MODERATED POSTERS, SESSION 2, HRC 2011

Long QT3 mice have disrupted sympathovagal balance and in vivo ventricular stimulation does not determine risk of sudden cardiac death, suggesting that a second perturbation to increase vagal tone may be critical

Abstract

Introduction

Long QT 3 (LQT3) is a cause of sudden cardiac death (SCD) by Torsade de Pointes (TdP). Sudden cardiac death often occurs during sleep, rest, and bradycardia, suggesting that heightened parasympathetic tone provokes TdP. It is challenging to ascertain risk of SCD in these patients. We performed in vivo electrophysiological studies (EPS), ventricular tachycardia (VT) stimulation and telemetry in LQT3 (ΔKPQ) and wild type (WT) mice, without and with provocation with the muscarinic agonist, carbachol.

Methods and results

PS were performed in young (8-week) and old (≥6 months of age) anaesthetized mice with a 1.1F catheter inserted into the right atrium via the internal jugular vein. ECG and EP parameters were recorded. Ventricular tachycardia stimulation was attempted with 1–5 extrastimuli, coupled at 75–10 ms following a train of 8 beats at 100 ms. This was repeated after injection with 0.5 mg/kg carbachol.

Telemetry probes were inserted intra-abdominally into young (12-week old) and old (≥6 months of age) mice. After a 2-week recovery period, ECGs were recorded in conscious mice for 48 h and studied for VT and ventricular ectopics (VE). An ECG post-carbachol was analysed. Heart rate variability (HRV) was measured from 12 to 2 pm, when murine vagal tone is highest. ECG and EP parameters are presented (Table).

One young WT developed VT. Of the older mice, 1 WT had a VE pre- and post-carbachol and 1 ΔKPQ had a VE post-carbachol.

ΔKPQ mice had disrupted sympathovagal balance shown by normalized low (9.8 ± 3.6 vs. 53.2 ± 5.6 nu, P = 0.004) and high (12.2 ± 3.1 vs. 46.7 ± 5.6 nu, P = 0.004) frequency power. On examination of telemetry ECGs, 1 young ΔKPQ had 2 pauses (435 and 394 ms) and 1 old ΔKPQ had 3 pauses (316, 308 and 378 ms), but no pauses were seen in WT. No VT was found.

Conclusion

To our knowledge, this is the first report of in vivo EPS in the ΔKPQ mouse. Our results concur with human studies where VT stimulation is unhelpful in predicting risk of SCD.

Heart rate variability assessment showed disrupted symapthovagal balance, but an increase in vagal tone with carbachol did not induce VT. It is feasible that a second perturbation sustaining high vagal tone, for example, through increased inhibitory G-protein activity, is responsible for TdP and pre-disposition to SCD in LQT3 patients.

RGS 4 KO mice are pre-disposed to atrial fibrillation and show disrupted sympathovagal balance in vivo, making RGS 4 a potential novel therapeutic target for atrial fibrillation

Abstract

Introduction

The electrophysiological basis of atrial fibrillation (AF) is not understood. Acetylcholine from the vagus nerve binds to M2 muscarinic receptors causing dissociation of α-, β-, and γ-subunits of the inhibitory G-protein, activating G-protein gated inward rectifying potassium (GIRK) channels. The result is bradycardia, shortening of the APD and propensity for AF.

Gi2 is the predominant cardiac G-protein and RGS 4 terminates Gi2.

Methods and results

In vivo studies were performed in RGS 4 KO (KO) and wild type (WT) mice.

Electrophysiological studies (EPS) were undertaken in 8-week old anaesthetized mice with a 1.1F catheter inserted into the right atrium via the internal jugular vein. ECG and EP parameters were recorded. Atrial fibrillation induction was attempted with burst pacing for 25 s at 100 to 10 ms, and repeated after injection of 0.5 mg/kg carbachol.

Telemetry probes were inserted intra-abdominally into 12-week-old mice. After a two week recovery period, ECGs were recorded in conscious mice for 48 h and studied for AF and atrial ectopics (AE). An ECG post-carbachol injection was analysed. Heart rate variability (HRV) was measured from 12 to 2 pm, when murine vagal tone is highest. ECG and EP parameters were comparable (Table).

KO mice developed AF (76.9 vs. 38.5%, P = 0.04). Mean duration of AF for WT was 70.2 ± 29.8 (1.9–770) vs. 222.6 ± 164.9 (1–2867.4, P = 0.69) seconds for KO mice. Although this did not reach significance, there was a trend to a longer duration of AF in KO mice. Carbachol did not increase AF in KO or WT mice (P = 0.28), although a trend was apparent.

Conscious KO mice were tachycardic (634.3 ± 52.6 vs. 562.6 ± 36.3 bpm, P = 0.03), and had an enhanced bradycardic response to carbachol (288.2 ± 37.9 vs. 524.3 ± 24.2 bpm, P = 0.02). ECG and HRV parameters of WT and KO mice without and with carbachol were comparable (P > 0.05).

Carbachol-treated KO mice had disrupted HRV (P = 0.008) compared with KO mice alone. This was not seen with WT treated with carbachol (P > 0.05).

Carbachol-treated KO mice had several pauses, 2–7 AE, but no AF. Wild type mice treated with carbachol had a maximum of one AE. Without carbachol, no AE or AF was seen in KO or WT mice.

Conclusions

This is the first report of AF and HRV in the RGS 4 KO mouse in vivo. These develop AF, are tachycardic, have an increased bradycardic response to carbachol and disrupted HRV. This signifies altered sympathovagal balance.

Mechanistic studies are underway to understand the electrophysiological basis of AF in the RGS 4 KO mouse. RGS 4 is a potential therapeutic target in the treatment of AF.

Arrhythmic burden in families with hypertrophic cardiomyopathy related to Myosin binding protein C mutations

Abstract

Introduction

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition and mutations in sarcomeric protein gene mutations are found in ∼60% of affected individuals. Myosin binding protein C (MYBPC3) mutations are the most frequent and are supposedly associated with a relatively benign phenotype. Adverse events in HCM are frequently related to arrhythmias including atrial fibrillation (AF) and ventricular tachycardia (VT), yet the incidence of arrhythmic events in this important subgroup of HCM remains unknown. We sought to characterize the arrhythmic burden in a large cohort of individuals with HCM associated with a MYBPC3 mutation.

Methods and results

Index cases and their relatives were evaluated with clinical examination, electrocardiogram (ECG) and transthoracic Echo. Genetic status was determined using standard techniques. Group 1 consisted of all affected mutation carriers, while Group 2 consisted of all mutation carriers for whom long-term follow-up (>12 months) was available. Group 1 comprised 59 index cases and 39 affected mutation carriers identified during familial evaluation (58 male, mean age at diagnosis 42.1 ± 16.1 years). The prevalence of AF at baseline in this group was 4.7%. Group 2 comprised 67 mutations carriers (mean age at baseline 37.1 ± 16.4 years) followed for 7.9 ± 4.5 years. In Group 2, an episode of symptomatic AF requiring treatment (either paroxysmal or persistent) occurred in 15 (22%) individuals and a thromboembolic stroke occurred in 5 (7.5%), one of which was fatal. Those developing AF had greater LA diameter (47 ± 8 vs. 38 ± 7 mm, P = 0.0001) and more heart failure symptoms (33 vs. 6%, P = 0.002). The incidence of a documented episode of NSVT (≥3 beats at 120 beats per minute) was 4.3% during long-term follow-up. Those with NSVT had greater LA diameter (45 ± 7 vs .37 ± 7, P = 0.0001), greater maximal wall thickness (21 ± 5 vs. 16 ± 7 mm, P = 0.001) and more frequent heart failure symptoms (26 vs. 5%, P = 0.002). Thirteen (19.4%) individuals received an implantable cardioverter defibrillator (ICD—12 for primary prevention), and 1 (1.5%) survived a cardiac arrest. No appropriate ICD therapies (shocks or anti-tachycardia pacing) occurred during 78 patient years of follow-up. During long-term follow-up, 3 (4.5%) sudden deaths occurred with an annual individual risk of 0.57%.

Conclusions

Contrary to early reports of a benign phenotype, atrial, and ventricular arrhythmias are commonly seen in individuals with HCM related to MYBPC3 mutations. Atrial fibrillation causes significant morbidity and mortality (related to stroke and heart failure) in HCM and is difficult to manage. Non-sustained ventricular arrhythmias are also common, while the overall annual risk of sudden death is low and comparable to previously published cohorts of patients with other sarcomeric protein gene mutations.

Left ventricular pacing and the difference in acute haemodynamic response within individual branches of the coronary sinus

Abstract

Introduction

It is not clear whether there is a large difference in acute haemodynamic response (AHR) to left ventricular (LV) pacing in different regions of the same coronary sinus (CS) vein. A Quartet quadripolar LV pacing lead has three ring electrodes spaced 20, 30, and 47 mm from the distal tip electrode. Using the cathodal programmability of the Quartet lead, we aimed to evaluate the AHR to pacing along a significant length of individual branches of the CS.

Methods and results

An acute haemodynamic study was attempted in 20 patients using a RADI pressure wire placed in the LV cavity via a retrograde femoral arterial approach. In each patient, we assessed AHR in a number of CS veins and along a significant proportion of each CS branch using three different bipolar configurations (D1–M2, M3–M2, and M3–P4). We compared the AHR achieved when pacing DDDLV using each different vector and also the highest AHR achieved in any position within the same patient with the lowest achieved in that patient. All measurements were compared with baseline AAI or VVI (for AF cases) pacing at 5–10 bpm above intrinsic rate. The AV delay was fixed at 100 ms and baseline was repeated before and after any change in pacing modality to account for drift in patients' haemodynamic state during the procedure secondary to factors such as sedation levels and change in intravascular volume. Sixty-four different CS positions in 19 patients were successfully assessed. In one patient we were unable to cannulate the CS. No significant difference in AHR was found overall between the pairs D1–M2 and M3–M2 (n = 51, P = 0.78), M3–M2 and M3–P4 (n = 46, P = 0.80) or D1–M2 and M3–P4 (n = 46, P = 0.98). The mean percentage difference in AHR between the CS branch vectors with the lowest and highest dP/dt_max was +6.5 ± 5.4%. A much larger difference of +16.9 ± 6.1% was seen, however, when comparing the highest and lowest AHR achieved using any vector in any position within the same patient.

Conclusion

A small difference in AHR is seen when pacing within the same branch of the CS compared with pacing in different branches in the same patient. This suggests that although the site of LV lead placement is important, the position within a CS branch is less important than choosing the right vein. Thus although the Quartet lead has been shown to be capable of overcoming problems with phrenic nerve stimulation and high capture thresholds, problems with poor AHR probably cannot be overcome in most patients by simply changing the pacing configuration and will require physical repositioning of the lead in a different CS branch.

Benefits of endocardial and multi-site pacing are dependent on the left ventricular electrical activation pattern and presence of ischaemic heart disease: insights from electro-anatomical mapping

Abstract

Introduction

Smooth, homogeneous left ventricular (LV) activation from septum to lateral wall (Type I pattern) seen using non-contact mapping (NCM) has been associated with lower cardiac resynchronization therapy (CRT) response rates than a functional line of block within the LV myocardium (Type II). Endocardial LV and multi-site stimulation represent alternative approaches to increase CRT response rates. We sought to evaluate the relationship between heart failure aetiology (HFA), LV activation pattern and response to conventional vs. endocardial LV and multi-site pacing in CRT.

Methods and reults

Patients scheduled to undergo CRT were studied. Heart failure aetiology and presence of myocardial scar were evaluated using coronary angiography and late gadolinium enhancement cardiac MR (LGE-CMR). An invasive EP study and NCM procedure was performed. The acute haemodynamic response to CRT was assessed using a pressure wire in the LV cavity to derive real-time LV dP/dt max. Pacing was performed in the following modes: AAI, DDD BIV-CS (trans-venous CS in the postero-lateral vein), DDD LV EN (endocardial), DDD BIV EN (endocardial), and multi-site LV pacing DDD TRI-V (BIV-CS and LV EN simultaneously). Left ventricular endocardial stimulation was performed using a roving decapolar catheter passed retrogradely via the femoral artery; recordings were made at 3–5 LV endocardial sites per patient. The acute haemodynamic response resulting from LV pacing configuration was calculated as the percentage change from fixed rate atrial pacing (ΔLV dP/dt max). Positive acute haemodynamic response was pre-defined as ΔLV dP/dt max >10%.

Ten patients were studied. All were in SR with LBBB and in New York Heart Association III. 2 F:8 M, age 63 ± 12 years, three ischaemic (ICM): seven non-ischaemic (DCM) aetiology. Left ventricular ejection fraction 24 ± 6%, QRSd 161 ± 24 ms. Left ventricular dP/dt max with AAI pacing was 866 ± 213 mmHg/s. There was a 22% increase to 1052 ± 313 mmHg/s with BIV-CS pacing. With LV endocardial pacing there was a greater increase from baseline of 1159 ± 345 mmHg/s (34%) and this was similar to the response with BIV endocardial pacing of 1163 ± 350 mmHg/s. This increased further with TRI-V pacing: 40% increase from baseline to 1219 ± 397 mmHg/s (P < 0.05 for all LV endocardial modes vs. conventional CRT; P = 0.08 for TRI-V vs. other LV endocardial modes).

Response rates to conventional BIV-CS pacing were 71% for DCM and 33% for ICM; 80% of patients with Type II vs. 40 % for Type I activation pattern. Ninety per cent patients responded to LV endocardial pacing and 100% responded to multi-site pacing.

Conclusion

Type I activation was commoner in ICM and conferred lower response rates. This may relate to the level of conduction block within the His-Purkinje system. Endocardial LV pacing and multi-site LV pacing increased the magnitude of acute response to CRT and may be particularly useful in patients with ICM or Type I activation.

The electrophysiological characteristics of ventricular arrhythmias and their relation to cardiac phenotype in hypertrophic cardiomyopathy

Abstract

Background

The triggers of ventricular arrhythmias (VA) leading to sudden cardiac death in hypertrophic cardiomyopathy (HCM) are ill defined. We sought to examine the electrophysiological characteristics of VA in HCM and study their relation to cardiac phenotype using stored intracardiac electrocardiograms from implantable cardioverter defibrillators (ICD).

Methods and Results

In a single centre, observational cohort study of 230 consecutively evaluated ICD recipients (median age 42 years, 97% primary prevention, 51% with ATP therapy) 56 non-clustered VA (39 treated with ATP and 17 with shocks) from 29 patients were analysed. Monomorphic ventricular tachycardia was the culprit arrhythmia in 86% of cases, ventricular fibrillation/flutter in 9% and polymorphic ventricular tachycardia in 5%. Prior to the onset of VA the rhythm was sinus in 67%, atrial fibrillation/flutter in 19 and 15% were paced ventricularly; tachycardia (cycle length <600 ms) was present in 25%. Ventricular arrhythmias were triggered by premature ventricular complexes (PVC) in 72% which were late-coupled (84%) as shown in the figure below (arrow). Short-long-short initiation was seen in 2 and 26% of VA were sudden-onset. Ventricular arrhythmias peaked at midday (with 20% occurring between 2300 and 0700), on Sundays and in May. The cardiac phenotype and time of the day did not predict the mode of initiation. Age at ICD implantation was the only independent predictor of VA cycle length (linear regression coefficient 0.67, 95% CI 0.02 to 1.32, P = 0.04). ATP terminated 67% of VA, but patients with ATP therapy had a similar incidence of appropriate shocks (log rank test P = 0.25) and syncope (log rank P = 0.23) to patients with VF zone only.

Conclusions

Most VAs are monomorphic ventricular tachycardias triggered by late-coupled PVCs. They are frequently terminated by ATP, but ATP does not reduce the frequency of ICD shocks. Younger HCM patients have more rapid VA, which may explain the peak of sudden cardiac death in early adulthood. The circadian periodicity is different from that observed in ischaemic heart disease, and is likely to relate to the distinct character of the arrhythmogenic substrate in HCM and its modulators.

Dynamic conduction and repolarization changes can help distinguish between arrhythmic right ventricular cardiomyopathy and benign right ventricular outflow tract tachycardia

Abstract

Introduction

Early arrhythmogenic right ventricular cardiomyopathy (ARVC) can appear clinically similar to benign focal RV outflow tract tachycardia/ectopy (RVOTT). We hypothesized that dynamic conduction and repolarization interactions within the right ventricle could be used to distinguish between ARVC and RVOTT.

Methods and results

Twenty-four patients (pts) with early manifestations of ARVC (minimial structural heart disease who fulfilled the familial/modified task force diagnostic criteria), underwent non-contact mapping of the right ventricle during a S1S2 pacing protocol. These were compared with 30 control pts (9 SVT, 21 RVOTT with normal hearts and >1 year follow-up without recurrence of VT following ablation). Activation and repolarization times during restitution curves were derived from 24 global sites per pt using semi-automated custom software. Fractionation was quantified as the number of deflections above a preset signal-to-noise threshold of the >30 Hz component of 1st differential of virtual unipolar electrograms. During steady-state pacing, no difference in activation recovery index (ARI) (198 ± 1 vs. 198 ± 1 ms), effective refractory period (ERP; 209 ± 4 vs. 213 ± 4 ms), or dispersion of repolarization (80 ± 25 vs. 84 ± 19 ms) existed between ARVC and control groups. The increase in conduction delay at ERP compared with steady state was raised in ARVC patients (43 ± 3 vs. 30 ± 3 ms, P = 0.01). Dispersion of repolarization increased at ERP to a maximum of 120 ± 26 ms in ARVC pts vs. 94 ± 29 ms in controls (P = 0.0012, Figure 1). A cut-off of measured dispersion of repolarization at 94 ms gave an 87% sensitivity and 58% specificity for ARVC diagnosis. EGMs were more fractionated in the outflow tract of ARVC patients, with a mean number of complex deflections per electrogram of 3.90 ± 0.05 vs. 3.50 ± 0.05 (P = 0.0001) in steady state, increasing to 4.13 ± 0.11 vs. 3.54 ± 0.08 at ERP (P < 0.0001). No sustained ventricular arrhythmias were induced during the pacing protocol in any of the ARVC pts.

Conclusion

Patients with early ARVC demonstrate increased dispersion of repolarization and degree of conduction delay, with more fractionation pre-ERP. Dynamic changes in conduction, repolarization, and electrogram morphology may aid earlier diagnosis of ARVC in patients with outflow tract ectopy.

Characteristics of eligible patients who are not referred for cardiac resynchronization therapy

Abstract

Introduction

Provision of cardiac resynchronization therapy (CRT) in the UK has lagged behind most of Western Europe and the USA for some years. Reasons for this may include failure to recognize and refer eligible patients. We examined simple demographics of patients eligible for CRT at our institution to see how these might influence referral patterns.

Methods and results

Patients with a discharge code for heart failure (either primary or co-existent condition) were identified over a 1-year period between May 2009 and April 2010. Electronic medical records and paper casenotes were reviewed and patients with documented assessment of left ventricular (LV) function were identified. Symptoms and ECG data were collected from patients with LVEF ≤35%. Patients with current or recent NYHA class III or IV symptoms, in sinus rhythm with QRS ≥120 ms were deemed potentially eligible for CRT. It was noted whether or not patients were under the care of a cardiologist. Demographics of eligible patients referred for CRT were compared with those of patients not referred using Student's t-test and χ².

A total of 1349 adult patients had discharge code for heart failure, 236 with LVEF ≤35%. Of 163 patients in sinus rhythm, 100 had QRS ≥120 ms. Eighteen patients were deemed ineligible for CRT due to NYHA class II or co-morbidities. Characteristics of 82 patients who were eligible for CRT are shown in Table 1. Data are presented as mean (SD) or n (%).

Conclusions

Among patients eligible for CRT, referral is more likely among patients who are younger, male, and with broader QRS. The findings suggest that older patients not under care of a cardiologist and those with lesser degree of bundle branch block may potentially be overlooked for appropriate treatment.