Acute effects of withdrawal of cardiac resynchronization therapy on left and right ventricular function, dyssynchrony, and contractile function in patients with New York Heart Association functional class I/II heart failure: MADIT-CRT.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves left ventricular (LV) function, size, mitral regurgitation, and clinical outcomes. Whether these improvements are due to the short-term effects of improvement in synchrony or contractile performance, or to long-term improvement in ventricular structure and function remains insufficiently elucidated. METHODS AND RESULTS: We used echocardiographic data from 63 patients enrolled in the MADIT-CRT trial who, after 1 year of CRT therapy, underwent echocardiographic evaluation with CRT turned both on and off within minutes. LV volumes, LV ejection fraction, left atrial (LA) volumes, and right ventricular function were assessed at baseline and in the on and off modes within a 5-minute time-frame at 12 months. Speckle-tracking strain analysis was used to assess LV dyssynchrony and contractile function. Interruption of long-term CRT resulted in acute deterioration of LV and RV function and acute increase in LV and LA volumes, although not to baseline. Acute withdrawal was also associated with increased dyssynchrony (SD time to peak transverse strain 178 ± 68 ms vs 195 ± 62 ms; P = .16; and SD time to peak longitudinal strain 108 ± 46 ms vs 125 ± 55 ms; P = .046). However, there was no deterioration in contractile function (global longitudinal strain), which had improved with CRT (-9.8 ± 4.3% vs -10.0 ± 3.7%; P = .93). CONCLUSIONS: Despite substantial LV reverse remodeling with CRT, interruption of long-term CRT after 12 months resulted in an acute worsening of LV size and function, LA volumes, and right ventricular function, with concomitant worsening of ventricular synchrony despite minimal change to the observed improvement in LV strain measures of contractile function. These findings suggest that the beneficial reverse remodeling associated with CRT may be mostly dependent on active pacing, although intrinsic improvements in contractile function may persist beyond termination of pacing.

Relationship between improvement in left ventricular dyssynchrony and contractile function and clinical outcome with cardiac resynchronization therapy: the MADIT-CRT trial.

AIMS: To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT. METHODS AND RESULTS: We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 ± 83 ms and -1 ± 2.9%. However, both LV dyssynchrony (CRT-D: -47 ± 83 ms vs. ICD: -6 ± 76 ms, P < 0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001). CONCLUSION: Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes.

Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) plus implantation of an implantable cardioverter defibrillator (ICD) reduced the risk of death or heart failure event in patients with mildly symptomatic heart failure, left ventricular dysfunction, and wide QRS complex compared with an ICD only. We assessed echocardiographic changes in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function. METHODS AND RESULTS: A total of 1,820 patients were randomly assigned to CRT plus an ICD or to an ICD only in a 3:2 ratio. Echocardiographic studies were obtained at baseline and 12 months later in 1,372 patients. We compared changes in cardiac size and performance between treatment groups and assessed the relationship between these changes over the first year, as well as subsequent outcomes. Compared with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (-26.2 versus -7.4 mL/m(2)), left ventricular end-systolic volume index (-28.7 versus -9.1 mL/m(2)), left ventricular ejection fraction (11% versus 3%), left atrial volume index (-11.9 versus -4.7 mL/m(2)), and right ventricular fractional area change (8% versus 5%; P<0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or heart failure, with adjustment for baseline covariates and treatment group; each 10% decrease in end-diastolic volume was associated with a 40% reduction in risk (P<0.001). CONCLUSIONS: CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure. Improvement in these measures accounted for the outcomes benefit. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Mechanical dyssynchrony after myocardial infarction in patients with left ventricular dysfunction, heart failure, or both.

BACKGROUND: Mechanical dyssynchrony is considered an independent predictor for adverse cardiovascular outcomes in patients with heart failure. However, its importance as a risk factor after myocardial infarction is not well defined. METHODS AND RESULTS: We examined the influence of mechanical dyssynchrony on outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echocardiography study. B-mode speckle tracking with velocity vector imaging was used to assess ventricular synchrony in 381 patients who had image quality sufficient for analysis. Time to regional peak velocity and time to strain rate were measured among 12 left ventricular segments from the apical 4- and 2- chamber views, and the SDs between all 12 segments were used as a measure of dyssynchrony. The relationships between the SD of time to regional peak velocity and strain rate and clinical outcome of death or heart failure were assessed. In a multivariate Cox model adjusted for clinical and echocardiographic variables, the SD of time to peak velocity (hazard ratio per 10 ms, 1.10; 95% confidence interval, 1.02 to 1.18; P=0.010) and the SD of time to strain rate (hazard ratio per 10 ms, 1.16; 95% confidence interval, 1.06 to 1.27; P=0.001) were independent predictors of death or heart failure. CONCLUSIONS: Left ventricular dyssynchrony is independently associated with increased risk of death or heart failure after myocardial infarction, suggesting that contractile pattern may play a role in post-myocardial infarction prognosis.

Left atrial remodelling in patients with myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALIANT Echo study.

AIMS: To assess the relationship between left atrial (LA) size and outcome after high-risk myocardial infarction (MI) and to study dynamic changes in LA size during long-term follow-up. METHODS AND RESULTS: The VALIANT Echocardiography study prospectively enrolled 610 patients with left ventricular (LV) dysfunction, heart failure (HF), or both following MI. We assessed LA volume indexed to body surface area (LAVi) at baseline, 1 month, and 20 months after MI. Baseline LAVi was an independent predictor of all-cause death or HF hospitalization (P = 0.004). In patients who survived to 20 months, LAVi increased a mean of 3.00 +/- 7.08 mL/m(2) from baseline. Hypertension, lower estimated glomerular filtration rate, and LV mass were the only baseline independent predictors of LA remodelling. Changes in LA size were related to worsening in MR and increasing in LV volumes. LA enlargement during the first month was significantly greater in patients who subsequently died or were hospitalized for HF than in patients without events. CONCLUSION: Baseline LA size is an independent predictor of death or HF hospitalization following high-risk MI. Moreover, LA remodelling during the first month after infarction is associated with adverse outcome.

Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial.

BACKGROUND: Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents. METHODS: Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170924. FINDINGS: 186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29). INTERPRETATION: Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.

Usefulness of right ventricular fractional area change to predict death, heart failure, and stroke following myocardial infarction (from the VALIANT ECHO Study).

Severe right ventricular dysfunction independent of left ventricular ejection fraction increased the risk of heart failure (HF) and death after myocardial infarction (MI). The association between right ventricular function and other clinical outcomes after MI was less clear. Two-dimensional echocardiograms were obtained in 605 patients with left ventricular dysfunction and/or clinical/radiologic evidence of HF from the VALIANT echocardiographic substudy (mean 5.0 +/- 2.5 days after MI). Clinical outcomes included all-cause mortality, cardiovascular (CV) death, sudden death, HF, and stroke. Baseline right ventricular function was measured in 522 patients using right ventricular fractional area change (RVFAC) and was related to clinical outcomes. Mean RVFAC was 41.9 +/- 4.3% (range 19.2% to 53.1%). The incidence of clinical events increased with decreasing RVFAC. After adjusting for 11 covariates, including age, ejection fraction, and Killip's classification, decreased RVFAC was independently associated with increased risk of all-cause mortality (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.31 to 1.98), CV death (HR 1.62, 95% CI 1.30 to 2.01), sudden death (HR 1.79, 95% CI 1.26 to 2.54), HF (HR 1.48, 95% CI 1.17 to 1.86), and stroke (HR 2.95, 95% CI 1.76 to 4.95), but not recurrent MI. Each 5% decrease in baseline RVFAC was associated with a 1.53 (95% CI 1.24 to 1.88) increased risk of fatal and nonfatal CV outcomes. In conclusion, decreased right ventricular systolic function is a major risk factor for death, sudden death, HF, and stroke after MI.

Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone. METHODS AND RESULTS: Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates. CONCLUSIONS: Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.

Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) echocardiographic study.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition attenuates ventricular remodeling and improves ventricular function in heart failure patients. Vasopeptidase inhibition has shown similar effects in experimental models. OBJECTIVES: The OVERTURE echocardiographic study was designed to test the hypothesis that the vasopeptidase inhibitor omapatrilat would attenuate ventricular remodeling and improve ventricular function to a greater extent than an ACE inhibitor. METHODS: Three hundred twenty-one patients with heart failure (New York Heart Association class > or = 2) were included in the OVERTURE echocardiographic substudy and were randomized to receive enalapril (10 mg twice a day) or omapatrilat (40 mg every day). Echocardiograms were performed at baseline and at 1 year (n = 214). Left ventricular size was estimated by summation of ventricular areas in apical and short-axis views and by calculation of ventricular volumes. Ejection fraction was calculated from ventricular volumes. RESULTS: Combined diastolic and systolic areas and volumes decreased significantly (mean diastolic area change -8.36 cm2, 95% CI -9.4 to -7.3 cm2; mean systolic change -8.4 cm2, 95% CI -9.5 to -7.3 cm2), and ejection fractions increased significantly (3.6%, 95% CI 2.6% to 4.6%) in both treatment groups from baseline to 1 year. There were no differences in the magnitude of improvement in ventricular size or function based on treatment assignment. Patients who died or were hospitalized for heart failure subsequent to the final assessment demonstrated the least degree of reverse remodeling. CONCLUSION: Ventricular size and function improved similarly after 1 year with ACE or vasopeptidase inhibition in patients with heart failure. Reverse remodeling was associated with improved outcome.

Left atrial volume and the benefit of cardiac resynchronization therapy in the MADIT-CRT trial.

BACKGROUND: Left atrial volume (LAV) is an important marker of heart failure (HF) severity. We hypothesized that LAV independently correlates with clinical outcomes in patients who receive cardiac resynchronization therapy with a defibrillator (CRT-D) and can be used for improved risk assessment in this population. METHODS AND RESULTS: The benefit of CRT-D versus defibrillator-only therapy in reducing the risk of HF or death was assessed by LAV (dichotomized at the upper quartile>52 mL/m2) among 1785 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study. Landmark analysis was used to evaluate the relationship between LAV response to CRT-D and subsequent clinical outcomes. Multivariable analysis showed that patients with a higher baseline LAV experienced 69% (P<0.001) and 59% (P=0.02) increased hazard for HF or death and for all-cause mortality, respectively, independently of baseline left ventricular volume. CRT-D was associated with a significant reduction in LAV compared with defibrillator-only therapy (-28% versus -10%, respectively; P<0.001). Landmark analysis showed that after CRT-D implantation each 1% reduction in LAV was independently associated with a corresponding 4% reduction in the hazard of subsequent HF or death (P<0.001). The assessment of LAV change after CRT implantation improved prediction of clinical response to the device compared with assessment of the corresponding changes in left ventricular volume. CONCLUSIONS: LAV is an independent correlate of clinical outcomes in mildly symptomatic HF patients treated with CRT-D. CRT exerts pronounced reverse remodeling effects on the left atrium that independently correlate with improved clinical outcomes after device implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Right ventricular function, pulmonary pressure estimation, and clinical outcomes in cardiac resynchronization therapy.

BACKGROUND: Right ventricular function (RVF) is an important determinant of outcome in patients with heart failure, and those with severe RV dysfunction have worse outcome after cardiac resynchronization therapy (CRT). We used data from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) Trial to determine whether therapy with CRT is influenced by or affects RV function and to define the relationship between RV function and outcomes. METHODS AND RESULTS: A total of 1820 patients were randomly assigned to CRT plus implantable cardioverter defibrillator or implantable cardioverter defibrillator-only in a 3:2 ratio. We assessed RVF as RV fractional area change by echocardiography at baseline and after 1 year of therapy (n=1511 and 1273, respectively). The median RV fractional area change was 41%, with 10.9% of patients <35% at baseline. Baseline RVF did not modify the treatment effect of CRT on the primary outcome (interaction P=0.19). Randomization to CRT-implantable cardioverter defibrillator was associated with a greater improvement in RVF (ΔRV fractional area change 8.1% versus 5.4%; P<0.001), and improvement in RVF was related to subsequent outcomes. Every 5-point increase in RV fractional area change was associated with a 22% reduction in event rates (hazard ratio, 0.78; 95% confidence interval, 0.66-0.92; P=0.003), although this was not independent of the concurrent improvement in left ventricular function. Baseline tricuspid regurgitant velocity, a measure of pulmonary systolic pressure, was predictive of events in a multivariate analysis (hazard ratio, 1.86; 95% confidence interval, 1.24-2.8; P=0.003). CONCLUSIONS: In this population with mild heart failure symptoms, CRT was associated with improvement in RVF, which improved in parallel with improvement in left ventricular function. Patients with the best RVF at 1 year demonstrated the lowest subsequent event rates. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01294449.

Effects of cardiac resynchronization therapy on left ventricular mass and wall thickness in mild heart failure patients in MADIT-CRT.

BACKGROUND: The effect of cardiac resynchronization therapy (CRT) on left ventricular wall thickness and left ventricular mass (LVM) is unknown. OBJECTIVES: To evaluate the effects of CRT on septal and posterior wall thickness (SWT and PWT) and LVM in patients with left bundle branch block (LBBB) and non-LBBB vs implantable cardioverter-defibrillator patients and to assess the relationship between CRT-induced changes and cardiac events. METHODS: We investigated 843 patients with LBBB and 366 patients with non-LBBB enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT) trial to analyze changes in SWT, PWT, and LVM at 12 months and subsequent outcome. The primary end point was heart failure or death; secondary end points included ventricular tachycardia, ventricular fibrillation, or death. RESULTS: In LBBB patients, reduction in SWT, PWT, and LVM was more pronounced in CRT defibrillator (CRT-D) than in implantable cardioverter-defibrillator (SWT:-6.7% ± 4.4% vs-1.0% ± 1.9%; PWT:-6.4% ± 4.3% vs-0.8% ± 1.9%; LVM:-23.6% ± 9.9% vs-5.1% ± 5.1%; P<.001 for all). In CRT-D patients with non-LBBB, LVM reduction was less pronounced; however, changes in SWT and PWT were comparable. Changes in LVM correlated with changes in left ventricular end-diastolic volume. In CRT-D patients with LBBB, reduction in SWT and LVM was associated with reduction in heart failure/death (SWT: hazard ratio 0.94; 95% confidence interval 0.89-0.99 per percent change; P = .03) and ventricular tachycardia/ventricular fibrillation/death (SWT: hazard ratio 0.95; 95% confidence interval 0.91-1.00; P = .04). CRT-D patients with non-LBBB did not show favorable reduction in clinical or arrhythmic end points related to changes in SWT, PWT, or LVM. CONCLUSIONS: CRT-D was associated with significant reduction in SWT, PWT, and LVM in patients with LBBB along with left ventricular volume changes and associated favorable clinical and arrhythmia outcomes.

Influence of ejection fraction on the prognostic value of sympathetic innervation imaging with iodine-123 MIBG in heart failure.

OBJECTIVES: The aim of this study was to determine whether left ventricular ejection fraction (LVEF) influences the relationship between abnormal myocardial sympathetic innervation imaging by iodine 123 meta-iodobenzylguanidine ((123)I-mIBG) and outcomes in patients with heart failure (HF). BACKGROUND: In systolic HF, both abnormal (123)I-mIBG imaging and reduced LVEF are associated with higher risk of cardiovascular events. Whether (123)I-mIBG imaging has the same predictive value across the LVEF spectrum is unclear. METHODS: Among 985 patients in the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial with New York Heart Association functional class II or III HF and site-reported LVEF ≤35%, the core laboratory-determined LVEFs were available for 901 subjects, ranging from 20% to 58% (mean LVEF 34 ± 7%), and was >35% in 386 subjects. RESULTS: The mean age of the study population was 62 ± 12 years, 80% were male, and the majority had New York Heart Association functional class II symptoms and HF of nonischemic etiology. At all levels of LVEF, the (123)I-mIBG heart-to-mediastinum ratio of <1.6 was associated with a higher risk of death or potentially lethal arrhythmic event and of the composite of cardiovascular death, arrhythmic event, and HF progression. Comparing subjects with LVEF ≤35% and >35%, there was no evidence of effect modification of LVEF on the risk associated with low heart-to-mediastinum ratio for death or arrhythmic event (adjusted hazard ratio: 2.39 [95% confidence interval (CI): 1.03 to 5.55] vs. 5.28 [95% CI: 1.21 to 23.02]; interaction p = 0.48) and for the composite (adjusted hazard ratio: 1.80 [95% CI: 1.01 to 3.23] vs. 2.41 [95% CI: 1.11 to 5.23]; interaction; p = 0.86). For death or arrhythmic event, the heart-to-mediastinum ratio appeared to improve the risk discrimination beyond clinical and biomarker data among both LVEF groups, with improvement in the model C-statistic (0.67 vs. 0.69, p = 0.03) and integrated discrimination improvement (p = 0.0008). CONCLUSIONS: (123)I-mIBG imaging has prognostic value across a spectrum of LVEFs. Further studies may be warranted to prospectively test the prognostic value of (123)I-mIBG imaging in patients with HF and an LVEF >35%.

Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study.

OBJECTIVES: The authors investigated predictors of left ventricular ejection fraction (LVEF) super-response to cardiac resynchronization therapy with defibrillator (CRT-D) and whether super-response translated into improved event-free survival in patients with mildly symptomatic heart failure (HF). BACKGROUND: Few data exist on predictors of super-response to CRT-D and associated morbidity and mortality in mildly symptomatic HF populations. METHODS: Patients were assigned to CRT-D with paired echocardiograms at baseline and at 12 months (n = 752). Super-response was defined by the top quartile of LVEF change. Best-subset regression analysis identified predictors of LVEF super-response. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to investigate associations of response category with development of nonfatal HF event or all-cause death. RESULTS: All 191 super-responders experienced an LVEF increase of ≥14.5% (mean LVEF increase 17.5 ± 2.7%). Six predictors were associated with LVEF super-response to CRT-D therapy: female sex (odds ratio [OR]: 1.96; p = 0.001), no prior myocardial infarction (OR: 1.80; p = 0.005), QRS duration ≥150 ms (OR: 1.79; p = 0.007), left bundle branch block (OR: 2.05; p = 0.006), body mass index <30 kg/m(2) (OR: 1.51; p = 0.035), and smaller baseline left atrial volume index (OR: 1.47; p < 0.001). Cumulative probability of HF or all-cause death at 2 years was 4% in super-responders, 11% in responders, and 26% in hypo-responders (log-rank p < 0.001 overall). In multivariate analysis, hyporesponse was associated with increased risk of HF or all-cause death, compared with super-response (hazard ratio: 5.25; 95% confidence interval: 2.01 to 13.74; p = 0.001). CONCLUSIONS: Six baseline factors predicted LVEF super-response in CRT-D-treated patients with mild HF. Super-response was associated with reduced risk of subsequent cardiac events. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Dyssynchrony, contractile function, and response to cardiac resynchronization therapy.

BACKGROUND: Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT. METHODS AND RESULTS: We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ≤30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ≤-8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block. CONCLUSIONS: Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Longitudinal and circumferential strain rate, left ventricular remodeling, and prognosis after myocardial infarction.

OBJECTIVES: We sought to investigate the clinical prognostic value of longitudinal and circumferential strain (S) and strain rate (SR) in patients after high-risk myocardial infarction (MI). BACKGROUND: Left ventricular (LV) contractile performance after MI is an important predictor of long-term outcome. Tissue deformation imaging might more closely reflect myocardial contractility than traditional measures of systolic functions. METHODS: The VALIANT (Valsartan in Acute Myocardial Infarction Trial) Echo study enrolled 603 patients with LV dysfunction, heart failure, or both 5 days after MI. We measured global peak longitudinal S and systolic SR (SRs) from apical 4- and 2-chamber views and global circumferential S and SRs from parasternal short-axis view with speckle tracking software (Velocity Vector Imaging, Siemens, Inc., Mountain View, California). We related global S and SRs to LV remodeling at 20-month follow-up and to clinical outcomes. RESULTS: Both longitudinal (mean: -5.1 ± 1.6 100/ms) and circumferential SRs (mean: -8.0 ± 2.8 100/ms) were predictive of death or hospital stay for heart failure (hazard ratio: 2.4, 95% confidence interval [CI]: 2.0 to 3.1, p < 0.001; hazard ratio: 1.3, 95% CI: 1.2 to 1.4, p < 0.001, respectively) after adjustment for clinical covariates by Cox proportional hazards, and longitudinal SRs further improved in predicting 18-month survivor on a model based on clinical and standard echocardiographic measures (increase in area under the receiver-operator characteristic curve: 0.13, p = 0.009). With multivariable logistic regression, circumferential SRs, but not longitudinal SRs, was strongly predictive of remodeling (odds ratio: 1.3, 95% CI: 1.1 to 1.4, p < 0.001). CONCLUSIONS: Both longitudinal and circumferential SRs were independent predictors of outcomes after MI, whereas only circumferential SRs was predictive of remodeling, suggesting that preserved circumferential function might serve to restrain ventricular enlargement after MI.

Prognostic implications of left ventricular mass and geometry following myocardial infarction: the VALIANT (VALsartan In Acute myocardial iNfarcTion) Echocardiographic Study.

OBJECTIVES: This study sought to understand prognostic implications of increased baseline left ventricular (LV) mass and geometric patterns in a high risk acute myocardial infarction. BACKGROUND: The LV hypertrophy and alterations in LV geometry are associated with an increased risk of adverse cardiovascular events. METHODS: Quantitative echocardiographic analyses were performed at baseline in 603 patients from the VALIANT (VALsartan In Acute myocardial iNfarcTion) echocardiographic study. The left ventricular mass index (LVMi) and relative wall thickness (RWT) were calculated. Patients were classified into 4 mutually exclusive groups based on RWT and LVMi as follows: normal geometry (normal LVMi and normal RWT), concentric remodeling (normal LVMi and increased RWT), eccentric hypertrophy (increased LVMi and normal RWT), and concentric hypertrophy (increased LVMi and increased RWT). Cox proportional hazards models were used to evaluate the relationships among LVMi, RWT, LV geometry, and clinical outcomes. RESULTS: Mean LVMi and RWT were 98.8 +/- 28.4 g/m(2) and 0.38 +/- 0.08. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, heart failure, stroke, or resuscitation after cardiac arrest was lowest for patients with normal geometry, and increased with concentric remodeling (hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.9 to 4.9), eccentric hypertrophy (HR: 3.1; 95% CI: 1.9 to 4.8), and concentric hypertrophy (HR: 5.4; 95% CI: 3.4 to 8.5), after adjusting for baseline covariates. Also, baseline LVMi and RWT were associated with increased mortality and nonfatal cardiovascular outcomes (HR: 1.22 per 10 g/m(2) increase in LVMi; 95% CI: 1.20 to 1.30; p < 0.001) (HR: 1.60 per 0.1-U increase in RWT; 95% CI: 1.30 to 1.90; p < 0.001). Increased risk associated with RWT was independent of LVMi. CONCLUSIONS: Increased baseline LV mass and abnormal LV geometry portend an increased risk for morbidity and mortality following high-risk myocardial infarction. Concentric LV hypertrophy carries the greatest risk of adverse cardiovascular events including death. Higher RWT was associated with an increased risk of cardiovascular complications after high-risk myocardial infarction.

Mitral regurgitation in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: prognostic significance and relation to ventricular size and function.

AIMS: Mitral regurgitation (MR) confers independent risk in patients with acute myocardial infarction. We utilized data from the VALsartan In Acute myocardial iNfarcTion echo study to relate baseline MR to left ventricular (LV) size, shape, and function, and to assess the relationship between baseline MR and progression of MR and cardiovascular (CV) outcomes. METHODS AND RESULTS: We studied 496 patients with heart failure (HF) and/or systolic dysfunction after MI who underwent echocardiography at a median of 5 days after MI. MR severity, quantified as the regurgitant jet area/left atrial area ratio, was assessed at baseline, one and 20 months post-MI and related to LV size, shape, function, and clinical outcomes. Increased MR at baseline was associated with larger LV end-diastolic and end-systolic volumes, increased sphericity index, and reduced ejection fraction (P trend < 0.001). Moderate-severe MR was an independent predictor of total mortality [adjusted hazard ratio (HR) 2.4 (1.1-5.3)], CV mortality [adjusted HR 2.7 (1.2-6.1)], hospitalization for HF [adjusted HR 2.5 (1.1-5.5)], or death or HF hospitalization [adjusted HR 2.5 (1.4-4.6)]. Patients with progression of MR during the first post-MI month were substantially more likely to die or develop HF (adjusted HR per increased MR grade 3.0, 95% CI 1.8-4.9). Progression of MR over 20 months in survivors was associated with increased hospitalizations for HF (P < 0.001). CONCLUSION: Following high-risk myocardial infarction, baseline mitral regurgitant severity is associated with larger LV volumes and worse LV function. Both baseline MR severity and progression of MR are associated with an increased likelihood of adverse outcomes.

Comparison of regional versus global assessment of left ventricular function in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction: the valsartan in acute myocardial infarction echocardiographic study.

BACKGROUND: Left ventricular (LV) ejection fraction (EF) and wall-motion index (WMI) have both been shown to be independent predictors of outcome after myocardial infarction (MI). OBJECTIVES: We sought to determine whether these two measurements of LV systolic function provide similar or complementary information about prognosis after MI. METHODS: Echocardiography was performed in 610 patients with LV dysfunction, heart failure, or both after MI enrolled in the Valsartan in Acute MI trial. LVEF was estimated by biplane Simpson's rule, and WMI was assessed using a 16-segment model in 502 patients with echocardiograms of sufficient quality for wall-motion assessment. RESULTS: Both LVEF and WMI were independent predictors of adverse outcome after MI. LVEF conferred no additional prognostic information in multivariable analysis including WMI (P = .39) or number of affected segments (P = .53), whereas WMI (P = .02) and total number of affected segments (P = .006) remained significant even when adjusting for LVEF. CONCLUSIONS: Assessment of regional dysfunction by WMI or the number of affected segments has slightly more prognostic value than LVEF in patients with LV dysfunction, heart failure, or both after MI. Regional assessment might be a more sensitive predictor of outcome than global assessment in patients with acute MI.