In chronic systolic heart failure and conduction system disease, cardiac resynchronization therapy (CRT) is the only known non-pharmacologic heart failure therapy that improves cardiac function, functional capacity, and survival while decreasing cardiac workload and hospitalization rates. While conventional bi-ventricular pacing has been shown to benefit patients with heart failure and conduction system disease, there are limitations to its therapeutic success, resulting in widely variable clinical response. Limitations of conventional CRT evolve around myocardial scar, fibrosis, and inability to effectively simulate diseased tissue. Studies have shown endocardial stimulation in closer proximity to the specialized conduction system is more effective when compared with epicardial stimulation. Several observational and acute haemodynamic studies have demonstrated improved electrical resynchronization and echocardiographic response with conduction system pacing (CSP). Our objective is to provide a systematic review of the evolution of CRT, and an introduction to CSP as an intriguing, though experimental physiologic alternative to conventional CRT.

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BackgroundIbrutinib is a tyrosine kinase inhibitor most commonly associated with atrial fibrillation. However, additional cardiotoxicities have been identified, including accelerated hypertension. The incidence and risk factors of new or worsening hypertension following ibrutinib treatment are not as well known.MethodsWe conducted a retrospective study of 144 patients diagnosed with B cell malignancies treated with ibrutinib (n=93) versus conventional chemoimmunotherapy (n=51) and evaluated their effects on blood pressure at 1, 2, 3 and 6 months after treatment initiation. Descriptive statistics were used to compare baseline characteristics for each treatment group. Fisher’s exact test was used to identify covariates significantly associated with the development of hypertension. Repeated measures analyses were conducted to analyse longitudinal blood pressure changes.ResultsBoth treatments had similar prevalence of baseline hypertension at 63.4% and 66.7%, respectively. There were no differences between treatments by age, sex and baseline cardiac comorbidities. Both systolic and diastolic blood pressure significantly increased over time with ibrutinib compared with baseline, whereas conventional chemoimmunotherapy was not associated with significant changes in blood pressure. Baseline hypertensive status did not affect the degree of blood pressure change over time. A significant increase in systolic blood pressure (defined as more than 10 mm Hg) was noted for ibrutinib (36.6%) compared with conventional chemoimmunotherapy (7.9%) at 1 month after treatment initiation. Despite being hypertensive at follow-up, 61.2% of patients who were treated with ibrutinib did not receive adequate blood pressure management (increase or addition of blood pressure medications). Within the ibrutinib group, of patients who developed more than 20 mm Hg increase in systolic blood pressure, only 52.9% had hypertension management changes.ConclusionsIbrutinib is associated with the development of hypertension and worsening of blood pressure. Cardiologists and oncologists must be aware of this cardiotoxicity to allow timely management of blood pressure elevations.

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Although ibrutinib-associated atrial and ventricular arrhythmias have been well described, there is little information about ibrutinib’s effects on other electrocardiographic parameters, particularly the QT interval. Using our database of 137 patients treated with ibrutinib, we retrospectively identified 21 patients in whom an electrocardiogram (ECG) was obtained both prior to and after ibrutinib exposure. All traditional ECG parameters as well as QT dispersion were manually measured by an electrophysiologist. Compared to baseline ECGs, post ibrutinib ECGs demonstrated QT interval shortening from 386 ms to 356 ms ( P = .007), corrected QT interval shortening using Bazett’s formula from 446 ms to 437 ms ( P = .04), and corrected QT interval shortening using Fridericia’s formula from 425 ms to 407 ms ( P = .003). QT dispersion also increased post ibrutinib exposure compared to baseline (39.8 ms vs 57.3 ms, P = .002). There was no significant change in other ECG parameters. In conclusion, both the absolute and corrected QT intervals significantly shortened after ibrutinib exposure, while there was a significant increase in QT dispersion. These findings may point to a common underlying electrophysiologic mechanism of ibrutinib-associated arrhythmias.

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Background - The formation of recipient-to donor atrio-atrial connections (AAC) in patients after orthotopic heart transplantation (OHT) is poorly understood. We sought to investigate the mechanisms of atrial tachyarrhythmias after OHT, the role of AACs, and their relationship to the immunological match. Methods - In a large series of OHT patients we performed a retrospective review of 42 patients who underwent catheter ablation for atrial arrhythmias. A realistic 3D computer model of human atria was used to study AAC conductivity. Results - Patient age was 55±15 years (71% male). 24/42 patients (57%) had bi-atrial anastomosis. An AAC was found in 9/42 patients (21%, right-sided in 5 patients with bi-atrial anastomosis, left-sided in 4 patients). The AAC became apparent at the time of the electrophysiology study 10.1±7.6 years after OHT (range 0.3-22.2 years). Donor-specific antibodies (DSAB) were present in no patient with AAC, but were present in 69% of patients without AAC, p=0.002. In all patients with AAC, a recipient atrial tachycardia propagated via AAC to the donor atrium (4 patients presented with atrial fibrillation). Simulations showed AAC conduction requires an isthmus of ≥2 mm and is cycle length (CL) and location dependent. Patients without AAC (n=13) frequently presented with donor atrial arrhythmias, in 77% cavo-tricuspid isthmus (CTI) flutter was ablated. The procedural success was high, although, 12 patients (29%) required re-ablation. Conclusions - AACs are found in 21% of OHT patients with atrial tachyarrhythmias and can manifest very early after OHT. Immune privilege characterized by the absence of DSAB may facilitate AAC formation. Propagation across an AAC is width, CL and location dependent. Patients with AAC present with focal atrial tachycardias or atrial fibrillation originating from the recipient atria; patients without most frequently present with CTI dependent atrial flutter. While multiple arrhythmias frequently require re-ablation, ablative therapy is highly effective.

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