Kevin Vernooy

Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block

OBJECTIVES We sought to investigate to what extent intra-ventricular asynchrony (intraVA) and inter-ventricular asynchrony (interVA) determine left ventricular (LV) function in canine hearts with left bundle branch block (LBBB) during ventricular pacing. BACKGROUND Pacing therapy improves LV pump function in patients with heart failure and abnormal ventricular conduction supposedly due to resynchronization. However, the relationship between LV pump function and measures of asynchrony is not well established. METHODS In 15 experiments, LV (various sites) and biventricular (BiV) pacing was performed at atrioventricular (AV) delays of 20 to 140 ms. Measured were the maximum rate of increase (dP/dt(max)) of LV pressure and LV stroke work (SW) (conductance catheter), interVA (time delay between the upslope of LV and RV pressures), and intraVA (from endocardial electrical activation maps). RESULTS Induction of LBBB increased interVA (-6.4 +/- 8.6 to -28.4 +/- 8.5 ms [RV earlier]) and intraVA (4.9 +/- 2.4 to 18.0 +/- 3.3 ms), whereas LV dP/dt(max) and SW decreased (-13 +/- 18% and -39 +/- 24%, respectively). During LBBB, LV and BiV pacing increased LV dP/dt(max) and SW (mean increases 14% to 21% and 11% to 15%, respectively) without changing diastolic function or preload. Optimal improvement in LV function was obtained consistently when intraVA returned to pre-LBBB values, while interVA remained elevated. Normalization of intraVA required AV delays shorter than the baseline PQ time during LV apex and BiV pacing, thus excluding endogenous LV activation, but AV delays virtually equal to the baseline PQ time (difference 4 +/- 9 ms, p = NS) during pacing at (mid)lateral LV sites to obtain fusion between pacing-induced and endogenous activation. CONCLUSIONS In LBBB hearts, optimal restoration of LV systolic function by pacing requires intra-ventricular resynchronization. The optimal AV delay to achieve this depends on both the site of pacing and baseline PQ time.

Induced Brugada-type electrocardiogram, a sign for imminent malignant arrhythmias.

Case presentation: A previously healthy 20-year-old man arrives at the emergency department for a consultation for mild fever. During his initial interview, he complains of palpitations to the triage nurse and therefore he undergoes an ECG, which is placed in the chart. A few minutes later, while awaiting his turn to be seen, he goes into cardiac arrest. The patient does not respond to resuscitation and dies in the emergency department. The autopsy reveals no cardiac structural abnormalities or evidence of myocarditis. The cause of death is determined as sudden unexplained cardiac death. The ECG from the emergency department revealed ST-segment elevation in the right precordial leads consistent with a Brugada ECG pattern. The Brugada syndrome is a heterogeneous genetic disease that predisposes to life-threatening ventricular tachyarrhythmias and sudden cardiac death (SCD). The syndrome is usually identified by a characteristic Brugada-type ECG that consists of ST elevation of a coved type in the precordial leads V1 to V3, although affected individuals may have a normal ECG.1,2 Because patients with Brugada syndrome usually become symptomatic at a relatively young age, early diagnosis is crucial to prevent SCD in those with a higher risk of developing an arrhythmic event.3 Approximately one fourth of the cases of Brugada syndrome are caused by loss of function mutations in the cardiac sodium channel SCN5A. Several nongenetic factors have been mentioned in the literature as possible inductors of the ECG pattern resembling Brugada syndrome.2 As such, a Brugada-type ECG may appear in some patients during febrile states …

Cardiac resynchronization: Insight from experimental and computational models

Cardiac resynchronization therapy (CRT) is a promising therapy for heart failure patients with a conduction disturbance, such as left bundle branch block. The aim of CRT is to resynchronize contraction between and within ventricles. However, about 30% of patients do not respond to this therapy. Therefore, a better understanding is needed for the relation between electrical and mechanical activation. In this paper, we focus on to what extent animal experiments and mathematical models can help in order to understand the pathophysiology of asynchrony to further improve CRT.

Beneficial effects of biventricular pacing in chronically right ventricular paced patients with mild cardiomyopathy

AIMS To investigate whether cardiac resynchronization therapy (CRT) by means of biventricular (BiV) pacing can improve left ventricular (LV) function, remodelling and clinical status in chronically right ventricular (RV) paced patients with mild cardiomyopathy. METHODS AND RESULTS Thirty-six chronically (10 +/- 7 years) RV paced patients with left ventricular ejection fraction (LVEF) < 40% or LVEDD > 55 mm, without an established indication for CRT, were subjected to 6 months RV and BiV pacing in a patient-blinded, randomized crossover design. Treatment-effects of BiV pacing were evaluated for LV function, LV remodelling and clinical status. As compared with RV pacing, BiV pacing significantly improved LV function (LVEF 46 +/- 12 vs. 39 +/- 12% and LVFS 24 +/- 7 vs. 21 +/- 7%) and reduced LV end-diastolic and end-systolic diameters and volumes (LVEDD 56 +/- 8 vs. 59 +/- 8 mm, LVESD 43 +/- 8 vs. 47 +/- 9 mm, LVEDV 132 +/- 65 vs.144 +/- 62 mL and LVESV 77 +/- 56 vs. 92 +/- 55 mL, respectively). In 19 patients (53%) response to BiV pacing was clinically relevant, defined as LVESV reduction >15%. BiV pacing also significantly improved NYHA classification. CONCLUSION BiV pacing following chronic RV pacing may improve LV function and reverse LV remodelling in patients with relatively mild LV dysfunction or remodelling. Hence, upgrade to BiV pacing might be considered in chronically RV paced patients with mild cardiomyopathy.

Cardiac Resynchronization Therapy State-of-the-Art of Current Applications, Guidelines, Ongoing Trials, and Areas of Controversy

More than 2 decades of research has established the role of cardiac resynchronization therapy (CRT) in medically refractory, mild to severe systolic heart failure (HF) with abnormal QRS duration and morphology. CRT confers a mortality benefit, reduces HF hospitalizations, and improves functional outcome in this population, but not all patients consistently demonstrate a positive CRT response. The reported nonresponder rate ranges between 20% and 40%, depending on the response criteria used.1 Efforts to improve response to CRT have focused on methods to optimize the correction of electrical and mechanical dyssynchrony (the primary target of CRT) and on improving patient selection and optimizing postimplant care. The present article reviews the state-of-the-art of CRT and discusses developments on potential promises and areas of controversy. Although CRT became common clinical practice >10 years ago, the last 2–3 years have shown a series of large clinical trials that clearly outlined the categories of patients that benefit of CRT. First of all, 3 landmark studies—REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE),2 Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT)3 and Resynchronization for Ambulatory Heart Failure Trial (RAFT)4—have been performed to investigate the effectiveness of CRT in HF patients with a wide QRS complex and mild symptoms (New York Heart Association [NYHA] class I–II), in which patients have been randomized to CRT-ON and CRT-OFF. The main findings were that REVERSE showed significant reverse remodeling, MADIT-CRT showed less hospitalization, and RAFT also showed significant reduction in mortality in the CRT arm. The CRT benefit shown in these studies is consistent with those from older studies performed in patients with more severe HF symptoms. Figure 1 displays that the increase in left ventricular (LV) ejection fraction (EF) by CRT is independent of baseline EF. Figure 1. Change in left ventricular ejection fraction after …

Mechano-energetics of the asynchronous and resynchronized heart

Abnormal electrical activation of the ventricles creates major abnormalities in cardiac mechanics. Local contraction patterns, as reflected by measurements of local strain, are not only out of phase, but often also show opposing length changes in early and late activated regions. As a consequence, the efficiency of cardiac pump function (the amount of stroke work generated by a unit of oxygen consumed) is approximately 30% lower in asynchronous than in synchronous hearts. Moreover, the amount of work performed in myocardial segments becomes considerably larger in late than in early activated regions. Cardiac Resynchronization Therapy (CRT) improves mechano-energetics of the previously asynchronous heart in various ways: it alleviates impediment of the abnormal contraction on blood flow, it increases myocardial efficiency, it recruits contraction in the previously early activated septum and it creates a more uniform distribution of myocardial blood flow. These factors act together to increase the range of cardiac work that can be delivered by the patients’ heart, an effect that can explain the increased exercise tolerance and quality of life reported in several CRT trials.

Comparison of a non-invasive arterial pulse contour technique and echo Doppler aorta velocity-time integral on stroke volume changes in optimization of cardiac resynchronization therapy

AIMS We investigated the accuracy and feasibility of a non-invasive arterial pulse contour technique for continuous measurement of stroke volume (SV) in optimization of atrioventricular (AV) delay in cardiac resynchronization therapy (CRT), by comparing SV changes assessed by Nexfin CO-Trek® (Nexfin) and echo Doppler aortic velocity-time integral (VTIao). Furthermore, we investigated whether AV-delay optimization increases the effect of CRT when compared with a default AV delay (120 ms). METHODS AND RESULTS In 23 CRT patients, biventricular pacing (BiVP) was applied at various AV delays, while recording 10 beats preceding BiVP (baseline) and the first 10 BiVP beats, for both methods in parallel. Agreement between Nexfin and VTIao measurements was evaluated (Bland-Altman) on beat-to-beat changes in SV, as well as on effects of BiVP (averaged over 8 beats) at various AV delays. Individual optimal AV delays, for Nexfin (AVopt-n) and VTIao (AVopt-ao), were derived from the second-order polynomial fitted to the effect measurements of 20 patients. In 252 episodes assessed, the difference between measurements (= Nexfin - VTIao) was -0.6 ± 8.1% for beat-to-beat SV changes and -1.3 ± 7.3% for effects of BiVP. Optimal AV delays for Nexfin were well related to AVopt-ao (R(2) = 0.69). The effect (%) of BiVP at the optimal AV delay was significantly larger than at the default AV delay: median difference (range) being +6.3% (0.1-14.4%; P < 0.001) for VTIao and +4.7% (0.0-14.0%; P < 0.001) for Nexfin. CONCLUSION Individual AV optimization increases the effect of CRT. Nexfin is a promising tool in individual CRT optimization, as Nexfin agrees with VTIao on measuring beat-to-beat SV changes and on assessing relative effects of BiVP on SV at various AV delays.

Absence of reverse electrical remodeling during regression of volume overload hypertrophy in canine ventricles.

OBJECTIVE Ventricular hypertrophy predisposes for cardiac arrhythmias, presumably due to prolongation of repolarization (electrical remodeling). The temporal relation between the development of hypertrophy and electrical remodeling, as well as their reversibility upon restoration of normal load, however, are poorly understood. This was investigated in the present study using volume overload hypertrophy induced by atrio-ventricular (AV) block and normalization of load by pacing. METHODS Dogs were subjected to either 16 weeks of AV-block (CAVB group, n=9) or 8 weeks of AV-block followed by 8 weeks of right ventricular (RV) pacing at physiological heart rate (CAVB+PACE group, n=9). RESULTS Left ventricular (LV) mass (2D-echocardiography) increased after 8 weeks of AV-block to approximately 30% above baseline and returned to 10+/-14% after 8 weeks of pacing. QT-time (surface ECG) also increased after AV-block. However, 8 weeks of pacing did not decrease QT and QTc-time (c=corrected for heart rate), neither during physiological pacing nor during temporary pacing at 100 beats/min. Lack of reverse electrical remodeling was confirmed by the absence of changes in LV and RV action potential duration (monophasic action potentials) at week 8 and 16. CONCLUSIONS In volume overload hypertrophy due to AV-block, structural and electrical remodeling develop in parallel but restoration of physiological heart rate causes dissociation between reverse structural remodeling and reverse electrical remodeling.

Strategies to improve cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) emerged 2 decades ago as a useful form of device therapy for heart failure associated with abnormal ventricular conduction, indicated by a wide QRS complex. In this Review, we present insights into how to achieve the greatest benefits with this pacemaker therapy. Outcomes from CRT can be improved by appropriate patient selection, careful positioning of right and left ventricular pacing electrodes, and optimal timing of electrode stimulation. Left bundle branch block (LBBB), which can be detected on an electrocardiogram, is the predominant substrate for CRT, and patients with this conduction abnormality yield the most benefit. However, other features, such as QRS morphology, mechanical dyssynchrony, myocardial scarring, and the aetiology of heart failure, might also determine the benefit of CRT. No single left ventricular pacing site suits all patients, but a late-activated site, during either the intrinsic LBBB rhythm or right ventricular pacing, should be selected. Positioning the lead inside a scarred region substantially impairs outcomes. Optimization of stimulation intervals improves cardiac pump function in the short term, but CRT procedures must become easier and more reliable, perhaps with the use of electrocardiographic measures, to improve long-term outcomes.

Pacing-Induced Dys-Synchrony Preconditions Rabbit Myocardium Against Ischemia/Reperfusion Injury

Background— Because increased mechanical load induces preconditioning (PC) and dys-synchrony increases loading in late-activated regions, we investigated whether dys-synchrony induced by ventricular pacing (VP) at normal heart rate leads to cardioprotection. Methods and Results— Isolated working rabbit hearts were subjected to 35 minutes of global ischemia and 2 hours of reperfusion. Seven hearts underwent VP PC (3 periods of 5 minutes VP at the posterior left ventricular [LV] wall), 7 hearts underwent ischemic preconditioning (IPC) (3 periods of 5 minutes of global ischemia), and 9 hearts served as control (C). LV pressure and sonomicrometry were used to assess global hemodynamics and segment work (SW) and end-diastolic segment length (EDSL) in anterior and posterior LV myocardium. Myocardial release of lactate and expression of proBNP mRNA were determined to gain insight in molecular processes involved in VP PC (*P<0.05). Infarct size (triphenyl tetrazolium chloride staining) was 18.3±13.0% in group C, and was uniformly reduced in the VP PC and IPC groups (1.8±0.8%*, and 3.5±3.1%*, respectively; and not significant between VP PC and IPC). LV posterior wall pacing (VP PC group) increased EDSL (by 6.3±5.8%*) and SW (to 335±207%*) in the LV anterior wall, whereas posterior wall SW decreased to negative values (−23±63%*). LV pacing did not significantly change lactate release and coronary flow but significantly increased proBNP mRNA expression in both anterior and posterior myocardium as compared with controls. Conclusions— Intermittent dys-synchrony is equally cardioprotective as “classical” IPC. Stretch-mediated signaling is a more likely trigger for VP PC than ischemia. VP PC is potentially applicable in cardiac surgery.