coll Cardiol. 2005;46:2208-2214.

In this retrospective analysis of the CONTAK-CD trial, the SPWMD did not predict response to CRT. This study failed to reproduce the findings from previous smaller studies with shorter follow-up.

22 Yu CM, Fung WH, Lin H, et al. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol. 2003;91:684-688.

This study evaluated a dyssynchrony index (standard deviation to peak systolic velocity among 12 basal and mid-LV segments) and showed that a preimplantation index value of 32.6 ms was able to segregate responders from nonresponders to CRT. Additionally, the dyssynchrony index was an independent predictor of reverse remodeling.

23 Yu CM, Fung JW, Zhang Q, et al. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 2004;110:66-73.

This study of nonischemic and ischemic HF patients showed that the TDI parameter of standard deviation to peak systolic velocity among 12 basal and mid-LV segments was a predictor of reverse remodeling at 3 months of follow-up. Strain-rate imaging parameters did not predict reverse remodeling.

24 Bax JJ, Marwick TH, Molhoek SG, et al. Left ventricular dyssynchrony predicts benefit of cardiac resynchronization therapy in patients with end-stage heart failure before pacemaker implantation. Am J Cardiol. 2003;92:1238-1240.

In this study of end-stage HF patients, a delay in the time to peak systolic velocity between the basal septum and lateral wall of greater than 60 ms predicted improvement in LVEF.

25 Bax JJ, Bleeker GB, Marwick TH, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol. 2004;44:1834-1840.

This study followed the effect of CRT out to 6 months of follow-up, and demonstrated that a dyssynchrony index (maximal difference in opposing basal segment delay > 65 ms) predicted response to CRT and portended a more favorable prognosis.

26 Richardson M, Freemantle N, Calvert MJ, et al. Predictors and treatment response with cardiac resynchronization therapy in patients with heart failure characterized by dyssynchrony: A pre-defined analysis from the CARE-HF trial. Eur Heart J. 2007;28:1827-1834.

In this analysis of the CARE-HF trial, the presence of interventricular dyssynchrony identified patients more likely to respond to CRT. This trial measured the preejection period difference in the aorta and pulmonary artery, a measurement of interventricular dyssynchrony (as opposed to intraventricular dyssynchrony).

27 Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation. 2008;117:2608-2616.

Given numerous single-center studies reporting the benefit of using echocardiographically derived parameters of dyssynchrony to predict response to CRT, this multicenter study was conducted. This study showed that there was large variability in the analysis of dyssynchrony parameters, and the ability of the parameters to predict CRT response varied widely. Therefore, none of the echocardiographic parameters studied here are currently recommended for use in selecting patients for CRT.

28 Solis J, McCarty D, Levine RA, et al. Mechanism of decrease in mitral regurgitation after cardiac resynchronization therapy: Optimization of the force-balance relationship. Circ Cardiovasc Imaging. 2009;6:444-450.

This study sought to evaluate the mechanisms by which CRT can reduce the degree of MR. Results demonstrated that CRT reduces leaflet tethering and increases the systolic duration of peak transmitral closing pressures.

29 Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: Long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759-1764.

This study of over 300 patients after myocardial infarction helped document the common prevalence of ischemic MR and its association with negative clinical outcomes.

30 Bouma W, van der Horst IC, Wijdh-den Hamer IJ, et al. Chronic ischaemic mitral regurgitation: Current treatment results and new mechanism-based surgical approaches. Eur J Cardiothorac Surg. 2010;37:170-185.

This article highlights surgical approaches to reduce the degree of ischemic MR. Visual representations of the anatomy and surgical repair techniques are provided.

31 Grossi EA, Patel N, Woo YJ, et al. Outcomes of the RESTOR-MV Trial (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve). J Am Coll Cardiol. 2010;56:1984-1993.

This study evaluated the use of the Coapsys device and demonstrated that ventricular reshaping (in addition to revascularization) decreased adverse outcomes and improved survival in patients with functional MR.

32 Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med. 2011;364:1395-1406.

33 Siminiak T, Hoppe UC, Schofer J, et al. Effectiveness and safety of percutaneous coronary sinus-based mitral valve repair in patients with dilated cardiomyopathy (from the AMADEUS trial). Am J Cardiol. 2009;104:565-570.

Coronary sinus-based mitral valve repair represents a novel percutaneous technique designed to reduce the degree of MR. This study demonstrated feasibility of this technique.

34 Acker MA, Bolling S, Shemin R, et al. Mitral valve surgery in heart failure: Insights from the ACORN Clinical Trial. J Thorac Cardiovasc Surg. 2006;132:568-577.

This study evaluated the CorCap cardiac support device, which is designed to reduce ventricular wall stress and promote beneficial reverse remodeling. Results showed that the CorCap produced a more elliptical shape of the LV along with decreased volumes.

35 Jones RH, Velazquez EJ, Michler RE, et al. Coronary bypass surgery with or without surgical ventricular reconstruction. N Engl J Med. 2009;360:1705-1717.

This landmark study of 1000 patients showed that adding SVR to CABG did not improve clinical outcomes, although it did reduce LV volumes.

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