Result of the left bundle branch area pacing data collection registry, an international multicenter study of conduction system pacing with a Tendril STS 2088 stylet-driven lead.

INTRODUCTION: Left bundle branch area (LBBA) pacing (LBBAP) has been proposed as an alternative therapy option in patients indicated for cardiac pacing to treat bradycardia or heart failure. The aim of the study was to evaluate the safety and effectiveness of LBBAP in patients implanted with a Tendril 2088 stylet-driven lead. METHODS: The international retrospective data collection registry included 11 sites from 5 countries globally. Patients with attempted implants of the Tendril lead in the LBBA were followed for at least 6 months post the implant attempt. The primary safety and efficacy endpoints were freedom from LBBAP lead-related serious adverse events and the composite of LBBA capture threshold of ≤2.0 V and R-wave amplitudes ≥5 mV (or ≥value at implant), respectively. RESULTS: Of 221 patients with attempted implants of the Tendril 2088 lead in the LBBA, 91.4% (202/221) had successful implants for LBBAP. Regardless of the LBBAP implant success, all patients were followed for at least 6 months (8.7 ± 7.3 months). Baseline characteristics: 44% female, 84% ≥65 years old, 34% coronary artery disease, and 86% of primary indications for pacemaker implant. Both primary safety and effectiveness endpoints were met (freedom from LBBAP lead-related serious adverse device effects of 99.5% and electrical performance composite success rate of 93%). The capture thresholds in LBBAP at implant and 6 months were 0.8 ± 0.3 V@0.4 ± 0.1 ms and 0.8 ± 0.3 V@0.4 ± 0.1 ms. The rate of patients with capture threshold rise ≥1 V was 1.5% through 6 months. The R-wave amplitudes in LBBAP at implant and 6 months were 9.3 ± 3.2 mV and 10.6 ± 3.0 mV. CONCLUSIONS: This large multicenter study demonstrates that the stylet-driven Tendril™ STS 2088 lead is safe and effective for LBBAP with high success and low complication rates.

Cardiac resynchronization therapy non-responder to responder conversion rate in the MORE-CRT MPP trial.

AIMS: To assess the impact of MultiPoint™ Pacing (MPP) in cardiac resynchronization therapy (CRT) non-responders after 6 months of standard biventricular pacing (BiVP). METHODS AND RESULTS: The trial enrolled 5850 patients who planned to receive a CRT device. The echocardiography core laboratory assessed CRT response before implant and after 6 months of BiVP; non-response to BiVP was defined as <15% relative reduction in left ventricular end-systolic volume (LVESV). Echocardiographic non-responders were randomized in a 1:1 ratio to receive MPP (541 patients) or continued BiVP (570 patients) for an additional 6 months and evaluated the conversion rate to the echocardiographic response. The characteristics of both groups at randomization were comparable. The percentage of non-responder patients who became responders to CRT therapy was 29.4% in the MPP arm and 30.4% in the BIVP arm (P = 0.743). In patients with ≥30 mm spacing between the two left ventricular pacing sites (MPP-AS), identified during the first phase as a potential beneficial subgroup, no significant difference in the conversion rate was observed. CONCLUSION: Our trial shows that ∼30% of patients, who do not respond to CRT in the first 6 months, experience significant reverse remodelling in the following 6 months. This finding suggests that CRT benefit may be delayed or slowly incremental in a relevant proportion of patients and that the percentage of CRT responders may be higher than what has been described in short-/middle-term studies. MultiPoint™ Pacing does not improve CRT response in non-responders to BiVP, even with MPP-AS.

Cardiac resynchronization therapy non-responder to responder conversion rate in the more response to cardiac resynchronization therapy with MultiPoint Pacing (MORE-CRT MPP) study: results from Phase I.

AIMS: To assess the impact of MultiPoint™ Pacing (MPP)-programmed according to the physician's discretion-in non-responders to standard biventricular pacing after 6 months. METHODS AND RESULTS: The study enrolled 1921 patients receiving a quadripolar cardiac resynchronization therapy (CRT) system capable of MPP™ therapy. A core laboratory assessed echocardiography at baseline and 6 months and defined volumetric non-response to biventricular pacing as <15% reduction in left ventricular end-systolic volume (LVESV). Clinical sites randomized patients classified as non-responders in a 1:1 ratio to receive MPP (236 patients) or continued biventricular pacing (231 patients) for an additional 6 months and evaluated rate of conversion to echocardiographic response. Baseline characteristics of both groups were comparable. No difference was observed in non-responder to responder conversion rate between MPP and biventricular pacing (31.8% and 33.8%, P = 0.72). In the MPP arm, 68 (29%) patients received MPP programmed with a wide LV electrode anatomical separation (≥30 mm) and shortest LV1-LV2 and LV2-RV timing delays (MPP-AS); 168 (71%) patients received MPP programmed with other settings (MPP-Other). MPP-AS elicited a significantly higher non-responder conversion rate compared to MPP-Other (45.6% vs. 26.2%, P = 0.006) and a trend in a higher conversion rate compared to biventricular pacing (45.6% vs. 33.8%, P = 0.10). CONCLUSIONS: After 6 months, investigator-discretionary MPP programming did not significantly increase echocardiographic response compared to biventricular pacing in CRT non-responders.

Rationale and design of a randomized clinical trial to assess the safety and efficacy of multipoint pacing therapy: MOre REsponse on Cardiac Resynchronization Therapy with MultiPoint Pacing (MORE-CRT MPP-PHASE II).

BACKGROUND: Although cardiac resynchronization therapy (CRT) is beneficial in most heart failure patients, up to 40% do not respond to CRT. Data from the MultiPoint Pacing (MPP) IDE trial and MORE-CRT MPP-PHASE I study suggest improved response in subjects in the MPP arm-programmed with wide left ventricular (LV) electrode anatomical separation (≥30 mm) and shortest timing delays of 5 milliseconds (MPP-AS)-compared with quadripolar biventricular (BiV) pacing. STUDY DESIGN: The MORE-CRT MPP-PHASE II trial is a prospective, randomized, multicenter study to assess the 6-month impact of MPP programmed to mandated MPP-AS settings in subjects who do not respond to 6 months of BiV pacing (MPP OFF). Approximately 5,000 subjects with a standard CRT indication will be enrolled and implanted with a quadripolar CRT system (Abbott) capable of delivering MPP. Only BiV pacing is activated at implant. At 6 months, subjects classified as CRT nonresponders (<15% reduction in LV end-systolic volume) are randomized (1:1) to MPP or continued BiV pacing. The mandated MPP parameters (eg, MPP-AS) are programmed to subjects randomized to the MPP arm. At 12 months, the 2 groups will be compared to determine if there is a difference in CRT response rate. CONCLUSIONS: This trial will evaluate whether MPP programmed to mandated MPP-AS settings improves LV reverse remodeling and clinical response to CRT in patients who fail to respond to 6 months of BiV pacing (www.clinicaltrials.gov identifier NCT02006069).

Rationale and design of a randomized trial to assess the safety and efficacy of MultiPoint Pacing (MPP) in cardiac resynchronization therapy: The MPP Trial.

BACKGROUND: Although the majority of Class III congestive heart failure (HF) patients treated with cardiac resynchronization therapy (CRT) show a clinical benefit, up to 40% of patients do not respond to CRT. This paper reports the design of the MultiPoint Pacing (MPP) trial, a prospective, randomized, double-blind, controlled study to evaluate the safety and efficacy of CRT using MPP compared to standard biventricular (Bi-V) pacing. METHODS: A maximum of 506 patients with a standard CRT-D indication will be enrolled at up to 50 US centers. All patients will be implanted with a CRT-D system (Quartet LV lead Model 1458Q with a Quadra CRT-D, Abbott) that can deliver both MPP and Bi-V pacing. Standard Bi-V pacing will be activated at implant. At 3 months postimplant, patients in whom the echocardiographic parameters during MPP are equal or better than during Bi-V pacing are randomized (1:1) to either an MPP or Bi-V arm. RESULTS: The primary safety endpoint is freedom from system-related complications at 9 months. Each patient's response to CRT will be evaluated using a heart-failure clinical composite score, consisting of a change in NYHA functional class, patient global assessment score, HF events, and cardiovascular death. The primary efficacy endpoint is the proportion of responders in the MPP arm compared with the Bi-V arm between 3 and 9 months. CONCLUSION: This trial seeks to evaluate whether MPP via a single quadripolar LV lead improves hemodynamic and clinical responses to CRT, both in clinical responders and nonresponders.

Performance of the Quadripolar CRT-D system: 5-Year Results from the Quadripolar Pacing Post Approval Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) is associated with challenges such as elevated capture thresholds, diaphragmatic stimulation, and lead instability. OBJECTIVE: Assess the chronic safety and efficacy of the quadripolar CRT-D device system with the Quartet 1458Q Left Ventricular (LV) lead in a CRT-indicated population followed for 5 years and evaluate all-cause mortality and impact of baseline characteristics on survival through 5 years. METHODS: Patients indicated for a CRT-D system were followed every 6 months post-implant for 5 years and assessed device performance and adverse events at each visit. The three primary endpoints were freedom from quadripolar CRT-D system-related complications through 5 years, freedom from Quartet 1458Q LV lead-related complications through 5 years, and the mean programmed pacing capture threshold at 5 years. RESULTS: The study enrolled 1,970 subjects at 71 sites. The quadripolar CRT-D system was successfully implanted in 97.2% of subjects. Freedom from quadripolar CRT-D device system-related complications through 5 years was 89.7% and freedom from Quartet 1458Q LV lead-related complications through 5 years was 95.7%. 3.49 % of subjects had LV lead-related complications and an overall LV lead complication rate was 0.0122 events per subject-year. A mean LV pacing capture threshold was 1.52 ± 1.01 V at 5 years. The 5-year survival rate was 67.4%. CONCLUSION: The quadripolar CRT-D system with the Quartet 1458Q LV lead exhibited low rates of complications and stable electrical performance through 5 years of follow-up and suggested a higher 5-year survival rate compared to traditional CRT systems.

Heart Size Difference Drives Sex-Specific Response to Cardiac Resynchronization Therapy: A Post Hoc Analysis of the MORE-MPP CRT Trial.

BACKGROUND: Studies have reported that female sex predicts superior cardiac resynchronization therapy (CRT) response. One theory is that this association is related to smaller female heart size, thus increased relative dyssynchrony at a given QRS duration (QRSd). Our objective was to investigate the mechanisms of sex-specific CRT response relating to heart size, relative dyssynchrony, cardiomyopathy type, QRS morphology, and other patient characteristics. METHODS AND RESULTS: This is a post hoc analysis of the MORE-CRT MPP (More Response on Cardiac Resynchronization Therapy with Multipoint Pacing)  trial (n=3739, 28% women), with a subgroup analysis of patients with nonischemic cardiomyopathy and left bundle-branch block (n=1308, 41% women) to control for confounding characteristics. A multivariable analysis examined predictors of response to 6 months of conventional CRT, including sex and relative dyssynchrony, measured by QRSd/left ventricular end-diastolic volume (LVEDV). Women had a higher CRT response rate than men (70.1% versus 56.8%, P<0.0001). In subgroup analysis, regression analysis of the nonischemic cardiomyopathy left bundle-branch block subgroup identified QRSd/LVEDV, but not sex, as a modifier of CRT response (P<0.0039). QRSd/LVEDV was significantly higher in women (0.919) versus men (0.708, P<0.001). CRT response was 78% for female patients with QRSd/LVEDV greater than the median value, compared with 68% with QRSd/LVEDV less than the median value (P=0.012). The association between CRT response and QRSd/LVEDV was strongest at QRSd <150 ms. CONCLUSIONS: In the nonischemic cardiomyopathy left bundle-branch block population, increased relative dyssynchrony in women, who have smaller heart sizes than their male counterparts, is a driver of sex-specific CRT response, particularly at QRSd <150 ms. Women may benefit from CRT at a QRSd <130 ms, opening the debate on whether sex-specific QRSd cutoffs or QRS/LVEDV measurement should be incorporated into clinical guidelines.

Result of the Physiologic Pacing Registry, an international multicenter prospective observational study of conduction system pacing.

BACKGROUND: Conduction system pacing (CSP), including both left bundle branch area pacing (LBBAP) and His-bundle pacing (HBP) has been proposed as an alternative therapy option for patients with indication for cardiac pacing to treat bradycardia or heart failure. OBJECTIVE: The purpose of this study was to evaluate implant success, safety, and electrical performances of HBP and LBBAP in the multinational Physiological Pacing Registry. METHODS: The international prospective observational registry included 44 sites from 16 countries globally between November 2018 and May 2021. RESULTS: Of 870 subjects enrolled, CSP lead implantation was attempted in 849 patients. Subjects with successful CSP lead implantation were followed for 6 months (5 ± 2 months). CSP lead implantation was successful in 768 patients (90.4%). Implant success was 95.2% (239/251) for LBBAP and 88.5% (529/598) for HBP (P = .002). Procedural duration and fluoroscopy duration were comparable between LBBAP and HBP (P = .537). Capture threshold at implant was 0.69 ± 0.39 V at 0.46 ± 0.15 ms in LBBAP and 1.44 ± 1.03 V at 0.71 ± 0.33 ms in HBP (P <.001). Capture threshold at 6 months was 0.79 ± 0.33 V at 0.44 ± 0.13 ms in LBBAP and 1.59 ± 0.97 V at 0.67 ± 0.31 ms in HBP (P <.001). Pacing threshold rise ≥1 V was observed at 6 months in 3 of 208 (1.4%) of LBBAP and 55 of 418 (13.2%) of HBP (P <.001). Serious adverse events related to implant procedure or CSP lead occurred in 5 of 251 (2.0%) with LBBAP and 25 of 598 (4.2%) with HBP (P = .115). CONCLUSION: This large prospective multicenter study demonstrates that CSP is technically feasible in most patients with relatively higher implant success and suggests that, with current technology, LBBAP may have better pacing parameters than HBP.

Heart size disparity drives sex-specific response to cardiac resynchronization therapy: a post-hoc analysis of the MORE-MPP CRT trial.

Background: Studies have reported that female sex predicts superior cardiac resynchronization therapy (CRT) response. One theory is that this association is related to smaller female heart size, thus increased "relative dyssynchrony" at given QRS durations (QRSd). Objective: To investigate the mechanisms of sex-specific CRT response relating to heart size, relative dyssynchrony, cardiomyopathy type, QRS morphology, and other patient characteristics. Methods: A post-hoc analysis of the MORE-CRT MPP trial (n=3739, 28% female), with a sub-group analysis of patients with non-ischaemic cardiomyopathy (NICM) and left bundle branch block (LBBB) (n=1308, 41% female) to control for confounding characteristics. A multivariable analysis examined predictors of response to 6 months of conventional CRT, including sex and relative dyssynchrony, measured by QRSd/LVEDV (left ventricular end-diastolic volume). Results: Females had a higher CRT response rate than males (70.1% vs. 56.8%, p<0.0001). Subgroup analysis: Regression analysis of the NICM LBBB subgroup identified QRSd/LVEDV, but not sex, as a modifier of CRT response (p<0.0039). QRSd/LVEDV was significantly higher in females (0.919) versus males (0.708, p<0.001). CRT response was 78% for female patients with QRSd/LVEDV>median value, compared to 68% < median value (p=0.012). Association between CRT response and QRSd/LVEDV was strongest at QRSd<150ms. Conclusions: In the NICM LBBB population, increased relative dyssynchrony in females, who have smaller heart sizes than their male counterparts, is a driver of sex-specific CRT response, particularly at QRSd <150ms. Females may benefit from CRT at a QRSd <130ms, opening the debate on whether sex-specific QRSd cut-offs or QRS/LVEDV measurement should be incorporated into clinical guidelines.

Atrial lead placement at the lower atrial septum: a potential strategy to reduce unnecessary right ventricular pacing.

AIMS: Right ventricular (RV) pacing has been shown to be potentially detrimental to left ventricular function. In conventional dual-chamber pacing the position of the atrial lead could influence duration of the atrio-ventricular (AV) intervals, which is one of the variables that could be associated with an increased percentage of RV pacing. We wanted to see if lead placement at selected atrial septal sites could reduce AV intervals in patients receiving a dual-chamber pacemaker or implantable cardioverter defibrillator. METHODS AND RESULTS: This was a prospective, acute, randomized single centre study that enrolled 57 patients. The atrial lead was placed in both the right atrial appendage (RAA) and the lower atrial septum (LAS) in each patient in random order. The P-wave durations, PR intervals, A sense-V sense (As-Vs), and A pace-V sense (Ap-Vs) intervals were measured at both atrial lead locations in each patient during device implant. The P-wave durations during sinus rhythm (SR), RAA pacing, and LAS pacing were 113 ± 19, 144 ± 27, and 84 ± 12 ms (RAA vs. LAS, P < 0.001), respectively. The PR intervals during SR, RAA pacing, and LAS pacing were 195 ± 47, 230 ± 61, and 167 ± 44 ms (RAA vs. LAS, P < 0.001), respectively. The As-Vs interval was 31% shorter in LAS pacing than in RAA pacing (134 ± 44 ms vs. 194 ± 52 ms, P < 0.001). The Ap-Vs interval was 24% shorter during LAS pacing than during RAA pacing (195 ± 45 ms vs. 257 ± 63 ms, P < 0.001). CONCLUSION: When compared with RAA pacing, LAS pacing was associated with a shorter P wave duration, PR interval, As-Vs, and Ap-Vs intervals. The potential long-term impact of the strategy of pacing from LAS in reducing unnecessary RV pacing needs to be explored in future studies.

CRT Efficacy in "Mid-Range" QRS Duration Among Asians Contrasted to Non-Asians, and Influence of Height.

OBJECTIVES: The purpose of this study was to test the hypotheses that cardiac resynchronization therapy (CRT) efficacy differed among Asians compared with non-Asian populations, differed between QRS duration (QRSd) ranges 120-149 and ≥150 ms, and was influenced by height in the multinational ADVANCE CRT trial. BACKGROUND: CRT guidelines, derived from trials among U.S./European patients, assign weaker recommendations to those with midrange QRSd (QRSd <150 ms). Patient height may modulate CRT efficacy. Together, these may affect CRT prescription and efficacy in Asia. METHODS: CRT response was assessed using the Clinical Composite Score 6 months postimplant (n = 934). Heart failure events and cardiac deaths were reported until 12 months. Asian and non-Asian patients were compared overall, by QRSd <150 ms (Asian n = 71 vs non-Asian n = 248), and QRSd ≥150 ms (Asian n = 180 vs non-Asian n = 435) and by height. RESULTS: Asians comprised 27% (251 of 934) of the primary study population. More Asians had QRSd ≥150 ms (72% [180 of 251] vs 64% [435 of 683] in non-Asian patients; P = 0.022). Overall CRT response was better in Asians vs non-Asians (Clinical Composite Score 85% vs 65%; P <0.001), and following QRSd dichotomization (QRSd <150 ms: 80% vs 59%; P <0.001; QRS ≥150 ms: 86% vs 69%; P < 0.001). HF events and cardiac deaths were fewer in Asians irrespective of QRSd (P < 0.001). Stepwise multivariable analysis indicated that in group QRSd <150 ms, nonischemic cardiomyopathy, number of other comorbidities (0-1 vs ≥4), and atrial fibrillation influenced CRT response. The trend favoring Asian race (OR: 1.46; 95% CI: 0.72-2.95) was eliminated (OR: 1.00; 95% CI: 0.47-2.11) when height or QRSd/height were included (QRSd/height P = 0.006; OR: 1.64; 95% CI: 1.15-2.35). In QRSd <150 ms, probability of CRT response diminished as height increased, but increased with QRSd/height, in both Asians and non-Asians. In QRSd ≥150 ms, height or QRSd/height had minimal effect in Asians or non-Asians. CONCLUSIONS: Height modulates CRT efficacy among patients with QRSd <150 ms and contributes to high probability of benefit from CRT among Asians. CRT should be encouraged among Asian patients with midrange QRSd. (Advance Cardiac Resynchronization Therapy [CRT] Registry; NCT01805154).

Left Ventricular Enlargement, Cardiac Resynchronization Therapy Efficacy, and Impact of MultiPoint Pacing.

BACKGROUND: Left ventricular (LV) epicardial pacing results in slowly propagating paced wavefronts. We postulated that this effect might limit cardiac resynchronization therapy efficacy in patients with LV enlargement using conventional biventricular pacing with single-site LV pacing, but be mitigated by LV stimulation from 2 widely spaced sites using MultiPoint pacing with wide anatomic separation (MPP-AS: ≥30 mm). We tested this hypothesis in the multicenter randomized MPP investigational device exemption trial. METHODS: Following implant, quadripolar biventricular single-site pacing was activated in all patients (n=506). From 3 to 9 months postimplant, among patients with available baseline LV end-diastolic volume (LVEDV) measures, 188 received biventricular single-site pacing and 43 received MPP-AS. Patients were dichotomized by median baseline LVEDV indexed to height (LVEDVIMedian). Outcomes were measured by the clinical composite score (primary efficacy end point), quality of life, LV structural remodeling (↑EF >5% and ↓ESV 10%) and heart failure event/cardiovascular death. RESULTS: LVEDVIMedian was 1.1 mL/cm. Baseline characteristics differed in patients with LVEDVI>Median versus LVEDVI≤Median. Among patients with LVEDVI>Median, biventricular single-site pacing was less efficacious compared to patients with LVEDVI≤Median (clinical composite score, 65% versus 79%). In contrast, MPP-AS programming generated greater clinical composite score response (92% versus 65%, P=0.023) and improved quality of life (-31.0±29.7 versus -15.7±22.1, P=0.038) versus biventricular single-site pacing in patients with LVEDVI>Median. Reverse remodeling trended better with MPP-AS programming. In patients with LVEDVI>Median, heart failure event rate increased following the 3-month randomization point with biventricular single-site pacing (0.0150±0.1725 in LVEDVI>Median versus -0.0190±0.0808 in LVEDVI ≤Median, P=0.012), but no heart failure event occurred in patients with MPP-AS programming between 3 and 9 months in LVEDVI>Median. All measured outcomes did not differ in patients receiving MPP-AS and biventricular single-site pacing with LVEDVI≤Median. CONCLUSIONS: Conventional biventricular single-site pacing, even with a quadripolar lead, has reduced efficacy in patients with LV enlargement. However, the greatest response rate in patients with larger hearts was observed when programmed to MPP-AS pacing.

Alterations in internal elastic lamina permeability as a function of age and anatomical site precede lesion development in apolipoprotein E-null mice.

Early atherosclerosis is characterized by the accumulation of plasma-borne macromolecules (eg, low-density lipoproteins) in the arterial intima, which is bordered by endothelial cells (EC) and the internal elastic lamina (IEL). This accumulation is believed to be secondary to increased EC permeability. We hypothesized that a decrease in IEL permeability may precede lesion development and contribute to macromolecular accumulation. To test this hypothesis, we quantified EC and IEL permeability in lesion-free areas of the thoracic and abdominal aortas of chow-fed C57BL/6 control and atherosclerotic-prone apolipoprotein E (apoE)-null mice at 3 and 5 months of age. Between 3 and 5 months of age, apoE-null mice begin to develop atherosclerotic lesions in the thoracic aorta. No significant differences in EC and IEL permeability were observed at either time in C57BL/6 control mice. In contrast, 78% and 19% decreases in IEL permeability of the thoracic aorta and abdominal aorta, respectively, were observed between 3 to 5 months of age in apoE-null mice (thoracic: 2.05+/-1.33 and 0.44+/-0.15 microm/min, P<0.001; abdominal: 1.13+/-0.58 and 0.93+/-0.44 microm/min, P<0.05). To further determine whether decreased IEL permeability is linked with atherosclerotic lesion development, we quantified IEL permeability in the greater and lesser curvature of the aortic arch. In apoE-null mice, the lesser curvature of the aortic arch develops lesions before the greater curvature. We found a significant and sustained decrease (59%) in IEL permeability in the lesser curvature of the aortic arch compared with the greater curvature. These data suggest that atherogenesis involves the pathological remodeling of the IEL, not the endothelium before lesion development. This remodeling may be attributable to local responses of the endothelium and smooth muscle cells to hyperlipidemia.

Safety and Efficacy of Multipoint Pacing in Cardiac Resynchronization Therapy: The MultiPoint Pacing Trial.

OBJECTIVES: The MultiPoint Pacing (MPP) trial assessed the safety and efficacy of pacing 2 left ventricular sites with a quadripolar lead in patients with heart failure indicated for a CRT-D device. BACKGROUND: Cardiac resynchronization therapy nonresponse is a complex problem where stimulation of multiple left ventricular sites may be a solution. METHODS: Enrolled patients were indicated for a CRT-D system. Bi-ventricular (Bi-V) pacing was activated at implant. Three months later, clinical response was assessed and the patient was randomized (1:1) to receive Bi-V pacing or MPP. Patients were followed for 6 months post-randomization and clinical response was again assessed. RESULTS: The CRT-D system was successfully implanted in 455 of 469 attempted implants (97%). A total of 381 patients were randomized to Bi-V or MPP at 3 months. The primary safety endpoint was met with freedom from system-related complications of 93.2%. The primary efficacy endpoint of the noninferiority comparison of nonresponder rates between the 2 arms was met. Patients randomized to MPP arm and programmed to pace from anatomically distant poles (MPP-AS) responded to therapy at significantly higher rates than MultiPoint pacing-other programmed settings (MPP-Other). Within this group, 87% were responders at 9 months, 100% designated as nonresponders at 3 months converted to responders at 9 months, and 54% experienced an incremental response compared to MPP-Other. Also within MPP-AS, 92% of patients with de novo CRT-D implant were classified as responders compared with patients with MPP-Other. CONCLUSIONS: MPP is safe and effective for treating heart failure. The study met the pre-specified hypothesis that response to MPP is noninferior to Bi-V pacing with a quadripolar left ventricular lead. (MultiPoint Pacing IDE Study [MPP IDE]; NCT01786993).

Disruption of protein kinase A interaction with A-kinase-anchoring proteins in the heart in vivo: effects on cardiac contractility, protein kinase A phosphorylation, and troponin I proteolysis.

Protein kinase A (PKA)-dependent phosphorylation is regulated by targeting of PKA to its substrate as a result of binding of regulatory subunit, R, to A-kinase-anchoring proteins (AKAPs). We investigated the effects of disrupting PKA targeting to AKAPs in the heart by expressing the 24-amino acid regulatory subunit RII-binding peptide, Ht31, its inactive analog, Ht31P, or enhanced green fluorescent protein by adenoviral gene transfer into rat hearts in vivo. Ht31 expression resulted in loss of the striated staining pattern of type II PKA (RII), indicating loss of PKA from binding sites on endogenous AKAPs. In the absence of isoproterenol stimulation, Ht31-expressing hearts had decreased +dP/dtmax and -dP/dtmin but no change in left ventricular ejection fraction or stroke volume and decreased end diastolic pressure versus controls. This suggests that cardiac output is unchanged despite decreased +dP/dt and -dP/dt. There was also no difference in PKA phosphorylation of cardiac troponin I (cTnI), phospholamban, or ryanodine receptor (RyR2). Upon isoproterenol infusion, +dP/dtmax and -dP/dtmin did not differ between Ht31 hearts and controls. At higher doses of isoproterenol, left ventricular ejection fraction and stroke volume increased versus isoproterenol-stimulated controls. This occurred in the context of decreased PKA phosphorylation of cTnI, RyR2, and phospholamban versus controls. We previously showed that expression of N-terminal-cleaved cTnI (cTnI-ND) in transgenic mice improves cardiac function. Increased cTnI N-terminal truncation was also observed in Ht31-expressing hearts versus controls. Increased cTnI-ND may help compensate for reduced PKA phosphorylation as occurs in heart failure.

Permeability change of arterial endothelium is an age-dependent function of lesion size in apolipoprotein E-null mice.

The remodeling process of the arterial wall in atherosclerosis involves intimal thickening, which can be related to the barrier functions of the endothelial cell layer (ECL) and internal elastic lamina (IEL) using horseradish peroxidase (HRP) as a tracer. To evaluate the ECL and IEL permeabilities (PECL and PIEL, respectively) and intimal transport parameters, e.g., apparent HRP velocity (VI) and diffusivity, we compared simulations with a mathematical model to experimental data. In this study, we injected HRP into the vein of apolipoprotein E-null mice and measured HRP concentration profiles in lesioned areas of aortas. Lesion size was characterized by lower, middle, and upper ranges of the intimal/medial thickness (deltaI/deltaM): 01.0. The PECL (in micrometers per minute) of 5-mo-old mice in the middle range (0.98+/-0.14) was significantly greater than that in the lower range (0.21+/-0.03) but not significantly different from mice in the upper range (0.99+/-0.55). The PECL of 12-mo-old mice increased significantly with the relative intimal thickness: 0.27+/-0.04 in the lower range, 1.12+/-0.15 in the middle range, and 1.74+/-0.24 in the upper range. In both age groups, VI (in micrometers per minute) increased significantly from lower to upper ranges of intimal thickness. However, PIEL did not change significantly with relative intimal thickness and age. In the upper range of intimal thickness, PECL and VI were significantly greater in 12-mo-old mice than in 5-mo-old mice. These data indicate an interaction between lesion growth and aging that leads to progressive loss in the integrity of the endothelial barrier function. Furthermore, the IEL is not a significant barrier between the intima and tunica media in the atherosclerotic process.

Speckle-tracking echocardiography correctly identifies segmental left ventricular dysfunction induced by scarring in a rat model of myocardial infarction.

Speckle-tracking echocardiography (STE) uses a two-dimensional echocardiographic image to estimate two orthogonal strain components. The aim of this study was to assess sensitivity of circumferential (S(circ)) and radial (S(rad)) strains to infarct-induced left ventricular (LV) remodeling and scarring of the LV in a rat. To assess the relationship among S(circ), S(rad), and scar size, two-dimensional echocardiographic LV short-axis images (12 MHz transducer, Vivid 7 echo machine) were collected in 34 Lewis rats 4 to 10 wk after ligation of the left anterior descending artery. Percent segmental fibrosis was assessed from histological LV cross sections stained by Masson trichrome. Ten normal rats served as echocardiographic controls. S(circ) and S(rad) were assessed by STE. Histological data showed consistent scarring of anterior and lateral segments with variable extension to posterior and inferior segments. Both S(circ) and S(rad) significantly decreased after myocardial infarction (P<0.0001 for both). As anticipated, S(circ) and S(rad) were lowest in the infarcted segments. Multiple linear regression showed that segmental S(circ) were similarly dependent on segmental fibrosis and end-systolic diameter (P<0.0001 for both), whereas segmental S(rad) measurements were more dependent on end-systolic diameter (P<0.0001) than on percent fibrosis (P<0.002). STE correctly identifies segmental LV dysfunction induced by scarring that follows myocardial infarction in rats.

Stent-based tempamine delivery on neointimal formation in a porcine coronary model.

BACKGROUND: Tempamine is one of new class of antioxidant agents, the nitroxides, which have shown a wide range of biological effects like suppressing free radical driven reactions to maintain cell functions. The objectives of this study were to evaluate the effect of a biodegradable polymer coated stent loaded with tempamine on in-stent neointimal formation. METHODS: Stainless steel stents were dip coated in biodegradable elastomeric poly (ester-amide) (co-PEA) or in polymer solution mixed with 50% (wt%) and 100% (wt%) tempamine. One group 100% (wt%) tempamine loaded stents were further dip coated in co-PEA polymer to form a top layer. Stainless steel bare, polymer-only, and different doses tempanine coated stents were implanted into porcine coronary arteries with a stent to artery ratio 1.2:1. Histomorphometric analysis was performed at 5 days and 6 weeks respectively. RESULTS: Histomorphometric analysis showed that the bare, polymer-only and tempamine-coated stents elicited a similar tissue response at 5 days. At 6 weeks, the peri-strut inflammation and neointimal hyperplasia of polymer-only stents were comparable to the bare stents. Compared to the bare stents, 50% tempanine coated stents had a trend to decrease the arterial injury (0.62 +/- 0.41 versus 0.34 +/- 0.18, P = 0.075) and neointimal hyperplasia (1.80 +/- 0.77 versus 1.27 +/- 0.39 mm2, P = 0.085). However, 100% tempanine coated showed significantly increased inflammatory response and neointimal formation. CONCLUSION: These co-PEA polymer coatings showed a biocompatible performance. Loaded with 50% tempamine had a trend to decrease neointimal hyperplasia. The 100% tempamine for stent-based delivery may have potential cytotoxic effects to arterial wall. Using a co-PEA polymer topcoat could effectively abolish these side effects.

Macromolecular transport in the arterial wall: alternative models for estimating barriers.

Early atherosclerosis, or atherogenesis, is characterized by the abnormal accumulation of plasma-borne macromolecules (e.g., LDL) in the arterial intima. The change of barrier characteristics of tissue in the arterial wall requires evaluation of macromolecular transport across the endothelial cell layer (ECL) and internal elastic lamina (IEL), the luminal and abluminal boundaries of the arterial intima, respectively. In this study, alternative mathematical models are derived from dynamic mass balances to describe macromolecular transport across the arterial wall. One model considers each medial layer as a spatially lumped compartment, whereas another model consists of a spatially lumped intima and spatially distributed media. Model simulations of a tracer concentration distribution in the arterial wall are compared with concentration distributions of horseradish peroxidase (HRP) after i.v. injection in mice. For each model, optimal parameter values are obtained that yield model outputs matching the data well for two different HRP circulation times. The model parameter estimates show that the ECL is the major barrier for macromolecular transport across the normal arterial wall. Sensitivity analysis indicates that the parameter estimates of the transport coefficients of the ECL and IEL are well determined. Optimal circulation times are determined and expected to yield improved precision of parameter estimates in future experiments to reflect disease progression.