Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial.

BACKGROUND: Current guidelines recommend coronary artery bypass graft surgery (CABG) when treating significant de novo left main coronary artery (LM) stenosis; however, percutaneous coronary intervention (PCI) has a class IIa indication for unprotected LM disease in selected patients. This analysis compares 5-year clinical outcomes in PCI- and CABG-treated LM patients in the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial, the largest trial in this group to date. METHODS AND RESULTS: The SYNTAX trial randomly assigned 1800 patients with LM or 3-vessel disease to receive either PCI (with TAXUS Express paclitaxel-eluting stents) or CABG. The unprotected LM cohort (N=705) was predefined and powered. Major adverse cardiac and cerebrovascular event rates at 5 years was 36.9% in PCI patients and 31.0% in CABG patients (hazard ratio, 1.23 [95% confidence interval, 0.95-1.59]; P=0.12). Mortality rate was 12.8% and 14.6% in PCI and CABG patients, respectively (hazard ratio, 0.88 [95% confidence interval, 0.58-1.32]; P=0.53). Stroke was significantly increased in the CABG group (PCI 1.5% versus CABG 4.3%; hazard ratio, 0.33 [95% confidence interval, 0.12-0.92]; P=0.03) and repeat revascularization in the PCI arm (26.7% versus 15.5%; hazard ratio, 1.82 [95% confidence interval, 1.28-2.57]; P<0.01). Major adverse cardiac and cerebrovascular events were similar between arms in patients with low/intermediate SYNTAX scores but significantly increased in PCI patients with high scores (≥33). CONCLUSIONS: At 5 years, no difference in overall major adverse cardiac and cerebrovascular events was found between treatment groups. PCI-treated patients had a lower stroke but a higher revascularization rate versus CABG. These results suggest that both treatments are valid options for LM patients. The extent of disease should accounted for when choosing between surgery and PCI, because patients with high SYNTAX scores seem to benefit more from surgery compared with those in the lower tertiles. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00114972.

Left Atrial Appendage Occlusion in the Elderly: Insights From PROTECT-AF, PREVAIL, and Continuous Access Registries.

BACKGROUND: Data on the safety and efficacy of left atrial appendage occlusion (LAAO) in elderly patients are limited. OBJECTIVES: This study aimed to compare the outcomes of LAAO between patients ≥80 and <80 years of age. METHODS: We included patients enrolled in randomized trials and nonrandomized registries of the Watchman 2.5 device. The primary efficacy endpoint was a composite of cardiovascular/unknown death, stroke, or systemic embolism at 5 years. Secondary endpoints included cardiovascular/unknown death, stroke, systemic embolism, and major and nonprocedural bleeding. Survival analyses were performed using the Kaplan-Meier, Cox proportional hazards, and competing risk analysis methods. Interaction terms were used to compare the 2 age groups. We also estimated the average treatment effect of the device with the use of inverse probability weighting. RESULTS: We studied 2,258 patients, of whom 570 (25.2%) were ≥80 years old, and 1,688 (74.8%) were <80 years old. Procedural complications at 7 days were similar in both age groups. The primary endpoint occurred in 12.0% in the device group vs 13.8% in the control group (HR: 0.9; 95% CI: 0.6-1.4) among patients <80 years of age and in 25.3% vs 21.7%, respectively (HR: 1.2; 95% CI: 0.7-2.0) among patients ≥80 (interaction P = 0.48). There was no interaction between age and treatment effect for any of the secondary outcomes. The average treatment effects of LAAO (compared with warfarin) were similar in the elderly population (compared with younger patients). CONCLUSIONS: Despite the higher event rates, octogenarians derive similar benefits from LAAO as their younger counterparts. Age alone should not preclude LAAO in otherwise suitable candidates.

Intracardiac vs Transesophageal Echocardiography for Left Atrial Appendage Occlusion With Watchman FLX in the U.S.

BACKGROUND: Intraprocedural imaging is critical for device delivery in transcatheter left atrial appendage occlusion (LAAO). Although pivotal trials of LAAO devices were conducted using transesophageal echocardiography (TEE), intracardiac echocardiography (ICE) is an emerging imaging modality. OBJECTIVES: This study compared outcomes after ICE- and TEE-guided Watchman FLX implantation in the SURPASS (SURveillance Post Approval AnalySiS Plan) nationwide LAAO registry. METHODS: Baseline characteristics were compared using chi-square and t-tests. Outcomes were reported in unadjusted and adjusted comparisons via propensity weighting. RESULTS: Between August 2020 and September 2021, LAAO was attempted in 39,759 patients at 698 sites, including 2,272 cases (5.7%) with ICE and 31,835 (80.0%) with TEE. ICE and TEE patients had similar baseline characteristics and mean procedural times (ICE 82 minutes vs TEE 78 minutes). ICE patients were less likely to receive general anesthesia (54% vs 98%, P < 0.01). Successful device implantation (98.3% vs 97.6%) and complete seal rates at 45 days were similar (n = 25,280; 83% vs 82%). Most adverse event rates were similar; unadjusted mortality rates at 45 days were 1.1% for ICE vs 0.8% for TEE (P = 0.14), and 1.0% vs 0.7% (P = 0.27) in adjusted analyses. Even after adjustment, pericardial effusion rates requiring intervention were significantly higher with ICE at 45 days (1.0% vs 0.5%; P = 0.02). This rate decreased as operators performed more ICE-guided procedures, although 82% of operators had performed <10 ICE-guided procedures overall. CONCLUSIONS: In the largest comparison to date, ICE use was infrequent. ICE and TEE both achieved high rates of complete LAAO. ICE was associated with significantly higher rates of pericardial effusion requiring intervention.

Using digital health technology to evaluate the impact of chocolate on blood pressure: Results from the COCOA-BP study.

Background: High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD). Consumption of dark chocolate, which is high in flavonoids that may reduce CVD risk, is an attractive intervention to reduce to BP. Additionally, the use of mobile health (mHealth) technologies (eg, telehealth, smartphones, and wearable devices) can improve outcomes in patients with CVD. Objective: The purpose of this study was to investigate the impact of dark chocolate intake on BP, subject use of mHealth, and integration of mHealth into a clinical trial. Methods: The COCOA-BP (ChOcolate COnsumption And Blood Pressure) study was a prospective, single-center, pre-/postintervention study that enrolled 62 healthy volunteers. The study consisted of 3 phases: smartwatch/smart BP monitor familiarization and washout from chocolate (week 1); control (week 2); and intervention (weeks 3 and 4). During the intervention phase, subjects consumed 50 g of dark chocolate per day. The primary endpoint was change in resting systolic BP between the intervention and control phases. Additional endpoints included device accuracy and correlation with physical activity. Results: Mean resting systolic BP was 116.4 mm Hg before chocolate intake among 62 participants (mean age 37 years; 61% female). After chocolate intake, mean resting systolic BP was 116.0 mm Hg (difference -0.4; P = .69). These findings suggest that 2 weeks of dark chocolate intake did not reduce resting systolic BP. There was poor agreement between mHealth device and standard (nurse-performed) measurements. Conclusion: In this study, short-term dark chocolate intake did not seem to reduce BP. mHealth technology shows great potential for use in clinical studies, but challenges related to device accuracy and compliance need to be addressed.

Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia.

Schizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of erbB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms.

Current State of Bioabsorbable Polymer-Coated Drug-Eluting Stents.

Drug-eluting stents (DES) have been shown to significantly reduce clinical and angiographic restenosis compared to bare metal stents (BMS). The polymer coatings on DES elute antiproliferative drugs to inhibit intimal proliferation and prevent restenosis after stent implantation. Permanent polymers which do not degrade in vivo may increase the likelihood of stent-related delayed arterial healing or polymer hypersensitivity. In turn, these limitations may contribute to an increased risk of late clinical events. Intuitively, a polymer which degrades after completion of drug release, leaving an inert metal scaffold in place, may improve arterial healing by removing a chronic source of inflammation, neoatherosclerosis, and/or late thrombosis. In this way, a biodegradable polymer may reduce late ischemic events. Additionally, improved healing after stent implantation could reduce the requirement for long-term dual antiplatelet therapy and the associated risk of bleeding and cost. This review will focus on bioabsorbable polymer-coated DES currently being evaluated in clinical trials.

The Tlx gene regulates the timing of neurogenesis in the cortex.

The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx-/- embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.

Loss of the tailless gene affects forebrain development and emotional behavior.

We are studying the role of the evolutionarily conserved tlx gene in forebrain development in mice. Tlx is expressed in the ventricular zone that gives rise to neurons and glia of the forebrain. We have shown by mutating the tlx gene in mice, that in the absence of this transcription factor, mutant animals survive, but suffer specific anatomical defects in the limbic system. Because of these developmentally induced structural changes, mice with a mutation in the tlx gene can function, but exhibit extreme behavioral pathology. Mice show heightened aggressiveness, excitability, and poor cognition. In this article, we present a summary of our findings on the cellular and behavioral changes in the forebrain of mutant animals. We show that absence of the tlx gene leads to abnormal proliferation and differentiation of progenitor cells (PCs) in the forebrain from embryonic day 9 (E9). These abnormalities lead to hypoplasia of superficial cortical layers and subsets of GABAergic interneurons in the neocortex. We examined the behavior of mutant animals in three tests for anxiety/fear: the open field, the elevated plus maze, and fear conditioning. Mutant animals are less anxious and less fearful when assessed in the elevated plus and open-field paradigm. In addition, mutant animals do not condition to either the tone or the context in the fear-conditioning paradigm. These animals, therefore, provide a genetic tool to delineate structure/function relationships in defined regions of the brain and decipher how their disruption leads to behavioral abnormalities.

Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain.

Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1beta cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1beta cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders.

Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.