Neurologic Complications of Unprotected Transcatheter Aortic Valve Implantation (from the Neuro-TAVI Trial).

Cerebral embolization during transcatheter aortic valve implantation (TAVI) can lead to a spectrum of clinically relevant manifestations, ranging from overt stroke to mild neurologic or cognitive deficits and subclinical cerebral infarcts. This study sought to determine the frequency of neurologic injury, cerebral ischemic lesions, and cognitive dysfunction in subjects undergoing contemporary commercial TAVI in the United States. Neuro-TAVR is the first prospective, multicenter study to use serial systematic neurologic and cognitive assessments and diffusion-weighted magnetic resonance imaging (at 4 ± 2 days after procedure) to investigate the incidence and severity of neurologic injury after contemporary unprotected TAVI in the United States. A total of 44 consecutive patients underwent TAVI at 5 US sites. Diffusion-weighted magnetic resonance imaging lesions were detected in 94%, with a mean of 10.4 ± 15.3 lesions per subject and a median total lesion volume of 295 mm3 (interquartile range 71.6 to 799.6 mm3). New neurologic impairment (worsening in National Institutes of Health Stroke Scale score from baseline with new cerebral lesions) occurred in 22.6% (7 of 31) of subjects at discharge and 14.8% (4 of 27) at 30 days. In addition, cognitive decrements from baseline were identified by the Montreal Cognitive Assessment in 33% (12 of 36) of subjects at discharge and 41% (13 of 32) at 30 days. In conclusion, this contemporary cohort of US patients confirms that TAVI results in cerebral infarction in most patients and that 1 in 5 patients have measurable neurologic impairment and 1 in 3 patients have decrease in cognitive measures by Montreal Cognitive Assessment score after TAVI, reinforcing the need for methods to mitigate the risk of brain injury during TAVI.

Carotid stenting versus endarterectomy for the treatment of carotid artery stenosis: Contemporary results from a large single center study.

OBJECTIVE: To compare the complication rates associated with carotid endarterectomy (CEA) versus carotid artery stenting (CAS). BACKGROUND: Carotid stenosis is a well-known cause of stroke and increased mortality. The safety of carotid revascularization may be related to symptom status, medical comorbidities, use of embolic protection devices, as well as operator experience and these factors may vary across patient populations within a single operating center. METHODS: We retrospectively analyzed patients with carotid artery stenosis admitted to our hospital for carotid revascularization between January 1, 2007 and December 1, 2013. The primary end point was a composite endpoint of periprocedural death, stroke, and myocardial infarction (MI). RESULTS: Of the 718 patients admitted for carotid revascularization 525 (73.1%) underwent CEA and 193 (26.9%) underwent CAS. Both groups demonstrated similar rates of the composite endpoint, MI, and death; the stenting group demonstrated a higher rate of stroke (4.2% vs. 1.3%; P = 0.020). Adjusting for baseline medical comorbidities and symptom status mitigated this difference (P = 0.091 and 0.113, respectively). When stratified by department performing CAS, there was a significant difference in the occurrence of stroke (P = 0.033), which likewise disappeared in the multivariate regression analysis. CONCLUSION: The risk of the composite endpoint did not differ significantly between those undergoing CAS versus CEA. The stenting group demonstrated a higher rate of periprocedural stroke, which was also apparent when patients were stratified by stenting department. These differences were likely driven by variation in baseline medical comorbidities and symptom status. © 2016 Wiley Periodicals, Inc.

An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland.

The Rho family small GTPase Cdc42 has been implicated in a wide range of cellular functions including the establishment of cell polarity and the remodeling of the actin cytoskeletal architecture, resulting in the tight regulation of cell growth and survival during developmental processes. The complete knock-out of Cdc42 in the mouse is embryonic-lethal, and its targeted deletion in various tissues has been shown to disrupt tissue homeostasis. Thus far, in most studies, the targeted deletion of Cdc42 occurred during embryogenesis. Here, we have used a conditional gene deletion strategy in mice to probe the specific role of Cdc42 during adult mammary gland function. Cdc42 conditional-knock-out females were unable to adequately nourish their pups, due to a disorganized epithelial compartment within their mammary glands. A closer examination showed that their mammary epithelial cells were not able to maintain functional alveolar lumens, due to an inability to establish normal apical/basal epithelial polarity, as well as proper cell-cell contacts. Loss of these essential epithelial characteristics led to a premature sloughing off of the Cdc42-null epithelial cells. Overall our findings demonstrate that Cdc42 plays essential roles in mammary gland function post pregnancy, where it helps to establish proper epithelial cell polarity and tissue homeostasis during lactation.

Safety and performance of a novel embolic deflection device in patients undergoing transcatheter aortic valve replacement: results from the DEFLECT I study.

AIMS: This study aimed to evaluate the safety and performance of the TriGuard™ Embolic Deflection Device (EDD), a nitinol mesh filter positioned in the aortic arch across all three major cerebral artery take-offs to deflect emboli away from the cerebral circulation, in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: The prospective, multicentre DEFLECT I study (NCT01448421) enrolled 37 consecutive subjects undergoing TAVR with the TriGuard EDD. Subjects underwent clinical and cognitive follow-up to 30 days; cerebral diffusion-weighted magnetic resonance imaging (DW-MRI) was performed pre-procedure and at 4±2 days post procedure. The device performed as intended with successful cerebral coverage in 80% (28/35) of cases. The primary safety endpoint (in-hospital EDD device- or EDD procedure-related cardiovascular mortality, major stroke disability, life-threatening bleeding, distal embolisation, major vascular complications, or need for acute cardiac surgery) occurred in 8.1% of subjects (VARC-defined two life-threatening bleeds and one vascular complication). The presence of new cerebral ischaemic lesions on post-procedure DW-MRI (n=28) was similar to historical controls (82% vs. 76%, p=NS). However, an exploratory analysis found that per-patient total lesion volume was 34% lower than reported historical data (0.2 vs. 0.3 cm3), and 89% lower in patients with complete (n=17) versus incomplete (n=10) cerebral vessel coverage (0.05 vs. 0.45 cm3, p=0.016). CONCLUSIONS: Use of the first-generation TriGuard EDD during TAVR is safe, and device performance was successful in 80% of cases during the highest embolic-risk portions of the TAVR procedure. The potential of the TriGuard EDD to reduce total cerebral ischaemic burden merits further randomised investigation.

Multi-drug-resistant hypertension caused by severe aortic coarctation presenting in late adulthood.

Aortic coarctation, a congenital narrowing in the region of the ligamentum arteriosium, is a rare etiology for multi-drug-resistant hypertension in adulthood; however, advances in stenting modalities may offer long-term improvements in morbidity and possibly even cure. We report on a female patient in her late 50s presenting with refractory hypertension and severely elevated renin levels, ultimately diagnosed with aortic coarctation and treated with percutaneous stent implantation, which resulted in successful blood pressure control with verapamil monotherapy. This case highlights the efficacy of endovascular stent implantation for the treatment of coarctation and the need for clinicians to consider this disease entity in the differential diagnosis of refractory hypertension even in late adulthood.

Stooling pattern and early nutritional exposures associated with necrotizing enterocolitis in premature infants.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency affecting premature infants. A better understanding of the clinical signs and symptoms associated with the disease may result in an improved ability to more effectively intervene in patient care. One of the clinical signs that have not been fully explored is the stooling pattern of preterm infants. This retrospective case-control study included 258 premature infants born prior to 29 weeks of gestation: 129 infants with NEC and 129 gestational age-matched controls. Data were collected from the medical record for the first 28 postnatal days. The relationships between the stooling pattern of premature infants and NEC were assessed via nonparametric techniques and linear mixed models. We identified few differences in the stooling pattern among infants with NEC and their unaffected counterparts. During the first week following birth, infants with NEC passed stool more frequently than controls. However, we found that these infants were taking nothing by mouth for fewer days in the first week following birth compared with controls. We also found that infants who developed NEC were fed smaller proportions of breast milk than healthy controls. Aberrant gut motility has been associated with prematurity and inflammatory bowel disease. However, our analyses did not identify any major differences in the stooling pattern among NEC case patients and controls. While further analyses may be needed, clinical suspicion for NEC should not be overwhelmingly influenced by the stooling pattern observed during the early neonatal period.

Dysautonomic responses during percutaneous carotid intervention: principles of physiology and management.

Percutaneous carotid artery stenting (CAS) has emerged as a less invasive alternative to carotid endarterectomy for the treatment of carotid atherosclerotic disease. The main risk of CAS is the occurrence of neuro-vascular complications; however, carotid artery stenting-related dysautonomia (CAS-D) (hypertension, hypotension, and bradycardia) is the most frequently reported problem occurring in the periprocedural period. Alterations in autonomic homeostasis result from baroreceptor stimulation, which occurs particularly at the time of balloon inflation in the region of the carotid sinus. The response can be profound enough to induce asystole or even complete cessation of postganglionic sympathetic nerve activity. Frequency and factors predisposing a patient to CAS-D have been investigated in several studies; however, there are significant discrepancies in results among reports. Lack of consistent findings may arise from using different methods and definitions, as well as other factors discussed in detail in this review. Furthermore, a correlation of CAS-D with short and long-term outcomes has been investigated only in small and mostly retrospective studies, explaining why its prognostic significance remains uncertain. In this manuscript, we have focused on risk factors, pathophysiology and management of periprocedural autonomic dysfunction. As there is no standardized approach to the treatment of CAS-D, we present an algorithm for the periprocedural management of patients undergoing CAS. The proposed algorithm was developed based on our procedural experience as well as data from the available literature. The Yale Algorithm was successfully implemented at our institution and we are currently collecting data for short- and long-term safety. © 2014 Wiley Periodicals, Inc.

Impact of nonculprit vessel myocardial perfusion on outcomes of patients undergoing percutaneous coronary intervention for acute coronary syndromes: analysis from the ACUITY trial (Acute Catheterization and Urgent Intervention Triage Strategy).

OBJECTIVES: This study evaluated the impact of nonculprit vessel myocardial perfusion on outcomes of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients. BACKGROUND: ST-segment elevation myocardial infarction patients have decreased perfusion in areas remote from the infarct-related vessel. The impact of myocardial hypoperfusion of regions supplied by nonculprit vessels in NSTE-ACS patients treated with percutaneous coronary intervention (PCI) is unknown. METHODS: The angiographic substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial included 6,921 NSTE-ACS patients. Complete 3-vessel assessments of baseline coronary TIMI (Thrombolysis In Myocardial Infarction) flow grade and myocardial blush grade (MBG) were performed. We examined the outcomes of PCI-treated patients according to the worst nonculprit vessel MBG identified per patient. RESULTS: Among the 3,826 patients treated with PCI, the worst nonculprit MBG was determined in 3,426 (89.5%) patients, including 375 (10.9%) MBG 0/1 patients, 475 (13.9%) MBG 2 patients, and 2,576 (75.2%) MBG 3 patients. Nonculprit MBG 0/1 was associated with worse baseline clinical characteristics. Patients with nonculprit MBG 0/1 versus MBG 3 had increased rates of 30-day (3.0% vs. 0.7%, p < 0.0001) and 1-year (4.4% vs. 1.0%, p < 0.0001) death. Similar results were found among patients with pre-procedural TIMI flow grade 3 in the culprit vessel, where nonculprit vessel MBG 0/1 (hazard ratio: 2.81 [95% confidence interval: 1.63 to 4.84], p = 0.0002) was the strongest predictor of 1-year mortality. CONCLUSIONS: Reduced myocardial perfusion in an area supplied by a nonculprit vessel is associated with increased short- and long-term mortality rates in NSTE-ACS patients undergoing PCI. Furthermore, worst nonculprit MBG is able to risk-stratify patients with normal baseline flow of the culprit vessel.

The prognostic importance of left ventricular function in patients with ST-segment elevation myocardial infarction: the HORIZONS-AMI trial.

AIM: Left ventricular (LV) dysfunction during and after hospitalization for ST-segment elevation myocardial infarction (STEMI) is associated with increased mortality. Whether baseline LV dysfunction impacts STEMI outcomes is not well studied. Furthermore, whether bivalirudin and paclitaxel-eluting stents (PES) are beneficial in patients with LV dysfunction is unknown. We studied the impact of left ventricular ejection fraction (LVEF) on outcomes of patients with STEMI in the HORIZONS-AMI trial. METHODS: LVEF was determined in 2648 (73.5%) of 3602 enrolled STEMI patients, who were divided into three groups according to LV function: (1) severely impaired (LVEF <40%); (2) moderately impaired (LVEF 40-50%); and (3) normal (LVEF ≥50%). RESULTS: Compared to patients with normal LV function, those with severely impaired LVEF had higher 1-year rates of net adverse clinical events (27.1 vs. 14.2%, p<0.0001), major adverse cardiovascular events (20.7 vs. 9.5%, p<0.0001), cardiac death (10.6 vs. 1.2%, p<0.0001), and non-coronary artery bypass graft major bleeding (12.5 vs. 6.6%, p=0.001), differences which persisted after adjustment for baseline characteristics. Among patients with LVEF <40%, treatment with bivalirudin compared to heparin+GPIIb/IIIa inhibitors resulted in reduced 1-year mortality (5.8 vs. 18.3%, p=0.007). Patients with LVEF <40% receiving PES rather than bare metal stents had lower rates of 1-year ischaemia-driven target lesion revascularization (2.9 vs. 12.6%, p=0.02) and reinfarction (4.5 vs. 14.7%, p=0.03). CONCLUSIONS: Among patients with STEMI undergoing primary percutaneous coronary intervention, adverse events are markedly increased in those with LVEF <40% during the index revascularization procedure. Nevertheless, these high-risk patients experience substantial clinical benefits from bivalirudin and PES.

Clinical implications for diffusion-weighted MRI brain lesions associated with transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) is increasingly used to treat patients with aortic stenosis deemed high or extreme surgical risk candidates. Despite improved survival and quality of life following the procedure, TAVR is not without its complications. Stroke is a major source of morbidity and mortality in patients undergoing the procedure, with rates similar to and often higher than those associated with surgery. Most studies show a consistent link between TAVR and embolic lesions visualized on diffusion-weighted magnetic resonance imaging. The question of whether these lesions lead to long-term cognitive consequences remains open, but given the large literature on silent strokes and cognition, this association is probable. Initial studies implementing cerebral embolic protection devices in TAVR have yielded promising results with decreased neurological complications and appearance of new lesions on imaging. In this article, we will review the evidence linking silent stroke with cognitive decline, and potential therapeutic options to prevent stroke related to TAVR, including cerebral protection devices currently under investigation.

Near-peer teaching in a required third-year clerkship.

Students who teach less experienced students within the same educational program are known as near-peer teachers. A number of studies have shown that near-peers are effective teachers in preclinical courses such as anatomy and physical examination. We hypothesized that near-peers could also be effective teachers in a clinical clerkship. We report on a pilot study in which near-peers participated in a training session and then taught a brief problem-focused skills curriculum to third-year students during a required ambulatory medicine rotation. The clerkship students assigned high ratings to the near-peer teachers, both on an absolute scale and relative to faculty. The results suggest that including near-peers as teachers in a clinical clerkship may be appropriate and that this concept deserves further investigation.

Challenges in cardiac device innovation: is neuroimaging an appropriate endpoint? Consensus from the 2013 Yale-UCL Cardiac Device Innovation Summit.

BACKGROUND: Neurological events associated with transcatheter aortic valve implantation are major contributors to morbidity and mortality. Choosing an appropriate endpoint to determine neuroprotection device efficacy is a key difficulty inhibiting the translation of the innovation from the laboratory to the bedside. Cost and sample size limitations inhibit the feasibility of using the rate of clinical (such as stroke or other cerebral) events as the primary efficacy endpoint. This paper focuses on consensus opinions from the 2013 Yale-University College London (UCL) Device Innovation Summit. DISCUSSION: Neuroimaging, specifically diffusion-weighted magnetic resonance imaging (DW MRI), may serve as a surrogate endpoint for clinical studies detecting cerebral events in which cost and sample-size limitations prohibit the use of clinical outcomes. A major limitation of using imaging to prove efficacy in cardiac device studies is that no standardized endpoint exists. Ongoing trials investigating cerebral protection devices for transcatheter aortic valve implantation are utilizing and reporting various qualitative and quantitative DW MRI values; however, single lesion volume, number of new lesions, and total lesion volume have been found to be the most reproducible and prognostically important imaging measures. SUMMARY: DW MRI may be a useful surrogate endpoint for clinical studies detecting cerebral events to determine the device's success in neurological protection. Consensus from the 2013 Yale-UCL Device Innovation Summit specifically recommends the reporting of mean single lesion volume, number of new lesions, and total volume, and encourages European Union (EU)-US regulatory consensus in the guidance of implementing this endpoint.

Diagnosing and characterizing coronary artery disease in women: developments in noninvasive and invasive imaging techniques.

Cardiovascular disease is the leading cause of death in men and women in the USA; yet, coronary artery disease (CAD) continues to be underrecognized and underdiagnosed in women. Noninvasive and invasive imaging techniques are constantly being developed in order to more accurately assess CAD. At the same time, the impact of gender on the interpretation and accuracy of these studies is still being elucidated. Furthermore, new imaging techniques have improved our understanding of CAD pathophysiology and progression and have begun to reveal gender differences in the development of CAD. This article will review current imaging techniques and their application to diagnosing and understanding CAD in women.

Implications of myocardial reperfusion on survival in women versus men with acute myocardial infarction undergoing primary coronary intervention.

We evaluated the effects of myocardial perfusion after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) on gender-based mortality rates. Research has demonstrated a gender-specific response of cardiomyocytes to ischemia and a potential increase in myocardial salvage in women compared with men. Myocardial blush grade (MBG), an angiographic surrogate of myocardial perfusion, is an independent predictor of early and late survival after AMI. Whether the incidence and prognosis of myocardial perfusion differs according to gender among patients with AMI undergoing PCI is unknown. MBG and short- and long-term mortality were evaluated in 1,301 patients (male = 935; female = 366) with AMI randomized to primary angioplasty ± abciximab versus stent ± abciximab. Following PCI, >96% of patients achieved final Thrombolysis In Myocardial Infarction 3 flow, of which MBG 2/3 was present in 58.3% of women versus 51.1% of men (p = 0.02). Worse MBG was an independent predictor of mortality in women at 30 days (7.4% for MBG 0/1 vs 2.4% for MBG 2/3, p = 0.04) and at 1-year (11.0% for MBG 0/1 vs 3.4% for MBG 2/3, p = 0.01); however, MBG was not associated with differences in mortality for men. In conclusion, impaired myocardial perfusion following PCI for AMI, indicated by worse MBG, is an independent predictor of early and late mortality in women but not in men. These findings imply an enhanced survival benefit from restoring myocardial perfusion for women compared with men during primary angioplasty and may have clinical implications for interventional strategies in women.

The link between vasculogenic erectile dysfunction, coronary artery disease, and peripheral artery disease: role of metabolic factors and endovascular therapy.

Erectile dysfunction (ED) is estimated to affect 150 million people worldwide and may indicate diffuse systemic macrovascular disease. Endothelial dysfunction represents the probable pathophysiological link between vasculogenic ED, coronary artery disease (CAD), and peripheral artery disease (PAD), and the artery size hypothesis along with evidence-based research support ED as the incident clinical event. Given that many common risk factors for atherosclerosis, including smoking, diabetes mellitus, hyperlipidemia, and obesity are prevalent and causative in patients with ED, it is likely that metabolic factors play a crucial role in the link between the two disorders. The interplay of these factors provides a unifying physiological, endocrinological, and behavioral model for the association between ED, CAD, and PAD. Current therapy is unlikely to reverse the natural history of ED. Percutaneous revascularization may improve ED symptoms, and thereby quality of life, in a select group of patients. Large prospective studies are needed to define male pelvic arterial anatomy and thus enhance the utilization of internal pudendal angiography and revascularization. In this review, we provide an overview of normal erectile anatomy and physiology, the pathophysiology of ED, currently accepted diagnostic imaging modalities and treatments for ED, and recently investigated endovascular therapies for ED.

Selection and timing for invasive therapy in non-ST-segment-elevation acute coronary syndrome.

While outcomes for ST-segment-elevation myocardial infarction has significantly decreased over the last years, patients presenting with non-ST-segment-elevation acute coronary syndromes (NSTEACS) still have a rather high mortality. Longer term mortality over 4 years is about double the mortality after a ST-segment-elevation myocardial infarction. The reason for the poorer prognosis is unclear but is very likely to be partially explained by the generally older age of NSTEACS patients. The optimal therapy for NSTEACS is less well defined. In this review, the authors specifically discuss the role of coronary angiography, how to decide which patient should undergo this procedure and whether there is an optimal time point. The review provides an up-to-date discussion about the best treatment strategies for NSTEACS.

Evaluation of XIENCE V everolimus-eluting and Taxus Express2 paclitaxel-eluting coronary stents in patients with jailed side branches from the SPIRIT IV trial at 2 years.

The aim of this study was to determine whether patients from the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions (SPIRIT) IV trial who underwent percutaneous coronary intervention, who had target lesions with jailed side branches, had improved clinical outcomes when treated with the XIENCE V versus Taxus Express(2) drug-eluting stent. In the SPIRIT III randomized trial, patients with target lesions with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had lower 2-year rates of major adverse cardiac events. The SPIRIT IV trial represents a larger more diverse patient population compared with SPIRIT III. In the large-scale, prospective, multicenter, randomized SPIRIT IV trial, 3,687 patients who underwent coronary stenting with up to 3 de novo native coronary artery lesions were randomized 2:1 to receive XIENCE V versus Taxus Express(2) stents. Two-year clinical outcomes of patients with or without jailed side branches after stenting were compared. A jailed side branch was defined as any side branch >1.0 mm in diameter within the target segment being stented, excluding bifurcations deemed to require treatment. Of the 3,687 patients in SPIRIT IV, a total of 1,426 had side branches that were jailed during angioplasty of the target lesion. Patients with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had significantly lower 2-year rates of target lesion failure (6.5% vs 11.9%, p = 0.001), major adverse cardiac events (6.6% vs 12.2%, p = 0.0008), ischemia-driven target vessel revascularization (4.1% vs 7.9%, p = 0.004), and stent thrombosis (0.6% vs 2.8%, p = 0.001). In conclusion, patients with jailed side branches after stenting with XIENCE V compared to Taxus Express(2) devices had superior clinical outcomes at 2 years in the large-scale randomized SPIRIT IV trial.

VEGF levels in humans and animal models with RDS and BPD: temporal relationships.

Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) contribute significantly to neonatal morbidity and mortality. Pulmonary function depends on the interaction between alveolar microvasculature and airspace development. While it has been shown in various animal models that vascular endothelial growth factor (VEGF) and its receptors increase in normal animal lung development, its pathophysiological role in neonatal respiratory failure is not yet entirely clear. Current animal and human studies exhibit controversial results. Though animal models are invaluable tools in the study of human lung disease, inherent differences in physiology mandate clarification of the timing of these studies to ensure that they appropriately correlate with the human stages of lung development. The purpose of this review article is to highlight the importance of considering the temporal relationship of VEGF and lung development in human neonates and developmentally-appropriate animal models with RDS and BPD.