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The self-expanding, intra-annular Navitor (Abbott Structural Heart) valve includes an outer cuff to reduce paravalvular leak (PVL) and large stent cells for future coronary access. The purpose of the PORTICO NG (Evaluation of the Portico NG [Next Generation] Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis) study is to evaluate the safety and effectiveness of the Navitor valve in patients with symptomatic, severe aortic stenosis who are at high or extreme surgical risk. PORTICO NG is a prospective, multicenter, global study with follow-up at 30 days, 1 year, and annually through 5 years. The primary endpoints are all-cause mortality and moderate or greater PVL at 30 days. Valve Academic Research Consortium-2 events and valve performance are assessed by an independent clinical events committee and echocardiographic core laboratory. A total of 260 subjects were treated at 26 clinical sites across Europe, Australia, and the United States between September 2019 and August 2022. The mean age was 83.4 ± 5.4 years, 57.3% were female, and the average Society of Thoracic Surgeons score was 3.9% ± 2.1%. At 30 days, the rate of all-cause mortality was 1.9%, and no subjects had moderate or greater PVL. The rate of disabling stroke was 1.9%, life-threatening bleeding was 3.8%, stage 3 acute kidney injury was 0.8%, major vascular complications were 4.2%, and new permanent pacemaker implantation was 19.0%. Hemodynamic performance included a mean gradient of 7.4 ± 3.5 mm Hg and an effective orifice area of 2.00 ± 0.47 cm2. The Navitor valve is safe and effective for the treatment of subjects with severe aortic stenosis who are at high or greater risk for surgery, which is supported by low rates of adverse events and PVL. (Evaluation of the Portico NG [Next Generation] Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis [PORTICO NG]; NCT04011722) [Display omitted] [ABSTRACT FROM AUTHOR]

Resolute Onyx polymer-based zotarolimus-eluting stents (ZES) were noninferior in safety and effectiveness to BioFreedom polymer-free biolimus A9-coated stents (DCS) in high-bleeding-risk (HBR) patients treated with 1-month dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) at 1 year. This study reports the final 2-year results of the randomized Onyx ONE trial. The Onyx ONE (A Randomized Controlled Trial With Resolute Onyx in One Month Dual Antiplatelet Therapy (DAPT) for High-Bleeding Risk Patients) trial randomly assigned HBR patients to treatment with ZES or DCS. Following 1-month DAPT, event-free patients received SAPT (either aspirin or a P2Y 12 inhibitor at physician discretion). The primary safety endpoint, a composite of cardiac death, myocardial infarction, or stent thrombosis at 1 year, was determined at 1 year. Rates of primary and secondary endpoints were calculated after final follow-up at 2 years. A total of 1,003 patients were randomly allocated to ZES and 993 patients to DCS. Follow-up was complete in 980 (97.7%) ZES patients and 962 (96.9%) DCS patients at 2 years. The primary safety endpoint occurred in 208 (21.2%) patients in the ZES group and 199 (20.7%) patients in the DCS group (risk difference: 0.5%; 95% CI: −3.1% to 4.2%; P = 0.78) at 2 years without significant differences in individual components of the composite endpoint. The secondary effectiveness endpoint occurred in 217 (22.1%) patients in the ZES group and 202 (21.0%) patients in the DCS group (risk difference: 1.1%; 95% CI: −2.5% to 4.8%; P = 0.54). Among patients at HBR treated with 1-month DAPT followed by SAPT, the Resolute Onyx polymer-based ZES had similar 2-year outcomes for the primary safety and secondary effectiveness endpoint compared with the BioFreedom polymer-free DCS. (A Randomized Controlled Trial With Resolute Onyx in One Month Dual Antiplatelet Therapy [DAPT] for High-Bleeding Risk Patients [Onyx ONE]; NCT03344653) [Display omitted] [ABSTRACT FROM AUTHOR]

Aortic stenosis is the most common valvular lesion requiring intervention and with an ageing population, its burden is likely to increase. Increasing comorbidity and a desire for less invasive treatment strategies has facilitated the expansion of percutaneous aortic valve therapies. Robust clinical trial data are now available to support the role of transcatheter aortic valve implantation (TAVI) in patients of prohibitive, high and now intermediate surgical risk. The introduction of a Medicare Benefits Schedule reimbursement is likely to see TAVI use grow exponentially in Australia over the next 5 years. Clinical trials evaluating low risk patients may be the final frontier to see TAVI become the standard of care for most patients with severe aortic stenosis. [ABSTRACT FROM AUTHOR]

Background--The aim of the Portico TAVI (transcatheter aortic valve implantation) system study was to evaluate outcomes ≤1 year after implantation of a novel resheathable, self-expanding TAVI system in a multicenter patient population with severe aortic stenosis (AS). Methods and Results--High-risk patients (n=222) with symptomatic severe AS (mean age, 83.0±4.6 years; 74.3% women) were enrolled across 12 centers in Europe and Australia. The study's primary end point was all-cause mortality at 30 days. A total of 209 patients who received the Portico TAVI system were available for follow-up after the 30-day visit. Data collection included hemodynamic assessment by echocardiography with core laboratory evaluation and assessment of functional status. Valve Academic Research Consortium-defined adverse events were adjudicated by an independent Clinical Events Committee. TAVI using the Portico valve led to a significant and persistent improvement in aortic valve function at 1 year. More than mild paravalvular leak was present in 5.7% and 7.5% of patients at 30 days and 1 year, respectively. Kaplan-Meier estimates at 30 days and 1 year were 3.6% and 13.8% for all-cause mortality, 3.6% and 9.6% for cardiovascular mortality, and 3.2% and 5.8% for major (disabling) stroke. After 30 days and ≤1 year of follow-up, adverse events included stage 3 acute kidney injury (n=3), major vascular complications (n=5), and life-threatening/disabling bleeding (n=3). Overall permanent pacemaker rate was 14.7%. At 1 year, 74.8% improved ≥1 New York Heart Association class compared with baseline (P<0.0001). Conclusions--The Portico TAVI system is safe and effective at 1 year, yielding low mortality and stroke rates in high-risk patients with severe AS. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to evaluate the short-term safety and performance of the full range of valve sizes offered within the Portico transcatheter aortic valve replacement system. Background The Portico transcatheter aortic heart valve is a fully resheathable, repositionable, and self-expanding bioprosthesis designed to achieve optimal valve position and hemodynamic performance and limit conduction disturbances. Methods Patients (n = 222) with symptomatic (New York Heart Association functional class ≥II) severe aortic stenosis considered by a multidisciplinary heart team to be at high surgical risk were recruited between December 2011 and September 2015 in this prospective, nonrandomized, multicenter study. Patients were implanted with the full range of Portico heart valves (23, 25, 27, and 29 mm) using the transfemoral approach. The primary endpoint was all-cause mortality at 30 days. Secondary endpoints included valve performance, improvement in functional class, and procedural outcomes as defined by Valve Academic Research Consortium criteria. Results A total of 220 patients (mean age 83.0 ± 4.6 years, 74.3% women, mean Society of Thoracic Surgeons score 5.8%) had valves implanted. All resheathing and repositioning attempts (n = 72) were successful. At 30 days, all-cause mortality was 3.6%. Procedural outcomes included disabling (major) stroke (3.2%), major vascular complications (7.2%), and permanent pacemaker implantation (13.5%). Compared with baseline, 75.8% of patients improved by ≥1 New York Heart Association functional class at 30 days. The rate of moderate paravalvular leak was 5.7%, with no severe paravalvular leak reported. No differences in paravalvular leak incidence and severity were observed among valve sizes (p = 0.24). Conclusions Across all valve sizes, use of the repositionable Portico transcatheter aortic valve replacement system resulted in safe and effective treatment of aortic stenosis in high-risk patients. [ABSTRACT FROM AUTHOR]

Objectives This study sought to assess the safety and effectiveness of the drug-filled stent (DFS) (Medtronic, Santa Rosa, California) in the treatment of patients with coronary artery disease. Background Polymer-free drug-eluting stents have the potential to improve clinical outcomes and facilitate shorter durations of dual antiplatelet therapy. The polymer-free DFS is made from a trilayered continuous wire with an outer cobalt chromium layer, a middle tantalum layer, and an inner lumen coated with sirolimus. Small laser-drilled holes on the abluminal stent surface control drug elution. Methods The RevElution trial enrolled 100 patients with de novo coronary lesions 2.25 to 3.50 mm in diameter and length ≤27 mm in 2 cohorts of 50 patients for angiographic, intravascular ultrasound, and clinical assessment at 9 or 24 months, with optical coherence tomography performed in a subset of 30 patients at each time period. The primary endpoint was angiographic in-stent late lumen loss at 9 months compared with Resolute zotarolimus-eluting stent (Medtronic) historical control data. Results Fifty patients with 56 lesions were treated with DFS in the 9-month cohort. In-stent late lumen loss was 0.26 ± 0.28 mm for DFS and 0.36 ± 0.52 mm for Resolute (p noninferiority <0.001). The binary angiographic restenosis rate was 0%. Median stent strut coverage by optical coherence tomography was 91.4%, 95.6%, and 99.1% at 1, 3, and 9 months, respectively. One non–Q-wave myocardial infarction occurred, with a 9-month target lesion failure rate of 2.1%. No stent thrombosis occurred. Conclusions At 9 months, the polymer-free DFS was safe and effective with high rates of early strut coverage and noninferior late lumen loss compared to Resolute. (Medtronic RevElution Trial [RevElution]; NCT02480348 ) [ABSTRACT FROM AUTHOR]

Objectives This analysis presents the first report of 1-year outcomes of the 120 patients enrolled in the REPRISE II (Repositionable Percutaneous Placement of Stenotic Aortic Valve Through Implantation of Lotus Valve System–Evaluation of Safety and Performance) study. Background The fully repositionable and retrievable Lotus Valve (Boston Scientific, Marlborough, Massachusetts) was designed to facilitate accurate positioning, early valve function, and hemodynamic stability during deployment and to minimize paravalvular regurgitation in patients undergoing transcatheter aortic valve replacement. Methods The study enrolled 120 symptomatic patients 70 years of age or older at 14 centers in Australia and Europe. Patients had severe calcific aortic stenosis and were deemed to be at high or extreme risk of surgery based on assessment by the heart team. Results The mean age was 84.4 ± 5.3 years, 57% (68 of 120) of patients were women, and the mean Society of Thoracic Surgeons score was 7.1 ± 4.6. The mean baseline aortic valve area was 0.7 ± 0.2 cm 2 , and the mean transvalvular pressure gradient was 46.4 ± 15.0 mm Hg. All patients were successfully implanted with a Lotus Valve, and 1-year clinical follow-up was available for 99.2% (119 of 120 of patients). The mean 1-year transvalvular aortic pressure gradient was 12.6 ± 5.7 mm Hg, and the mean valve area was 1.7 ± 0.5 cm 2 . A total of 88.6% patients had no or trivial paravalvular aortic regurgitation at 1 year by independent core lab adjudication, and 97.1% of patients were New York Heart Association functional class I or II. At 1 year, the all-cause mortality rate was 10.9% (13 of 119 patients), disabling stroke rate was 3.4% (4 of 119 patients), disabling bleeding rate was 5.9% (7 of 119 patients), with no repeat procedures for valve-related dysfunction. A total of 31.9% (38 of 119 patients) underwent new permanent pacemaker implantation at 1 year. Conclusions At 1 year of follow-up, the Lotus Valve demonstrated excellent valve hemodynamics, no moderate or severe paravalvular regurgitation, and significant and sustained improvement in New York Heart Association functional class status, with good clinical outcomes. (Repositionable Percutaneous Placement of Stenotic Aortic Valve Through Implantation of Lotus Valve System–Evaluation of Safety and Performance [REPRISE II]; NCT01627691 ) [ABSTRACT FROM AUTHOR]

Renal denervation has emerged as a novel approach for the treatment of patients with drug-resistant hypertension. To date, only limited data have been published using multielectrode radiofrequency ablation systems. In this article, we present the 12-month data of EnligHTN I, a first-in-human study using a multielectrode ablation catheter. EnligHTN I enrolled 46 patients (average age, 60±10 years; on average 4.7±1.0 medications) with drug-resistant hypertension. Eligible patients were on ≥3 antihypertensive medications and had a systolic blood pressure (BP) ≥160 mm Hg (≥150 mm Hg for diabetics). Bilateral renal artery ablation was performed using a percutaneous femoral approach and standardized techniques. The average baseline office BP was 176/96 mm Hg, average 24-hour ambulatory BP was 150/83 mm Hg, and average home BP was 158/90 mm Hg. The average reductions (mm Hg) at 1, 3, 6, and 12 months were as follows: office: -28/-10, -27/-10, -26/-10, and -27/-11 mm Hg (P<0.001 for all); 24-hour ambulatory: -10/-5, -10/-5, -10/-6 (P<0.001 for all), and -7/-4 for 12 months (P<0.0094). Reductions in home measurements (based on 2-week average) were -9/-4, -8/-5,-10/-7, and -11/-6 mm Hg (P<0.001 at 12 months). At 12 months, there were no signals of worsening renal function and no new serious or life-threatening adverse events. One patient with baseline nonocclusive renal artery stenosis progressed to 75% diameter stenosis, requiring renal artery stenting. The 12-month data continue to demonstrate safety and efficacy of the EnligHTN ablation system in patients with drug-resistant hypertension. Home BP measurements parallel measurements obtained with 24-hour ambulatory monitoring. [ABSTRACT FROM AUTHOR]

Epicardial plaque burden and endothelial function are recognized predictors of coronary events. We aimed to investigate mechanistic relationships between atheroma volume and endothelial function in patients with non-ST-segment-elevation myocardial infarction (NSTEMI) using intravascular ultrasound.In coronary vessels of patients with near-normal or minimal angiographic disease (n=23) and NSTEMI (n=24), intravascular ultrasound-derived measures (percent atheroma volume), arterial remodeling index, and segmental lumen volumes were performed in contiguous 5-mm epicardial segments. Repeat intravascular ultrasound imaging was performed after consecutive 5-minute intracoronary infusions (vehicle solution, 0.30 μg/min and 0.60 μg/min intracoronary salbutamol) to measure changes in segmental lumen volume (endothelium-dependent function). Male sex, diabetes mellitus, smoking, higher triglycerides, and lower high-density lipoprotein cholesterol were more prevalent in the NSTEMI group. Patients with NSTEMI demonstrated greater segmental percent atheroma volume (40.4±12 versus 27.5±14%, P<0.001), remodeling index (1.2 [1.0-1.5] versus 1.0 [0.9-1.0], P<0.001), and displayed less endothelium-dependent vasomotion (% change segmental lumen volume: 2.1±0.89 versus 5.1±0.89%, P=0.02) compared to patients with minimal angiographic disease. No significant difference in endothelial function between both groups was observed when controlling for plaque burden. Multivariate analysis for change in segmental lumen volume identified percent atheroma volume (β=-0.18, P=0.0004), high-sensitivity C-reactive protein >2 mg/L (β=-3.1, P=0.03), diabetes mellitus (β=-6.9, P<0.0001), low-density lipoprotein cholesterol levels (β=-0.04, P=0.01), and smoking (β=-3.2, P=0.01) as independent associates.Although coronary endothelial vasoreactivity is blunted in the setting of NSTEMI, this is a reflection of the greater volume of atherosclerosis and cardiovascular risk factors. Thus, the relationship between coronary endothelium-dependent vasomotor reactivity and atheroma volume remains constant irrespective of the nature of the clinical presentation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI. Methods and Results: Sprague-Dawley rats were used. Allogeneic prospectively isolated MSC (“low” dose 1 × 106 or “high” dose 2 × 106 cells) were delivered by transepicardial injection immediately after MI (“early-low,” “early-high”), or 1 week later (“late-low,” “late-high”). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration. Conclusions: The nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients. [Copyright &y& Elsevier]

Objectives: This study sought to compare the efficacy and safety results after coronary implantation of a combined sirolimus-eluting CD34 antibody coated Combo stent (OrbusNeich Medical, Ft. Lauderdale, Florida) with the paclitaxel-eluting Taxus Liberté stent (PES) (Boston Scientific, Natick, Massachusetts). This report summarizes the first-in-man randomized, controlled multicenter REMEDEE trial (Randomized study to Evaluate the safety and effectiveness of an abluMinal sirolimus coatED bio-Engineered StEnt) angiographic, intravascular ultrasound, and clinical results up to 12 months. Background: Drug-eluting stents have limited restenosis and reintervention but are complicated by especially late and very late stent thrombosis and accelerated neoatherosclerosis. Alternative or adjunct technologies should address these limitations. Methods: One hundred eighty-three patients with de novo native coronary artery stenoses were randomized 2:1 to Combo stent or PES implantation. The primary endpoint is the angiographic in-stent late lumen loss at 9 months, which was tested for noninferiority between the 2 stent groups. Secondary endpoints include the occurrence of major adverse cardiac events. Results: The Combo stent was found to be noninferior to the PES in 9-month angiographic in-stent late lumen loss with 0.39 ± 0.45 mm versus 0.44 ± 0.56 mm (pnoninferiority = 0.0012). At 12 months, the occurrence of major adverse cardiac events was 8.9% in the Combo group and 10.2% in the PES group (p = 0.80) with no difference in mortality, occurrence of myocardial infarction, or target lesion revascularization. No stent thrombosis was reported in either group. Conclusions: In the REMEDEE trial the Combo stent has shown to be effective by meeting the primary noninferiority angiographic endpoint and safe, with an overall low rate of clinical events in both stent groups, including no stent thrombosis up to 12 months. [Copyright &y& Elsevier]

Background: Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown. Objective: To examine the effect of progressive weight gain on the substrate for AF. Methods: Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor. Results: Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels. Conclusions: Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF. [Copyright &y& Elsevier]

Abstract: Background: Cumulative dose-dependent nonischemic cardiomyopathy (NICM) remains a significant risk with the use of some chemotherapeutic agents. In this context, omega-3 polyunsaturated fatty acids (PUFA) have been investigated for their cardioprotective potential in rodent and in vitro models of anthracycline toxicity, with conflicting results. This study evaluated prophylactic omega-3 PUFA supplementation in a large-animal model of anthracycline-induced NICM. Methods and Results: Merino sheep were randomized to oral drenching with omega-3 PUFA (fish oil; n = 8) or olive oil placebo (n = 9) 3 weeks before commencing repeated intracoronary infusions of doxorubicin (DOX) to induce cardiac dysfunction. Cumulative DOX dose was 3.6 mg/kg. Drenching was continued for 12 weeks after final DOX exposure. Despite significant increases in tissue omega-3 PUFA levels (P < .05 vs placebo), omega-3–treated sheep displayed greater signs of anthracycline cardiotoxicity than placebo animals, consisting of left ventricular dilatation and a greater decline in ejection fraction (P < .05), although myocardial fibrosis burden was similar in both groups. Conclusions: Dietary intake of omega-3 PUFA fails to prevent and may indeed exacerbate DOX-induced cardiotoxicity. Clinical use of omega-3 supplementation during chemotherapy should be deferred until more information is available regarding the mechanisms of interaction between fatty acids and the myocardium during anthracycline exposure. [Copyright &y& Elsevier]

The article introduces the technology, computed tomography coronary angiography (CTCA). It is stated that CTCA shows consistency in excluding severe coronary artery disease (CAD) discreetly. It is declared most applicably used by symptomatic patients with low or intermediate pretest probability of CAD. Appropriate use and limitations of this developing technology to prevent possible misuse is also discussed.

The article compares the effectiveness of zotarolimus-eluting stents with polymer formulations in the RESpOnse EvaLUation of the MedTronic Endeavor CR ABT-578 Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions (RESOLUTE), Evaluated the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions (ENDEAVOR II) and ZoMaxx I trials. RESOLUTE had less neointimal coverage. The boidurable polymer in RESOLUTE was linked with neointimal suppression in zotarolimus-eluting stents.

Background: It has been suggested that omega-3 polyunsaturated fatty acids (n-3 PUFAs) may prevent the development of atrial fibrillation (AF). Objective: The purpose of this study was to evaluate the impact of these agents on development of the AF substrate in heart failure (HF). Methods: In this study, HF was induced by intracoronary doxorubicin infusions. Twenty-one sheep [7 with n-3 PUFAs treated HF (HF-PUFA), 7 with olive oil–treated HF controls (HF-CTL), 7 controls (CTL)] were studied. Open chest electrophysiologic study was performed with assessment of biatrial effective refractory period (ERP) and conduction. Cardiac function was monitored by magnetic resonance imaging. Atrial n-3 PUFAs levels were quantified using chromatography. Structural analysis was also performed. Results: Atrial n-3 PUFAs levels were twofold to threefold higher in the HF-PUFA group. n-3 PUFAs prevented the development of HF-related left atrial enlargement (P = .001) but not left ventricular/atrial dysfunction. Atrial ERP was significantly lower in the HF-PUFA group (P <.001), but ERP heterogeneity was unchanged. In addition, n-3 PUFAs suppressed atrial conduction abnormalities seen in HF of prolonged P-wave duration (P = .01) and slowed (P <.001) and heterogeneous (P <.05) conduction. The duration of induced AF episodes in HF-PUFA was shorter (P = .02), although AF inducibility was unaltered (P = NS). A 20% reduction of atrial interstitial fibrosis was seen in the HF-PUFA group (P <.05). Conclusion: In this ovine HF study, chronic n-3 PUFAs use protected against adverse atrial remodeling by preventing atrial enlargement, fibrosis, and conduction abnormalities leading to shorter AF episodes despite lower ERP. [ABSTRACT FROM AUTHOR]

Objectives: This study set out to evaluate the safety and efficacy of allogeneic bone marrow mesenchymal precursor cells (MPC) delivered by multisegmental, transendocardial implantation in the setting of nonischemic cardiomyopathy (NICM). Background: Prospectively isolated MPC have shown capacity to mediate cardiovascular repair in myocardial ischemia. However, their efficacy in NICM remains undetermined. Methods: Mesenchymal precursor cells were prepared from ovine bone marrow by immunoselection using the tissue nonspecific alkaline phosphatase, or STRO-3, monoclonal antibody. Fifteen sheep with anthracycline-induced NICM were assigned to catheter-based, transendocardial injections of allogeneic MPC (n = 7) or placebo (n = 8), under electromechanical mapping guidance. Follow-up was for 8 weeks, with end points assessed by cardiac magnetic resonance, echocardiography, and histology. Results: Intramyocardial injections were distributed similarly throughout the left ventricle in both groups. Cell transplantation was associated with 1 death late in follow-up, compared with 3 early deaths among placebo animals. Left ventricular end-diastolic size increased in both cohorts, but MPC therapy attenuated end-systolic dilation and stabilized ejection fraction, with a nonsignificant increase (37.3 ± 2.8% before, 39.2 ± 1.4% after) compared with progressive deterioration after placebo (38.8 ± 4.4% before, 32.5 ± 4.9% after, p < 0.05). Histological outcomes of cell therapy included less fibrosis burden than in the placebo group and an increased density of karyokinetic cardiomyocytes and myocardial arterioles (p < 0.05 for each). These changes occurred in the presence of modest cellular engraftment after transplantation. Conclusions: Multisegmental, transendocardial delivery of cell therapy can be achieved effectively in NICM using electromechanical navigation. The pleiotropic properties of immunoselected MPC confer benefit to nonischemic cardiac disease, extending their therapeutic potential beyond the setting of myocardial ischemia. [Copyright &y& Elsevier]

Background: Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor. Objective: The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension. Methods: Thirty-two sheep were studied: 21 with induced “one-kidney, one-clip” hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters. Results: The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis. Conclusion: Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF. [ABSTRACT FROM AUTHOR]

Background: Hypertension is frequently complicated by the development of atrial fibrillation (AF). However, the mechanisms of this link remain poorly understood. In addition, whether short-term hypertension can result in a substrate for AF is not known. Objective: The purpose of this study was to characterize the atrial substrate predisposing to AF due to short-duration hypertension. Methods: Sixteen sheep were studied: 10 had induced hypertension for 7 ± 4 weeks via the “one-kidney, one-clip” model, and six were controls. Cardiac magnetic resonance imaging was used to assess functional changes. Open-chest electrophysiological study was performed using a custom-made 128-electrode epicardial plaque applied to both right (RA) and left atria (LA), including the Bachmann''s bundle, to determine effective refractory periods (ERPs) and conduction velocity at four pacing cycle lengths from six sites. Tissue specimens were harvested for structural analysis. Results: The hypertensive group demonstrated the following compared with controls: higher blood pressure (P <.0001), enlarged LA (P <.05), reduced LA ejection fraction (P <.05), uniformly higher mean ERP (P <.001), slower mean conduction velocity (P <.001), higher conduction heterogeneity index (P <.0001), greater AF inducibility (P = .03), and increased AF durations (P = .04). Picrosirius red staining of atrial tissues revealed increased interstitial fibrosis (P <.0001). There was also evidence of increased inflammatory cell infiltrates (P <.0001). Conclusion: Short-duration hypertension is associated with significant atrial remodeling characterized by atrial enlargement/dysfunction, interstitial fibrosis, inflammation, slowed/heterogeneous conduction, increased ERP, and greater propensity for AF. [Copyright &y& Elsevier]

Objectives: The purpose of the study was to understand determinants of infarct size in a primary percutaneous intervention (PCI) population treated with pexelizumab compared with placebo. Background: In the multicenter APEX-AMI (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction) trial, pexelizumab did not reduce 90-day mortality. Cardiac magnetic resonance (CMR) with delayed enhancement was used in a substudy evaluating infarct size and left ventricular ejection fraction (LVEF). Methods: Consecutive patients undergoing primary PCI for first myocardial infarction (MI) as part of the APEX-AMI trial were enrolled in this substudy at 5 centers. The CMR was completed on days 3 to 5 (n = 99) and day 90 (n = 83) following PCI. Central core lab-masked analyses for quantified LVEF, volumes, and infarct size by planimetry were performed. Results: Patients were 60 ± 12 years of age, male (n = 83 [84%]), had similar time from symptom onset to presentation (median 2.6 h vs. 2.5 h; p = 1.0), and similar baseline ST-segment deviation (13.5 mm vs. 14 mm; p = 0.59) in both groups. Pexelizumab-treated patients had smaller infarct size (day 3 LV 10.5% vs. 16.2%, p = 0.022; day 90 LV 5.9% vs. 12.4%, p = 0.015) and higher LVEF (day 3 50.3% vs. 46.2%, p = 0.073; day 90 53.9% vs. 49.3%, p = 0.036) compared with placebo-treated patients. The median peak creatine kinase in the pexelizumab group was also significantly less than placebo (922 mg/dl vs. 1,973 mg/dl; p = 0.03). Notably, the pexelizumab group had lower Thrombolysis In Myocardial Infarction (TIMI) flow grade pre-PCI (46.9% vs. 75.0%; p = 0.018), a difference not seen in the overall APEX-AMI study. A multivariate model including baseline features and pexelizumab treatment found anterior MI location and pre-PCI TIMI flow to be significant independent predictors infarct size (p = 0.001), whereas pexelizumab was not (p = 0.29). No death, heart failure, or shock was noted in either substudy group at 90 days. Conclusions: In a CMR substudy of pexelizumab in MI, baseline TIMI flow grade and anterior location were the only predictors of infarct size, with a reduction of pre-PCI TIMI flow grade 0 by 28%, leading to a 35% reduction in infarct size. (The APEX-AMI Trial; NCT00091637) [Copyright &y& Elsevier]

Background: Information regarding left atrial (LA) substrate in conditions predisposing to atrial fibrillation (AF) is limited. Objective: This study sought to characterize the left atrial remodeling that results from chronic atrial stretch caused by atrial septal defect (ASD). Methods: Eleven patients with hemodynamically significant ASDs and 12 control subjects were studied. The following were evaluated using multipolar catheters: effective refractory period (ERP) at 7 sites, P-wave duration (PWD), conduction time, and inducibility of AF. LA electroanatomic maps were created to determine atrial activation, and regional conduction and voltage abnormalities. Results: Patients with ASDs showed significant LA enlargement (P <0.001), unchanged or prolonged atrial ERPs, increase in LA conduction times (P = 0.03), prolonged PWD (P <0.001), regional conduction slowing (P <0.001), greater number of double potentials or fractionated electrograms (P <0.0001), reduced atrial voltage (P <0.001), and more frequent electrical scar (P = 0.005) compared with control subjects. In addition, patients with ASDs showed a greater propensity for sustained AF with single extrastimuli (4 of 11 vs. 0 of 12, P = 0.04). Conclusion: ASDs are associated with chronic left atrial stretch, which results in remodeling characterized by LA enlargement, loss of myocardium, and electrical scar that results in widespread conduction abnormalities but with no change or an increase in ERP. These abnormalities were associated with a greater propensity for sustained AF. [Copyright &y& Elsevier]

Abstract: Background: There is a paucity of published experience investigating novel treatment strategies in preclinical and clinical studies of nonischemic cardiomyopathy. We set out to validate an ovine model of doxorubicin-induced cardiomyopathy, using cardiac magnetic resonance (CMR) to assess cardiac function. Methods and Results: Ten Merino sheep (51 ± 8 kg) underwent intracoronary infusions of doxorubicin (1 mg/kg dose) every 2 weeks. Cardiac magnetic resonance was performed at baseline and at 6 weeks after final doxorubicin dose, along with transthoracic echocardiography, measurement of right heart pressure, and cardiac output. After final CMR examination, heart specimens were harvested for histologic analysis. The total dose of doxorubicin administered per animal was 3.8 ± 0.5 mg/kg. Two animals died prematurely during the study protocol, with evidence of myocarditis. In the remaining 8 sheep, left ventricular ejection fraction dropped from 46.2 ± 4.7% to 31.3 ± 8.5% (P < .001), accompanied by reductions in fractional shortening (31.6 ± 1.8% baseline versus 18.2 ± 3.9% final, P < .01), cardiac output (3.8 ± 0.6 L/min versus 3.0 ± 0.4 L/min, P < .05) and right ventricular ejection fraction (39.5 ± 5.6% versus 28.9 ± 9.6%, P < .05). However, significant end-diastolic dilatation of the left ventricle was not observed. Delayed gadolinium uptake was detected by CMR in 2 sheep, in a typical nonischemic pattern. Widespread, multifocal histologic abnormalities consisted of cardiomyocyte degeneration, vasculopathy, inflammatory infiltrates, and replacement fibrosis. Conclusions: Moderate-severe cardiac dysfunction was reproducibly achieved through high-dose intracoronary doxorubicin, with acceptable animal mortality. CMR provides a powerful tool for assessing myocardial function, structural remodeling, and viability in such models. [Copyright &y& Elsevier]

Supplemental Digital Content is available in the text. Background: Despite treatment guidance endorsing shortened dual antiplatelet therapy (DAPT) duration in high bleeding risk (HBR) patients after drug-eluting stents, limited evidence exists to support these recommendations. The present study was designed to examine the safety and effectiveness of 1-month DAPT duration following percutaneous coronary intervention with zotarolimus-eluting stents in HBR patients. Methods: Onyx ONE Clear was a prospective, multicenter, nonrandomized study evaluating the safety and effectiveness of 1-month DAPT followed by single antiplatelet therapy in HBR patients undergoing percutaneous coronary intervention with Resolute Onyx drug-eluting stents. The primary analysis of cardiac death or myocardial infarction between 1 month and 1 year was performed in the prespecified one-month clear population of patients pooled from the Onyx ONE US/Japan study and Onyx ONE randomized controlled trial. One-month clear was defined as DAPT adherence and without major adverse events during the first month following percutaneous coronary intervention. Results: Among patients enrolled in Onyx ONE US/Japan (n=752) and Onyx ONE randomized controlled trial (n=1018), 1506 patients fulfilled one-month clear criteria. Mean HBR characteristics per patient was 1.6 with 44.7% having multiple risks. By 2 months and 1 year, respectively, 96.9% and 89.3% of patients were taking single antiplatelet therapy. Between 1 month and 1 year, the rate of the primary end point was 7.0%. The 1-sided upper 97.5% CI was 8.4%, less than the performance goal of 9.7% (P <0.001). Conclusions: Among HBR patients who were event free before DAPT discontinuation at 1 month, favorable safety and effectiveness through 1 year support treatment with Resolute Onyx drug-eluting stents as part of an individualized strategy for shortened DAPT duration following percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier NCT03647475. [ABSTRACT FROM AUTHOR]

Background Obesity and pericardial adipose tissue are independent risk factors for atrial fibrillation (AF) and adverse cardiac structural remodeling. The effect of weight reduction on pericardial adipose tissue and cardiac structure remains unknown. Methods We prospectively performed cardiac magnetic resonance imaging on 87 participants with AF undergoing either structured weight management (intervention) or general lifestyle advice (control). We measured pericardial adipose tissue, atrial and ventricular volumes, and myocardial mass at baseline and 12 months. Results In total, 69 participants underwent baseline and 12-month follow-up cardiac magnetic resonance imaging (intervention n = 36 and controls n = 33). From baseline to 12 months, weight loss (kg, mean [95% CI]) was greater in the intervention group from 101.5 kg (97.2-105.8 kg) to 86.5 kg (81.2-91.9 kg) as compared with controls from 102.6 kg (97.2-108.1 kg) to 98.7 kg (91.0-106.3 kg) (time-group interaction P < .001). The intervention group showed a reduction in left atrial volumes (mL) from 105.0 mL (98.9-111.1 mL) to 96.4 mL (91.6-101.1 mL), whereas the change in the control group was from 108.8 mL (99.6-117.9 mL) to 108.9 mL (99.8-118.0 mL) (time-group interaction P < .001). There was a decline in pericardial adipose tissue (cm 3 ) from 140.9 cm 3 (129.3-152.4 cm 3 ) to 118.8 cm 3 (108.1-129.6 cm 3 ) and myocardial mass (g) from 137.6 g (128.1-147.2 g) to 123.1 g (114.5-131.7 g) in the intervention group, whereas the change in the control group was from 143.2 cm 3 (124.6-161.7 cm 3 ) to 147.2 cm 3 (128.9-165.4 cm 3 ) for pericardial adipose tissue and 138.3 g (124.8-151.8 g) to 140.7 g (127.4-154.1 g) for myocardial mass (both variables, time-group interaction P < .001). Conclusions Weight reduction results in favorable structural remodeling and a reduction in pericardial adipose tissue burden. [ABSTRACT FROM AUTHOR]