Peter Paul H.M. Delnoy

Rationale and design of the PRAETORIAN trial: A Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter-defibrillator therapy

BACKGROUND Implantable cardioverter-defibrillators (ICDs) are widely used to prevent fatal outcomes associated with life-threatening arrhythmic episodes in a variety of cardiac diseases. These ICDs rely on transvenous leads for cardiac sensing and defibrillation. A new entirely subcutaneous ICD overcomes problems associated with transvenous leads. However, the role of the subcutaneous ICD as an adjunctive or primary therapy in patients at risk for sudden cardiac death is unclear. STUDY DESIGN The PRAETORIAN trial is an investigator-initiated, randomized, controlled, multicenter, prospective 2-arm trial that outlines the advantages and disadvantages of the subcutaneous ICD. Patients with a class I or IIa indication for ICD therapy without an indication for bradypacing or tachypacing are included. A total of 700 patients are randomized to either the subcutaneous or transvenous ICD (1:1). The study is powered to claim noninferiority of the subcutaneous ICD with respect to the composite primary endpoint of inappropriate shocks and ICD-related complications. After noninferiority is established, statistical analysis is done for potential superiority. Secondary endpoint comparisons of shock efficacy and patient mortality are also made. CONCLUSION The PRAETORIAN trial is a randomized trial that aims to gain scientific evidence for the use of the subcutaneous ICD compared with the transvenous ICD in a population of patients with conventional ICD with respect to major ICD-related adverse events. This trial is registered at ClinicalTrials.gov with trial ID NCT01296022.

Validation of a peak endocardial acceleration-based algorithm to optimize cardiac resynchronization: early clinical results

Aims Cardiac resynchronization therapy (CRT) involves time-consuming procedures to achieve an optimal programming of the system, at implant as well as during follow-up, when remodelling occurs. A device equipped with an implantable sensor able to measure peak endocardial acceleration (PEA) has been recently developed to monitor cardiac function and to guide CRT programming. During scanning of the atrioventricular delay (AVD), PEA reflects both left ventricle (LV) contractility (LV dP/dtmax) and transmitral flow. A new CRT optimization algorithm, based on recording of PEA (PEAarea method) was developed, and compared with measurements of LV dP/dtmax, to identify an optimal CRT configuration. Methods and results We studied 15 patients in New York Heart Association classes II–IV and with a QRS duration >130 ms, who had undergone implantation of a biventricular (BiV) pulse generator connected to a right ventricular (RV) PEA sensor. At a mean of 39 ± 15 days after implantation of the CRT system, the patients underwent cardiac catheterization. During single-chamber LV or during BiV stimulation, with initial RV or LV stimulation, and at settings of interventricular intervals between 0 and 40 ms, the AVD was scanned between 60 and 220 ms, while LV dP/dtmax and PEA were measured. The area of PEA curve (PEAarea method) was estimated as the average of PEA values measured during AVD scanning. A ≥10% increase in LV dP/dtmax was observed in 12 of 15 patients (80%), who were classified as responders to CRT. In nine of 12 responders (75%), the optimal pacing configuration identified by the PEAarea method was associated with the greatest LV dP/dtmax. Conclusion The concordance of the PEAarea method with measurements of LV dP/dtmax suggests that this new, operator-independent algorithm is a reliable means of CRT optimization.

Dominant frequency of atrial fibrillation correlates poorly with atrial fibrillation cycle length.

Background—Localized sites of high frequency during atrial fibrillation (AF) are used as target sites to eliminate AF. Spectral analysis is used experimentally to determine these sites. The purpose of this study was to compare dominant frequencies (DF) with AF cycle length (AFCL) of unipolar and bipolar recordings. Methods and Results—Left and right atrial endocardial electrograms were recorded during AF in 40 patients with lone AF, using two 20-polar catheters. Mean age was 53±9.9 years. Unipolar and bipolar electrograms were recorded simultaneously during 16 seconds at 2 right and 4 left atrial sites. AFCLs and DFs were determined. QRS subtraction was performed in unipolar signals. DFs were compared with mean, median, and mode of AFCLs; 4800 unipolar and 2400 bipolar electrograms were analyzed. Intraclass correlation was poor for all spectral analysis protocols. Best correlation was accomplished with DFs from unipolar electrograms compared with median AFCL (intraclass correlation coefficient, 0.67). A gradient in median AFCL of >25% was detected in 16 of 40 patients. In 13 of 16 patients (81%) with a frequency gradient of >25%, the site with highest frequency was located in the left atrium (posterior left atrium in 8 patients). The site with shortest median AFCL and highest DF corresponded in 25% if unipolar and in 31% if bipolar electrograms were analyzed. Conclusions—DFs from unipolar and bipolar electrograms recorded during AF correlated poorly with mean, median, and mode AFCL. If a frequency gradient >25% existed, the site with highest DF corresponded to the site of shortest median AFCL in only 25% of patients. Because spectral analysis is being used to identify ablation sites, these data may have important clinical implications.

Clinical response of cardiac resynchronization therapy in the elderly

BACKGROUND Although prevalence of heart failure increases with age, in most clinical trials of cardiac resynchronization therapy (CRT), older patients are not included. Observational studies of effects of CRT in older patients had a small sample size. In the present study, the clinical and echocardiographic response to CRT in a larger group of elderly (age > 75 years) patients was evaluated. METHODS In this prospective observational study of 266 consecutive patients, CRT was performed in 107 elderly patients (40%) and 159 (60%) younger patients (age < or = 75 years). Echocardiographic and clinical parameters were evaluated at baseline and at 3, 12, and 24 months. RESULTS In the elderly group, mean age was 79 years compared with 67 years in patients aged < or = 75 years. Clinical baseline characteristics between the 2 groups were comparable. During follow-up, there was a comparable and sustained improvement in both groups according to New York Heart Association (NYHA) class, quality of life score, and left ventricular (LV) ejection fraction. Clinical response, defined as survival with improvement (> or = 1 score) of NYHA class without hospital admittance for heart failure, was seen in 67% and 69% (group aged < or = 75 years) versus 65% and 60% (group aged > 75 years) after 3 months and 1 year, respectively. Reverse LV remodeling defined as LV end-systolic volume reduction > or = 10% was seen in 79% and 87% (group aged < or = 75 years) versus 71% and 79% (group aged > 75 years) after 3 months and 1 year, respectively. Hospitalization for heart failure decreased significantly in both groups in the year after CRT. A subgroup analysis of 39 octogenarians (> 80 years) also showed a significant improvement in NYHA class and LV ejection fraction in this subgroup. Also, LV reverse remodeling occurred in a similar extent (75% and 84%) after 3 months and 1 year, respectively. CONCLUSIONS This study shows a clinical and echocardiographic improvement of CRT in patients aged > 75 years and even so in octogenarians.

Predictive factors of sustained sinus rhythm and recurrent atrial fibrillation after a radiofrequency modified Maze procedure

BACKGROUND Preoperative atrial fibrillation (AF) in patients scheduled for elective open-heart surgery is a well-known phenomenon. The cut and sew Maze procedure or variant Maze procedures abolish AF in 45-95% of patients during short- to intermediate-term follow-up. We determined preoperative and postoperative factors predictive of sustained sinus rhythm (SR) and recurrent AF in an elderly cohort of patients with structural heart disease who underwent cardiac surgery. PATIENTS AND METHODS From November 1995 to November 2003, 285 patients with structural heart disease and permanent AF were scheduled for elective cardiac surgery. All patients underwent a radiofrequency (RF) modified Maze procedure as an adjunct to the open-heart operation. Patients were followed in the outpatient clinic or follow-up data were obtained from attending doctors. Patients are being followed in an ongoing registry; however for the patients who are the subject of this paper follow-up ended November 2006. Preoperative factors predicting recurrent AF postoperatively were assessed, as were factors associated with sustained SR. RESULTS Two hundred and eighty-five patients (mean age 68.0+/-9.6 years) underwent a total of 655 open-heart procedures and concomitant RF Maze surgery. In-hospital mortality was 4.6% (13 patients). Mean and median duration of AF were 60.9+/-68.7 months and 26 months (range 6-396), respectively. Median follow-up was 36.5 months (range 27-114 months). Sustained SR, including atrial rhythm or an atrial-based paced rhythm was present in 59% of patients at 1 year, in 54.4% at 3 years, in 53.4% at 5 years and in 57.1% of patients at the latest follow-up. Stroke was reported in six patients (2.1%). Factors predictive of postoperative AF recurrence were duration of permanent AF, preoperative atrial fibrillation wave and preoperative left atrial (LA) size. Postoperative angiotensin converting enzyme (ACE) inhibitor therapy was associated with SR during follow-up. LA size decreased during follow-up in patients with sustained SR, whereas LA size increased in case of recurrent AF. CONCLUSIONS In this group of elderly patients with permanent AF in the setting of structural heart disease who underwent cardiac surgery and a RF Maze procedure as a concomitant procedure, the duration of AF, preoperative atrial fibrillation wave and preoperative LA size were predictive of recurrent AF, whereas left ventricular ejection fraction, left ventricular diameters and invasive hemodynamic parameters were not. Postoperative ACE inhibitor therapy was associated with sustained SR. Furthermore, sustained SR after RF Maze surgery was associated with decreased LA dimensions.

Intermediate to Long-Term Results of Radiofrequency Modified Maze Procedure as an Adjunct to Open-Heart Surgery

BACKGROUND Of patients scheduled for elective open heart surgery, a substantial number of patients have preoperative atrial fibrillation (AF). The cut-and-sew Maze procedure and variant Maze procedures abolish AF in 45% to 95% during short- to intermediate-term follow-up. Limited data are available about maintenance of sinus rhythm during intermediate- to long-term follow-up. The objective of the present study was to assess the association between postoperative rhythm and mortality and stroke. METHODS From November 1995 to November 2003, 258 patients with structural heart disease and permanent AF with a duration of longer than 12 months were scheduled for elective cardiac surgery and included in a registry. They underwent a radiofrequency modified Maze procedure as an adjunct to the open heart operation. Patients were followed in the outpatient clinic, and follow-up data were obtained from medical correspondence of attending physicians. For this paper, follow-up ended November 2006; however, patients are being followed in an ongoing registry. RESULTS Two hundred fifty-eight patients (mean age, 68.1 +/- 9.5 years) with permanent AF underwent cardiac surgical procedures and concomitant radiofrequency Maze surgery; 213 patients (82.5%) underwent more than one procedure. Mean duration of permanent AF was 66.6 +/- 69.8 months (range, 16 to 96). Preoperatively, 82.9% of patients were in New York Heart Association class III. In-hospital mortality was 3.9% (10 patients), and during a mean follow-up of 43.7 +/- 25.9 months (range, 27 to 114), 73 patients (28.3%) died. Left ventricular ejection fraction was normal in 44.6%, moderately decreased in 42.5%, and poor in 12.9% of patients. Sustained sinus rhythm, including atrial rhythm or an atrial-based paced rhythm was present in 69% of patients at 1 year, in 56% at 3 years, in 52% at 5 years, and in 57% of patients at the latest follow-up. Antiarrhythmic drugs were used by 64% of survivors who were free of atrial fibrillation. Oral anticoagulation therapy was taken by 99% of patients. Stroke was reported in 4 patients (1.6%). CONCLUSIONS The RF modified Maze procedure abolishes AF in the majority of patients with structural heart disease and longstanding permanent AF. Postoperative rhythm was not predictive of all-cause mortality, cardiac mortality, and stroke, neither in the whole group nor in the subgroups defined by preoperative left ventricular ejection fraction and New York Heart Association class. The stroke rate was very low in this group with longstanding AF.

Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory Blood Pressure Response After Renal Denervation

Blood pressure (BP) response to renal denervation (RDN) is highly variable and its effectiveness debated. A procedural end point for RDN may improve consistency of response. The objective of the current analysis was to look for the association between renal nerve stimulation (RNS)–induced BP increase before and after RDN and changes in ambulatory BP monitoring (ABPM) after RDN. Fourteen patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia at 4 sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP changes were monitored and correlated to changes in ambulatory BP at a follow-up of 3 to 6 months after RDN. RNS resulted in a systolic BP increase of 50±27 mm Hg before RDN and systolic BP increase of 13±16 mm Hg after RDN (P<0.001). Average systolic ABPM was 153±11 mm Hg before RDN and decreased to 137±10 mm Hg at 3- to 6-month follow-up (P=0.003). Changes in RNS-induced BP increase before versus immediately after RDN and changes in ABPM before versus 3 to 6 months after RDN were correlated, both for systolic BP (R=0.77, P=0.001) and diastolic BP (R=0.79, P=0.001). RNS-induced maximum BP increase before RDN had a correlation of R=0.61 (P=0.020) for systolic and R=0.71 (P=0.004) for diastolic ABPM changes. RNS-induced BP changes before versus after RDN were correlated with changes in 24-hour ABPM 3 to 6 months after RDN. RNS should be tested as an acute end point to assess the efficacy of RDN and predict BP response to RDN.

Contractility sensor-guided optimization of cardiac resynchronization therapy: results from the RESPOND-CRT trial

Aims Although cardiac resynchronization therapy (CRT) is effective in patients with systolic heart failure (HF) and a wide QRS interval, a substantial proportion of patients remain non-responsive. The SonR contractility sensor embedded in the right atrial lead enables individualized automatic optimization of the atrioventricular (AV) and interventricular (VV) timings. The RESPOND-CRT study investigated the safety and efficacy of the contractility sensor system in HF patients undergoing CRT. Methods and results RESPOND-CRT was a prospective, randomized, double-blinded, multicentre, non-inferiority trial. Patients were randomized (2:1, respectively) to receive weekly, automatic CRT optimization with SonR vs. an Echo-guided optimization of AV and VV timings. The primary efficacy endpoint was the rate of clinical responders (patients alive, without adjudicated HF-related events, with improvement in New York Heart Association class or quality of life), at 12 months. The study randomized 998 patients. Responder rates were 75.0% in the SonR arm and 70.4% in the Echo arm (mean difference, 4.6%; 95% CI, −1.4% to 10.6%; P < 0.001 for non-inferiority margin −10.0%) (Table 2). At an overall mean follow-up of 548 ± 190 days SonR was associated with a 35% risk reduction in HF hospitalization (hazard ratio, 0.65; 95% CI, 0.46–0.92; log-rank P = 0.01). Conclusion Automatic AV and VV optimization using the contractility sensor was safe and as effective as Echo-guided AV and VV optimization in increasing response to CRT. ClinicalTrials.gov number NCT01534234

Association between frequent cardiac resynchronization therapy optimization and long-term clinical response: a post hoc analysis of the Clinical Evaluation on Advanced Resynchronization (CLEAR) pilot study

Aims The long-term clinical value of the optimization of atrioventricular (AVD) and interventricular (VVD) delays in cardiac resynchronization therapy (CRT) remains controversial. We studied retrospectively the association between the frequency of AVD and VVD optimization and 1-year clinical outcomes in the 199 CRT patients who completed the Clinical Evaluation on Advanced Resynchronization study. Methods and results From the 199 patients assigned to CRT-pacemaker (CRT-P) (New York Heart Association, NYHA, class III/IV, left ventricular ejection fraction <35%), two groups were retrospectively composed a posteriori on the basis of the frequency of their AVD and VVD optimization: Group 1 (n = 66) was composed of patients ‘systematically’ optimized at implant, at 3 and 6 months; Group 2 (n = 133) was composed of all other patients optimized ‘non-systematically’ (less than three times) during the 1 year study. The primary endpoint was a composite of all-cause mortality, heart failure-related hospitalization, NYHA functional class, and Quality of Life score, at 1 year. Systematic CRT optimization was associated with a higher percentage of improved patients based on the composite endpoint (85% in Group 1 vs. 61% in Group 2, P < 0.001), with fewer deaths (3% in Group 1 vs. 14% in Group 2, P = 0.014) and fewer hospitalizations (8% in Group 1 vs. 23% in Group 2, P = 0.007), at 1 year. Conclusion These results further suggest that AVD and VVD frequent optimization (at implant, at 3 and 6 months) is associated with improved long-term clinical response in CRT-P patients.

Upgrading to Biventricular Pacing Guided by Pressure–Volume Loop Analysis During Implantation

Pressure–Volume Loop Analyses during CRT Implants. Introduction: cardiac resynchronization therapy (CRT) may improve prognosis in patients with chronic right ventricular (RV) pacing, and optimal lead position can decrease nonresponders. We evaluated the clinical and echocardiographic response to CRT in patients with previous chronic RV pacing, using pressure–volume loop analyses to determine the optimal left ventricular (LV) lead position during implantation.