Cardiac resynchronization therapy: results,challenges and perspectives for the future

Abstract

Heart failure (HF) is considered as an epidemic and affects 2% of the population in the Western world. About 15–30% of patients with HF and reduced ejection fraction (HFrEF) also have prolonged QRS duration on the surface ECG, most commonly as a result of left-bundle branch block (LBBB). Increased QRS duration is a marker of a dyssynchronous activation, and subsequent contraction, pattern in the left ventricle (LV). When dyssynchrony is superimposed on the failing heart it further reduced systolic function and ultimately worsens outcome. During the past 15 years several randomized controlled clinical trials have documented that resynchronization of the dyssynchronous failing heart with a biventricular pacemaker – cardiac resynchronization therapy (CRT) – which can restore a more synchronous activation and contraction pattern. This translates in halted or reversed disease progression and improved clinical outcome, including reduced mortality.

In this review, we will discuss several aspects of CRT including mechanisms of dyssynchrony and resynchronization in the failing heart, evidence of CRT efficacy derived from clinical trials and current challenges in CRT including patient selection and optimization of therapy delivery. Last, we will discuss future perspectives including the role of CRT to prevent adverse events in patients with an indication for antibradycardia pacing, the role of leadless pacing in the CRT setting as well as a new clinical arena where dyssynchrony and resynchronization may be important.     

Heart rate and dyssynchrony in patients with cardiac resynchronization therapy: a pilot study

Objectives: The objective of this pilot study was to describe the impact of paced heart rate on left ventricular (LV) mechanical dyssynchrony in synchronous compared to dyssynchronous pacing modes in patients with heart failure.

Methods: Echocardiography was performed in 14 cardiac resynchronization therapy (CRT) patients at paced heart rates of 70 and 90 bpm in synchronous- (CRT), and dyssynchronous (atrial pacing?+?wide QRS activation) pacing modes. LV dyssynchrony was quantified using the 12-segment standard deviation model (Ts-SD) derived from Tissue Doppler Imaging. In addition, cardiac cycle intervals were assessed using cardiac state diagrams and stroke volume (SV) and filling pressure were estimated.

Results: Ts-SD decreased significantly with CRT at 90 bpm (25?±?12?ms) compared to 70 bpm (35?±?15?ms, p?=?.01), but remained unchanged with atrial pacing at different paced heart rates (p?=?.96). The paced heart rate dependent reduction in Ts-SD was consistent when Ts-SD was indexed to average Ts and systolic time interval. Cardiac state diagram derived analysis of cardiac cycle intervals demonstrated a significant reduction of the pre-ejection interval and an increase in diastole with CRT compared to atrial pacing. SV was maintained at the higher paced heart rate with CRT pacing but decreased with atrial pacing.

Discussion: Due to the small sample size in this pilot study general and firm conclusions are difficult to render. However, the data suggest that pacing at higher heart rates acutely reduces remaining LV dyssynchrony during CRT, but not during atrial pacing with dyssynchronous ventricular activation. These results need confirmation in a larger patient cohort.     

Combined electrical and global markers of dyssynchrony predict clinical response to Cardiac Resynchronization Therapy

Aim. To assess potential additional value of global left ventricular (LV) dyssynchrony markers in predicting cardiac resynchronization therapy (CRT) response in heart failure (HF) patients. Methods. We included 103 HF patients (mean age 67 ± 12 years, 83% male) who fulfilled the guidelines criteria for CRT treatment. All patients had undergone full clinical assessment, NT-proBNP and echocardiographic examination. Global LV dyssynchrony was assessed using total isovolumic time (t-IVT) and Tei index. On the basis of reduction in the NYHA class after CRT, patients were divided into responders and non-responders. Results. Prolonged t-IVT [0.878 (range, 0.802–0.962), p = 0.005], long QRS duration [0.978 (range, 0.960–0.996), p = 0.02] and high tricuspid regurgitation pressure drop [1.047 (range, 1.001–1.096), p = 0.046] independently predicted response to CRT. A t-IVT ≥ 11.6 s/min was 67% sensitive and 62% specific (AUC 0.69, p = 0.001) in predicting CRT response. Respective values for a QRS ≥ 151 ms were 66% and 62% (AUC 0.65, p = 0.01). Combining the two variables had higher specificity (88%) in predicting CRT response. In atrial fibrillation (AF) patients, only prolonged t-IVT [0.690 (range, 0.509–0.937), p = 0.03] independently predicted CRT response. Conclusion. Combining prolonged t-IVT and the conventionally used broad QRS duration has a significantly higher specificity in identifying patients likely to respond to CRT. Moreover, in AF patients, only prolonged t-IVT independently predicted CRT response.     

A Post hoc analysis on rhythm and high intensity interval training in cardiac resynchronization therapy

Objectives. Evaluate the effects of a 6-month High Intensity Interval Training (HIIT) program on (1) functional capacity and health-related quality of life, (2) multiple blood biomarkers, (3) echocardiographic parameters, and (4) exercise performance, in patients in cardiac resynchronization therapy (CRT) stratified by the presence of atrial fibrillation (AF), targeting the following questions: (1) Does CRT provide similar benefits in patients in AF and sinus rhythm (SR)?; and (2) Does HIIT provides similar benefits in patients in AF and SR? Design. Estimates were available at baseline and 6 months after CRT implantation in 37 patients with heart failure. Patients were randomized after CRT to a 24-week HIIT group or to a usual care group (CON). In this sub-analysis, HIIT (AF = 7; SR = 11) and CON (AF = 9; SR = 10) were stratified by the presence of AF. Results. Patients in AF benefitted to a lesser degree from CRT in functional status than patients in SR (23.8–46.0%). However, HIIT induced superior improvements in patients in AF compared to CON (23.9–61.0%). Decreases in TNF-α (8.5–42.9%), BNP (15.3–34.6%) and left ventricular mass (9.6–26.2%) were only observed in patients in SR, whereas increases in peak oxygen uptake were only observed in patients in AF (19.5–23.2%). HIIT improved exercise capacity (8.8–59.4%) in patients in SR. Conclusions. Patients in AF or SR undergoing CRT demonstrated distinct benefits from device implantation and from HIIT as an adjunctive therapeutic strategy. This suggests that both mainstay and adjunctive therapeutics may need to be managed differently in patients in AF and SR.     

Effect of biventricular pacing therapy in patients with dilated cardiomyopathy with severe congestive heart failure

Objectives: Biventricular pacing (BVP) therapy has recently emerged as an effective treatment for patients with moderate to severe congestive heart failure (CHF) and ventricular asynchrony all over the world. However, this therapy is not yet available in Japan. We evaluated the effects of BVP in patients with severe CHF due to dilated cardiomyopathy (DCM). Subjects: Four patients with medically refractory severe CHF due to DCM in New York Heart Association functional class III or IV heart failure underwent BVP therapy. We combined the implantation of the left ventricular (LV) epicardial lead via small thoracotomy following right atrial and ventricular intravenous leads under general anesthesia. We evaluated to determine whether improvements of ventricular function, ventricular size, mitral regurgitation, functional status, frequency of hospitalization, and quality of life were associated with BVP therapy. Results: BVP improved LV systolic function, decreased LV size and mitral regurgitation, and shortened prolonged QRS interval. The patients’ symptoms, exercise tolerance, frequency of hospitalization, and quality of life were also dramatically improved by BVP. Furthermore, combination of BVP and oral administration of amiodarone significantly prevented recurrence of ventricular tachycardia and paroxysmal atrial fibrillation, and maintained sinus rhythm for a long period. Conclusions: In view of these findings, BVP therapy may contribute to the development of new therapeutic method for patients with severe CHF due to DCM.     

Atrial high-rate episodes predict clinical outcome in patients with cardiac resynchronization therapy

Objectives. Up to 50% of patients qualified for cardiac resynchronization therapy (CRT) have documented atrial fibrillation (AF) prior to CRT-implantation. This finding is associated with worse prognosis but few studies have evaluated the importance of post-implant device-detected AF. This study aimed to assess the prognostic impact of device-detected atrial high-rate episodes (AHRE), as a surrogate for AF. Design. Data were retrospectively obtained from consecutive patients receiving CRT. Baseline clinical data and data from CRT device-interrogations, performed at a median of 12.2 months after CRT-implantation, were evaluated with regard to prediction of the composite endpoint of death, heart transplant or appropriate shock therapy. Median follow-up time was 51 months post-implant. Results. The study included 377 patients. Preoperative AF was present in 49% and associated with worse outcome. The cumulative burden of AHRE at 12 months post-implant was an independent predictor of the primary endpoint. During the first 12 months after CRT-implantation, AHRE were detected in 25% of the patients with no preoperative diagnosis of AF. This finding was not associated with worse outcome. Conclusions. In CRT recipients, the cumulative burden of AHRE during the first year of follow-up was associated with worse long-term clinical outcome. Prospective trials are needed to determine if a rhythm control strategy is to be preferred in patients with CRT.     

扩张型心肌病心脏再同步化治疗的术中配合与并发症护理

对7例扩张型心肌病患者行心脏再同步化治疗,术中与医生密切的配合与病情观察,严密监测起搏器性能,进行心电监护,预防切口囊袋感染,避免膈神经刺激及电极移位,防止气胸,血性心包的并发症发生。结果本组病例均安全度过围手术期,无并发症发生,起搏功能良好,心衰症状明显改善,生活质量提高。     

Coronary sinus cannulation with a steerable catheter during biventricular device implantation

Objectives. To determine whether a steerable catheter with electrogram guidance (CS-assist group) could facilitate access to the coronary sinus (CS) during cardiac resynchronization therapy (CRT) implantation. Design. Consecutive patients who underwent CRT implantation were recruited prospectively into the CS-assist group (n = 81) and compared with those using conventional techniques without an electrogram guidance (conventional group, n = 101). Results. The CS cannulation success rate was clearly greater in the CS-assist group (100%) than that in the conventional group (95%, p < 0.05), with significantly shorter mean procedure time (52.6 ± 20.6 min vs. 73.2 ± 40.9 min, p < 0.01) and fluoroscopy time (3.6 ± 3.2 min vs. 14.2 ± 20.4 min, p < 0.01). In the five CS cannulation failure cases, mean procedure time (144.0 ± 37.0 min) and fluoroscopy time (57.8 ± 24.8 min) were significantly longer than those in the other patients (61.2 ± 32.3 and 8.2 ± 13.6 min, respectively, n = 177, both p < 0.01). Conclusions. Using the steerable catheter with real-time electrogram guidance, location of and access to the CS is more rapid and successful, which may improve the success of the CRT implantation and may give significant time savings.     

Declining Coronary Heart Disease Mortality in Iceland: Contribution by Incidence,Recurrence and Case Fatality Rate

Objective : To analyse to what extent the recent decline in coronary heart disease mortality in Iceland is due to changes in incidence, recurrence and case fatality rates. Design : A countrywide registration of myocardial infarction (MI) in people aged 25-74 was performed in Iceland during 1981-1999 according to the MONICA protocol. Possible cases were found by review of all hospital discharge records, autopsy records and death certificates. Results : MI death rate declined by 63% in males and 51% in females, most in the youngest age groups in men (86%) and least in the oldest (49%). In women there was not a significant difference in age groups. Overall the age-adjusted reduction in MI death rate was 55.4% in both sexes combined; of this 23.1% was due to incidence reduction, 22.8% to recurrence reduction and 11.6% to case fatality reduction. In the youngest age groups the decline in incidence contributed most to the decline in MI death rate (62% in men and 71% in women), but thereafter the decline in case fatality in men. In the older age groups decline in recurrence rate has greater weight. Conclusion : The recent decline in MI mortality under the age of 75 years in Iceland is due to reduction in incidence and recurrence rate by about 40% each and to reduction in case fatality by 20%.     

Effect of long-term remote ischemic conditioning on inflammation and cardiac remodeling

Background. Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischemic heart failure (CIHF). Methods. Prespecified post-hoc analysis of a prospective, exploratory and outcome-assessor blinded study. Twenty-one patients with compensated CIHF and 21 matched controls without heart failure or ischemic heart disease were treated with RIC once daily for 28?±?4 days. RIC was conducted as 4 cycles of 5?minutes upper arm ischemia followed by 5?minutes of reperfusion. We evaluated circulating markers of inflammation and cardiac remodeling at baseline and following long-term RIC. Results. RIC reduced C-reactive protein from 1.5 (0.6–2.5) to 1.3 (0.6–2.1) mg/l following long-term RIC treatment (p?=?.02) and calprotectin from 477 (95% CI 380 to 600) to 434 (95% CI 354 to 533) ng/ml (p?=?.03) in patients with CIHF, but not in matched controls. Overall, RIC did not affect circulating markers related to adaptive or innate immunology or cardiac remodeling in patients with CIHF. Among patients with CIHF and N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels above the geometric mean of 372?ng/l, long-term RIC treatment reduced soluble ST2 (n?=?9) from 22.0?±?3.7 to 20.3?±?3.9?ng/ml following long-term RIC treatment (p?=?.01). Conclusion. Our findings suggest that long-term RIC treatment has mild anti-inflammatory effects in patients with compensated CIHF and anti-remodeling effects in those with increased NT-proBNP levels. This should be further investigated in a randomized sham-controlled trial.     

Impact of cardiac arrest resuscitated donors on heart transplant recipients' outcome

Objective

To evaluate the influence of cardiac arrest?resuscitated donors (CARDs) on the outcome of heart recipients.

End-stage renal failure and cardiac mortality after heart transplantation

BACKGROUND: Coronary artery disease (CAD) is the leading cause of mortality after the first year of heart transplantation. End-stage renal failure (ESRF) is more frequent because of long-term survival. Impact of ESRF on cardiac mortality in heart transplant patients is unappreciated. The hypothesis of accelerated CAD in uremic patients has been suggested. METHODS: In Pitié La Salpêtrière hospital, 1211 heart transplants have been performed between 1982 and 2001. Thirty-three patients have reached ESRF. A case-control study was performed to identify risk factors responsible for ESRF and to appreciate the impact of ESRF on cardiac mortality. RESULTS: In cases at 6 months, serum creatinine tended to be higher (159 +/- 31 micromol/L vs. 141 +/- 44 micromol/L, p = 0.06) and cyclosporine (CSA) dosage (mg/kg) was significantly lower (5.4 +/- 1.8 mg/kg vs. 7.7 +/- 2.7 mg/ kg, p = 0.002). Mean triglyceride level after transplantation until dialysis was significantly lower in cases (2.18 +/- 0.82 mmol/L vs. 1.48 +/- 0.62 mmol/L, p = 0.002). In cases and controls, cardiac mortality was responsible for 67% (10 of 15) and 38% (three of eight) of all deaths, respectively. High triglyceride level (> or = 2 mmol/L) was associated with cardiac mortality [p < 0.03, hazard ratio (HR) = 3.89]. Kaplan Meier cardiac free survival rates were significantly lower in cases than in controls (p < 0.03). CONCLUSION: These data suggest that CSA nephrotoxicity could result from individually determined susceptibility and that hypertriglyceridemia may have a negative impact on renal function and cardiac mortality. The risk of cardiac mortality is increased in heart transplant patients with ESRF. The hypothesis of accelerated atherosclerosis in ESRF patients after heart transplantation leading to higher cardiac mortality incidence needs further study.     

心内科老年患者院内心源性猝死临床病因分析

目的探讨心内科老年患者发生院内心源性猝死的临床原因,便于指导临床干预。方法回顾性分析我院2006年8月～2013年9月心内科住院老年患者48例,分析患者发生心源性猝死的临床病因及时间过程。结果48例心内科老年患者出现院内心源性猝死的临床病因主要有冠心病17例（35．42％）、扩张型心肌病7例（14．58％）、高血压性心脏病6例（12．50％）及风湿性心脏病5例（10．42％）。患者心源性猝死主要发生于病情恶化6h以内,约45例（93．75％）。结论冠心病、扩张型心肌病、高血压性心脏病以及风湿性心脏病患者容易出现院内心源性猝死,患者往往在病情恶化后6h内死亡,需要密切关注该类住院患者的病情进展,并进行有效监护和及时抢救。