Kaushik Guha

Association of Fibrosis With Mortality and Sudden Cardiac Death in Patients With Nonischemic Dilated Cardiomyopathy

IMPORTANCE Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions. OBJECTIVE To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy. DESIGN, SETTING, AND PATIENTS Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011. MAIN OUTCOME MEASURES Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation. RESULTS Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio [HR], 2.96 [95% CI, 1.87-4.69]; absolute risk difference, 16.2% [95% CI, 8.2%-24.2%]; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 [95% CI, 3.15-8.72]; absolute risk difference, 22.6% [95% CI, 14.6%-30.6%]; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 [95% CI, 1.50-3.92]; P < .001) and the extent (HR, 1.11 [95% CI, 1.06-1.16]; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 [95% CI, 1.95-5.31], P < .001; and by fibrosis extent: HR, 1.15 [95% CI, 1.10-1.20], P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 [95% CI, 2.75-7.74], P < .001; and by fibrosis extent: HR, 1.10 [95% CI, 1.05-1.16], P < .001), and the HF composite (by fibrosis presence: HR, 1.62 [95% CI, 1.00-2.61], P = .049; and by fibrosis extent: HR, 1.08 [95% CI, 1.04-1.13], P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 [95% CI, 0.11-0.41]; P = .001 and 0.29 [95% CI, 0.11-0.48]; P = .002, respectively). CONCLUSIONS AND RELEVANCE Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.

The Prevalence and Prognostic Significance of Right Ventricular Systolic Dysfunction in Nonischemic Dilated Cardiomyopathy

Background— Cardiovascular magnetic resonance is the gold-standard technique for the assessment of ventricular function. Although left ventricular volumes and ejection fraction are strong predictors of outcome in dilated cardiomyopathy (DCM), there are limited data regarding the prognostic significance of right ventricular (RV) systolic dysfunction (RVSD). We investigated whether cardiovascular magnetic resonance assessment of RV function has prognostic value in DCM. Methods and Results— We prospectively studied 250 consecutive DCM patients with the use of cardiovascular magnetic resonance. RVSD, defined by RV ejection fraction ⩽45%, was present in 86 (34%) patients. During a median follow-up period of 6.8 years, there were 52 deaths, and 7 patients underwent cardiac transplantation. The primary end point of all-cause mortality or cardiac transplantation was reached by 42 of 86 patients with RVSD and 17 of 164 patients without RVSD (49% versus 10%; hazard ratio, 5.90; 95% confidence interval [CI], 3.35–10.37; P<0.001). On multivariable analysis, RVSD remained a significant independent predictor of the primary end point (hazard ratio, 3.90; 95% CI, 2.16–7.04; P<0.001), as well as secondary outcomes of cardiovascular mortality or cardiac transplantation (hazard ratio, 3.35; 95% CI, 1.76–6.39; P<0.001), and heart failure death, heart failure hospitalization, or cardiac transplantation (hazard ratio, 2.70; 95% CI, 1.32–5.51; P=0.006). Assessment of RVSD improved risk stratification for all-cause mortality or cardiac transplantation (net reclassification improvement, 0.31; 95% CI 0.10–0.53; P=0.001). Conclusions— RVSD is a powerful, independent predictor of transplant-free survival and adverse heart failure outcomes in DCM. Cardiovascular magnetic resonance assessment of RV function is important in the evaluation and risk stratification of DCM patients.

Association between mid-wall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction

Background: Current guidelines only recommend the use of an implantable cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF) <35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70% to 80% of such patients have an LVEF >35%. Patients with an LVEF >35% also have low competing risks of death from nonsudden causes. Therefore, those at high risk of SCD may gain longevity from successful implantable cardioverter defibrillator therapy. We investigated whether late gadolinium enhancement (LGE) cardiovascular magnetic resonance identified patients with dilated cardiomyopathy without severe LV systolic dysfunction at high risk of SCD. Methods: We prospectively investigated the association between midwall LGE and the prespecified primary composite outcome of SCD or aborted SCD among consecutive referrals with dilated cardiomyopathy and an LVEF ≥40% to our center between January 2000 and December 2011 who did not have a preexisting indication for implantable cardioverter defibrillator implantation. Results: Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the prespecified end point, compared with 7 of 298 (2.3%) without (hazard ratio [HR], 9.2; 95% confidence interval [CI], 3.9–21.8; P<0.0001). Nine patients (8.9%) with LGE compared with 6 (2.0%) without (HR, 4.9; 95% CI, 1.8–13.5; P=0.002) died suddenly, whereas 10 patients (9.9%) with LGE compared with 1 patient (0.3%) without (HR, 34.8; 95% CI, 4.6–266.6; P<0.001) had aborted SCD. After adjustment, LGE predicted the composite end point (HR, 9.3; 95% CI, 3.9–22.3; P<0.0001), SCD (HR, 4.8; 95% CI, 1.7–13.8; P=0.003), and aborted SCD (HR, 35.9; 95% CI, 4.8–271.4; P<0.001). Estimated HRs for the primary end point for patients with an LGE extent of 0% to 2.5%, 2.5% to 5%, and >5% compared with those without LGE were 10.6 (95% CI, 3.9–29.4), 4.9 (95% CI, 1.3–18.9), and 11.8 (95% CI, 4.3–32.3), respectively. Conclusions: Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF ≥40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00930735.

Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in non-ischaemic dilated cardiomyopathy

Echocardiographic studies have shown that left atrial volume (LAV) predicts adverse outcome in small heart failure (HF) cohorts of mixed aetiology. However, the prognostic value of LAV in non‐ischaemic dilated cardiomyopathy (DCM) is unknown. Cardiovascular magnetic resonance (CMR) allows accurate and reproducible measurement of LAV. We sought to determine the long‐term prognostic significance of LAV assessed by CMR in DCM.

Right ventricular dysfunction is a predictor of non-response and clinical outcome following cardiac resynchronization therapy

BackgroundCardiac resynchronization therapy (CRT) is an established treatment in advanced heart failure (HF). However, an important subset does not derive a significant benefit. Despite an established predictive role in HF, the significance of right ventricular (RV) dysfunction in predicting clinical benefit from CRT remains unclear. We investigated the role of RV function, assessed by cardiovascular magnetic resonance (CMR), in predicting response to and major adverse clinical events in HF patients undergoing CRT.MethodsSixty consecutive patients were evaluated with CMR prior to CRT implantation in a tertiary cardiac centre. The primary end-point was a composite of death from any cause or unplanned hospitalization for a major cardiovascular event. The secondary end-point was response to therapy, defined as improvement in left ventricular ejection fraction ≥ 5% on echocardiography at one year.ResultsEighteen patients (30%) met the primary end-point over a median follow-up period of 26 months, and 27 out of 56 patients (48%) were considered responders to CRT. On time-to-event analysis, only atrial fibrillation (HR 2.6, 95% CI 1.02-6.84, p = 0.047) and RV dysfunction, either by a reduced right ventricular ejection fraction-RVEF (HR 0.96, 95% CI 0.94-0.99, p = 0.006) or tricuspid annular plane systolic excursion-TAPSE (HR 0.88, 95% CI, 0.80-0.96, p = 0.006), were significant predictors of adverse events. On logistic regression analysis, preserved RVEF (OR 1.05, 95% CI 1.01-1.09, p = 0.01) and myocardial scar burden (OR 0.90, 95% CI 0.83-0.96, p = 0.004) were the sole independent predictors of response to CRT. Patients with marked RV dysfunction (RVEF < 30%) had a particularly low response rate (18.2%) to CRT.ConclusionsRight ventricular function is an important predictor of both response to CRT and long-term clinical outcome. Routine assessment of the right ventricle should be considered in the evaluation of patients for CRT.

A reduction in total isovolumic time with cardiac resynchronisation therapy is a predictor of clinical outcomes

BACKGROUND Total isovolumic time (t-IVT) reflects left ventricular (LV) asynchrony (when the ventricle is neither ejecting nor filling). It is prolonged in left bundle branch block (LBBB). Cardiac resynchronisation therapy (CRT) is a treatment for patients with heart failure, reduced LV ejection fraction and LBBB. CRT shortens t-IVT, but the long-term clinical benefit of such reduction after CRT has not been studied in this patient group. METHODS Seventy-three patients who underwent CRT had t-IVT measured before and after CRT implantation. The study end-point was a composite of unplanned heart failure hospitalisation and all-cause mortality. RESULTS Baseline t-IVT showed considerable scatter: 30 patients had t-IVT values longer than 15s/min (upper 95% limit of normal). The change in t-IVT with CRT was also variable: t-IVT shortened in 50 patients (from 16.2 ± 4.8s/min to 11.7 ± 3.7s/min: group A), and lengthened in 23 patients (from 11.7 ± 4.2s/min to 14.5 ± 4.33 s/min: group B). The magnitude of change in t-IVT with CRT negatively correlated with baseline t-IVT (r=-0.619, p<0.001); thus t-IVT (significantly longer in group A than group B before CRT: 16.2 ± 4.8s/min vs. 11.7 ± 4.2s/min, p<0.001) became significantly shorter in group A compared to group B after CRT (11.7 ± 3.7s/min vs. 14.5 ± 4.3s/min, p=0.005). After follow-up of 30 months, 70% group A patients had event-free survival compared to 39% group B patients. The presence of any fall in t-IVT after CRT was an independent predictor of event-free survival. CONCLUSION T-IVT is a marker of global cardiac asynchrony that has predictive capacity on functional, symptomatic, and mortality endpoints in patients with advanced heart failure.

Cardiac resynchronization therapy for critically ill patients with left ventricular systolic dysfunction

BACKGROUND The experience of cardiac resynchronization therapy (CRT) in critically ill patients with cardiogenic shock or advanced heart failure is limited and inadequately described in literature. METHODS CRT implants performed in patients on the cardiothoracic intensive care unit (ICU) at a tertiary cardiac centre during 2007-2010 were retrospectively studied. RESULTS We identified 24 patients, 17 male, of median age 76 years (IQR 11) treated with a CRT pacemaker (n=10) or CRT defibrillator (n=14). Prior to implantation median left ventricular ejection fraction (LVEF) was 26% (IQR 13) and median QRS duration 146 ms (IQR 29). Eleven (46%) patients were post elective cardiac surgery and 8 (33%) post emergency cardiac surgery or intervention with high prevalence of co-morbidities. Nineteen patients required inotropic support pre-implantation, 8 patients were on mechanical circulatory support and 18 were on mechanical ventilation. Post CRT LVEF improved from 26% to 39% (p=0.027) and the estimated glomerular filtration rate increased from 42 ml/min/1.73 m(2) (IQR 26) to 63 ml/min/1.73 m(2) (IQR 48, p=0.001). All but one patient were successfully weaned from inotropic support within a median of 4 days (IQR 5) post CRT and 22/24 (92%) survived to hospital discharge. After a median follow up of 392 days (IQR 538), 7 (33%) patients died. In-hospital and one year mortality rates were 8.3% and 29.4% respectively. Ten out of 12 patients (83%) were alive at long-term (22 ± 9 months) follow up. CONCLUSIONS CRT may assist weaning from circulatory and respiratory support in critically ill patients with left ventricular systolic dysfunction.

Relation of dosing of the renin-angiotensin system inhibitors after cardiac resynchronization therapy to long-term prognosis.

Dosing of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with heart failure (HF) treated with cardiac resynchronization therapy (CRT) may affect long-term outcomes. Retrospective data were collected at baseline and follow-up for consecutive patients who had CRT implanted and attended the institutional specialist HF pacing clinic. The study end point was death from any cause or hospitalization for worsening HF 24 months after implantation. Ninety-one patients (72 men, 68 ± 12 years old) with decreased left ventricular ejection fraction (24 ± 6%) were included. At baseline 85 patients (93%) were on ACE inhibitors/ARBs. At 6 months 3 patients had died and 86 of 88 (98%) were on ACE inhibitors/ARBs. Doses were uptitrated from 55 ± 35% of target dose (TD) at baseline to 62 ± 31% TD at month 6 (p = 0.018), whereas blood pressure was unchanged. Patients treated with <50% TD of ACE inhibitors/ARBs (n = 20) at month 6 had worse 24-month event-free survival than those on 50% to 99% TD (n = 38, p = 0.011, log-rank test) or ≥100% TD (n = 30, p = 0.007, log-rank test). Failure to achieve a dose ≥50% TD of ACE inhibitors/ARBs at 6 months after CRT implantation was an independent predictor of all-cause mortality or hospitalization (hazard ratio 3.99, 95% confidence interval 1.66 to 9.62, p = 0.002) after adjustment for potential confounders including age, estimated glomerular filtration rate, diabetes and New York Heart Association class. In conclusion optimal dosing of ACE inhibitors/ARBs is an independent predictor of prognosis in patients with HF treated with CRT and it can be achieved by a structured follow-up within a specialized HF pacing clinic.

General Anesthesia Versus Sedation for Implantation of a Biventricular Pacing Device for Cardiac Resynchronization Therapy

OBJECTIVE Heart failure carries significant risk for major noncardiac surgery. Whether this risk is transferable to minor surgery is less well-documented. Thus, the aim of this study was to assess the outcome of a contemporary cohort of heart failure patients undergoing cardiac resynchronization therapy (CRT) device insertion under general anesthesia or sedation. DESIGN Retrospective observational study. SETTING Tertiary cardiac specialist hospital. PARTICIPANTS Heart failure patients. INTERVENTIONS CRT insertion under general anesthesia or sedation. MEASUREMENTS AND MAIN RESULTS Anesthesia, heart failure, and outcome data were collected on a consecutive series of patients having CRT device insertion between 2002 and 2010. A total of 242 patients were managed by the anesthesia department during the study period. After exclusion criteria were applied, data for 183 patients were analyzed. Immediate perioperative (<24 hours) mortality was zero; 30-day mortality of 138 patients was 2.2%. One patient (0.5%) required unplanned intensive care admission. A comparison was made between the sedation (n = 76) group and the general anesthesia (GA) group (n = 107). When compared with the sedation group, the GA group had more intraoperative hypotension (26.2% versus 4.0%, p<0.00001). There was no difference between the GA and sedation groups with regard to 30-day mortality (1.4% versus 3.1%, p = 0.57), unplanned intensive care admission (0% versus 1.3%, p = 0.42), and length of stay in days (3 versus 3, p = 0.82). CONCLUSION The authors found that patients with heart failure undergoing CRT insertion with concurrent general anesthesia or sedation had minimal immediate perioperative risk and that there was no difference in postoperative outcome between general anesthesia and sedation.

Ivabradine: A Current Overview

Ivabradine, acting on the funny channel (If) in the sino-atrial node, reduces myocardial oxygen demand without inducing hypotension. It was developed as a specific bradycardic agent in the 1980s, avoiding the adverse effects of more traditional antianginal agents (beta-blockers and calcium channel antagonists). This has seen significant interest in this first-in-class treatment, and is perceived as a promising drug in the management of ischaemic heart disease and heart failure. There has been much clinical research conducted exploring its role in these fields, to try to elucidate potential benefits and target patient group. The side effect profile of ivabradine ensures it is well tolerated, and consistently leads to a reduction in heart rate. This review discusses the drug development and trial data in ischaemic heart disease and chronic left ventricular systolic dysfunction. Key clinical trials and observational studies are discussed in depth to examine potential explanations of unexpected or diverging results. The emerging role of ivabradine in acute decompensated heart failure is explored with recent trial data, providing a potential novel treatment avenue in this difficult to manage patient cohort. The role of intravenous ivabradine, as a beneficial tool in the acute hospital setting, when oral medication is not ideal, or where fast onset of action is required, in cardiac computerised tomography for example, is also discussed. Future directions for research are highlighted, including options for further elucidating unexplained results from previous studies.