High-risk percutaneous coronary intervention with or without mechanical circulatory support: Will Impella show superiority in the PROTECT IV randomized trial?

BACKGROUND: PROTECT IV is a current enrolling randomized controlled trial evaluating high-risk percutaneous coronary intervention (HR-PCI) with prophylactic Impella versus no Impella to reduce the composite primary endpoint of all-cause death, stroke, myocardial infarction (MI), or cardiovascular hospitalization. In a PROTECT IV-like cohort of patients who underwent HR-PCI without Impella, we aimed to report the rate of major adverse events to determine whether the trial is adequately powered. METHODS AND RESULTS: A total of 700 patients meeting similar inclusion/exclusion criteria of PROTECT IV who underwent HR-PCI without Impella at a single tertiary center from 2008 to 2022 were included in the analysis. The composite rates of all-cause death, MI, target lesion revascularization, and target vessel revascularization at 1, 2, and 3 years were estimated using the Kaplan-Meier method, and the results were used to calculate the sample size under the constant hazard ratio assumption and expected number of events to be observed used in planning PROTECT IV. The primary endpoint occurred in 30.8 % of patients at 2 years. PROTECT IV assumes a hazard ratio of 0.75 using a multivariate Cox regression, which, under a 5 % level and 90 % power, yields 516 events. This implies a 2-year primary outcome rate of 50 % for the non-Impella arm. CONCLUSION: Therefore, PROTECT IV estimates that a sample size of 1252 patients is required for Impella to be declared superior to the non-Impella group. Using our observed 2-year outcome of 30.8 %, we estimate that PROTECT IV requires 1966 patients, demonstrating that PROTECT IV is probably underpowered.

Racial Disparities in Outcomes of Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction Secondary to Spontaneous Coronary Artery Dissection.

Spontaneous coronary artery dissection (SCAD) is a rare cause of ST-segment elevation myocardial infarction (STEMI), predominantly affecting women. Because primary percutaneous coronary intervention (PPCI) is reserved for a select group of patients, vulnerable and minority patients may experience delays in appropriate management and adverse outcomes. We examined the racial differences in the outcomes for patients with SCAD who underwent PPCI for STEMI. Records of patients aged ≥18 years who underwent PPCI for SCAD-related STEMI between 2016 and 2020 were identified from the National Inpatient Sample database. Clinical, socioeconomic, and hospital characteristics were compared between non-White and White patients. Weighted multivariate analysis assessed the association of race with inpatient mortality, length of stay (LOS), and hospitalization costs. The total weighted estimate of patients with SCAD-STEMI who underwent PPCI was 4,945, constituting 25% non-White patients. Non-White patients were younger (56 vs 60.7 years, p <0.001); had a higher prevalence of diabetes, acute renal failure, and obesity; and were more likely to be uninsured and be in the lowest income group. Inpatient mortality (7.7% vs 8.4%, p = 0.74) and hospitalization costs ($34,213 vs $31,858, p = 0.27) were similar for non-White and White patients, and the adjusted analysis did not show any association between the patients' race and inpatient mortality (odds ratio 0.60, 95% confidence interval [CI] 0.32 to 1.13, p = 0.11) or hospitalization costs (ß [ß coefficient]: 215, 95% CI -4,193 to 4,623, p >0.90). Similarly, there was no association between the patients' race and LOS (incident rate ratio 1.20, 95% CI 1.00 to 1.45, p = 0.054). The weighted multivariate analysis showed that age; clinical co-morbidities such as diabetes, acute renal failure, valvular dysfunction, and obesity; low-income status; and hospitalization in the western region were associated with adverse outcomes. In conclusion, our study does not show any differences in inpatient mortality, LOS, and hospitalization costs between non-White and White patients who underwent PPCI for SCAD-related STEMI.

Bioprosthetic Aortic Valve Thrombosis: Definitions, Clinical Impact, and Management: A State-of-the-Art Review.

Bioprosthetic aortic valve thrombosis is frequently detected after transcatheter and surgical aortic valve replacement due to advances in cardiac computed tomography angiography technology and standardized surveillance protocols in low-surgical-risk transcatheter aortic valve replacement trials. However, evidence is limited concerning whether subclinical leaflet thrombosis leads to clinical adverse events or premature structural valve deterioration. Furthermore, there may be net harm in the form of bleeding from aggressive antithrombotic treatment in patients with subclinical leaflet thrombosis. This review will discuss the incidence, mechanisms, diagnosis, and optimal management of bioprosthetic aortic valve thrombosis after transcatheter aortic valve replacement and bioprosthetic surgical aortic valve replacement.

Androgen and glucocorticoid profiles throughout extended uniparental paternal care in the eastern hellbender salamander (Cryptobranchus a. alleganiensis).

The behavioral endocrinology associated with reproduction and uniparental male care has been studied in teleosts, but little is known about hormonal correlates of uniparental male care in other ectotherms. To address this gap, we are the first to document the seasonal steroid endocrinology of uniparental male hellbender salamanders during the transition from pre-breeding to nest initiation, and through the subsequent eight months of paternal care. In doing so, we investigated the correlates of nest fate and clutch size, exploring hellbenders' alignment with several endocrinological patterns observed in uniparental male fish. Understanding the endocrinology of hellbender paternal care is also vital from a conservation perspective because high rates of nest failure were recently identified as a factor causing population declines in this imperiled species. We corroborated previous findings demonstrating testosterone and dihydrotestosterone (DHT) to be the primary androgens in hellbender reproduction, and that cortisol circulates as the most abundant glucocorticoid. However, we were unable to identify a prolactin or a "prolactin-like" peptide in circulation prior to or during parental care. We observed âˆ¼ 80 % declines in both primary androgens during the transition from pre-breeding to nest initiation, and again as paternal care progressed past its first month. In the days immediately following nest initiation, testosterone and DHT trended higher in successful individuals, but did not differ with males' clutch size. We did not observe meaningful seasonality in baseline glucocorticoids associated with breeding or nesting. In contrast, stress-induced glucocorticoids were highest at pre-breeding and through the first two months of care, before declining during the latter-most periods of care as larvae approach emergence from the nest. Neither baseline nor stress-induced glucocorticoids varied significantly with either nest fate or clutch size. Both stress-induced cortisol and corticosterone were positively correlated with total length, a proxy for age in adult hellbenders. This is consistent with age-related patterns in some vertebrates, but the first such pattern observed in a wild amphibian population. Generally, we found that nesting hellbenders adhere to some but not all of the endocrinological patterns observed in uniparental male teleosts prior to and during parental care.

Temporal trends with the Evolut family of self-expanding transcatheter heart valves: A single-center experience.

BACKGROUND: The Evolut self-expanding valve (SEV) systems (Medtronic), were designed to accommodate varying valve sizes and reduce paravalvular leak (PVL) while maintaining a low delivery profile. These systems have evolved between product generations, alongside valve deployment techniques changing over time. AIMS: This study aimed to examine whether these changes impacted clinical outcomes. METHODS: EPROMPT is a prospective, investigator-initiated, postmarketing registry of consecutive patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) using the Evolut PRO/PRO+ SEV system. A total of 300 patients were divided into three consecutive cohorts of 100 patients according to implantation date (January to October 2018, November 2018 to July 2020, and August 2020 to November 2021). Procedural and clinical outcomes over these time periods were compared. RESULTS: Valve Academic Research Consortium (VARC)-2 device implantation success improved over time (70.0% vs. 78.0% vs. 88.8%, p = 0.01), with a similar trend for VARC-3 device success (94.7% vs. 81.7% vs. 96.8%, p < 0.001). PVL (all degrees) frequency was likewise reduced over time (31.0% vs. 17.0% vs. 19.2%, p = 0.04). Furthermore, a trend was noticed toward shorter procedure times and shorter length of stay. However, postprocedural pacemaker implantation rates did not significantly differ (15.2% vs. 21.1% vs. 14.0%, p = 0.43). CONCLUSION: During a 3-year period, we demonstrated better TAVR outcomes with newer SEV iterations, alongside changes in implantation techniques, which might result in better procedural and clinical outcomes. However, we did not see a significant change in peri-procedural pacemaker rates for SEV.

Exploring the interplay between coronary microvascular dysfunction and mental health.

BACKGROUND: The intricate relationship between mental health disorders, notably anxiety and depression, and chest pain associated with non-obstructive coronary artery disease has become a focus of investigation. METHODS: This study from the Coronary Microvascular Disease Registry (CMDR) evaluated the association of mental health disorders and coronary microvascular dysfunction (CMD) among patients with angina with no obstructive coronary artery disease (ANOCA) who had undergone comprehensive invasive physiological testing for CMD. Clinical data regarding baseline characteristics, comorbidities, and noninvasive cardiac testing were obtained from chart review. The primary outcome of interest was the potential relationship between mental health diagnoses and the presence of CMD. RESULTS: Of patients included in the CMDR, 27 % (41/152) had at least one documented mental health disorder diagnosis (International Classification of Diseases, Tenth Revision codes) and CMD. There was no difference in mental health diagnosis prevalence between CMD-positive and CMD-negative patients (21.1 % vs. 28.9 %, p = 0.34). The most common mental health diagnoses were depression (15.8 %) and anxiety (15.8 %). Furthermore, 46.3 % (19/41) of patients with mental health disorders were prescribed psychiatric medications, with the most common being benzodiazepines (26.8 %). CONCLUSION: Patients with chest pain not due to CMD did not have an increased prevalence of mental health disorders compared with patients with ANOCA due to CMD, challenging the notion of a psychosomatic component in the pathogenesis of ANOCA.

Coronary microvascular dysfunction and inflammation: Insights from the Coronary Microvascular Disease Registry.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with various inflammatory conditions that worsen endothelial dysfunction. This study aimed to investigate the relationship between CMD and inflammation using common inflammatory markers derived from complete blood count (CBC) analysis. METHODS: Information was gathered from the Coronary Microvascular Disease Registry to examine the neutrophil-to-lymphocyte ratio (NLR), eosinophil-to-monocyte ratio (EMR), and monocyte-to-high-density lipoprotein ratio (MHR) in a cohort of patients with angina who showed non-obstructive coronary arteries and underwent invasive physiological assessments for CMD. RESULTS: Of the 171 patients studied, 126 were CMD-negative and 45 were CMD-positive, constituting two groups of interest. The average age of all patients was 61.7 ± 11.1 years, and 63.7 % were female. No significant differences were observed between the two groups in terms of baseline characteristics, cardiovascular risk factors, or potential anti-inflammatory medications. Furthermore, there were no statistically significant differences in NLR (2.54 ± 3.71 vs. 2.52 ± 2.28, p = 0.97), EMR (0.3 ± 0.21 vs. 0.34 ± 0.29, p = 0.31), or MHR (0.02 ± 0.01 vs. 0.01 ± 0.01, p = 0.54) between CMD-positive and CMD-negative patients. CONCLUSION: Our findings did not show a noteworthy connection between CMD and inflammation, as suggested by various simple CBC-based biomarkers.

Coronary microvascular dysfunction and cancer therapy-related cardiovascular toxicity.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been implicated as a potential mechanism in the pathophysiology of different clinical presentations, including ischemia and no obstructive coronary artery disease (INOCA), myocardial infarction and nonobstructive coronary arteries (MINOCA), stress cardiomyopathy, heart failure, and myocarditis. There are limited data about the role of CMD in cancer therapy-related cardiovascular toxicities. CASE PRESENTATIONS: Four women with a diagnosis of active cancer receiving treatment who developed subsequent MINOCA or INOCA presented for cardiac catheterization. Upon coronary angiography showing no obstructive coronary arteries, coronary function testing was performed to evaluate for CMD. METHODS: Coronary physiology was assessed measuring non-hyperemic (resting full-cycle ratio [RFR]) and hyperemic (fractional flow reserve [FFR]) indices using a physiologic pressure wire. The wire also measured coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and RFR using thermodilution technology. CMD was confirmed if the CFR was <2.5 and the IMR was >25. RESULTS: Among 4 patients with diagnosis of active cancer presenting with chest pain, there was no evidence of obstructive coronary artery disease, leading to separate diagnoses of INOCA, MINOCA, stress cardiomyopathy, and myocarditis. We found CMD in 2 patients (1 with INOCA and 1 with immune checkpoint inhibitor-related myocarditis). CONCLUSIONS: CMD may play a role in cardiovascular toxicities. Further coronary physiology studies are needed to understand the mechanisms of cancer therapy-related cardiovascular toxicity and CMD, as well as optimal preventive and treatment options.

Comparing planned versus ad hoc coronary microvascular assessment: Early findings from the Coronary Microvascular Disease Registry.

BACKGROUND: Coronary microvascular dysfunction (CMD) is an etiology for angina with non-obstructive coronary disease. However, the initial adoption of CMD assessment, whether planned or conducted ad hoc, is limited. We characterize planned and ad hoc CMD assessments and highlight evolving trends of a CMD referral center. METHODS: We analyzed outpatient data from the Coronary Microvascular Disease Registry from 2021 to 2023. Patients were categorized into planned or ad hoc CMD assessment groups, and baseline characteristics, hospital stay, medications, and physiological measurements were compared. Secondary analysis evaluated a CMD referral center's evolution. RESULTS: Of 101 included outpatients, 67.3 % underwent ad hoc procedures and 32.7 % planned procedures. Average age was 63.1 ± 10.1 years. The planned procedure group was 87.9 % female, and the ad hoc procedure group was 51.5 % female. There were no significant differences in index of microvascular resistance or coronary flow reserve between groups. Hospital stay duration was <1 day for both groups, and neither reported complications. Ad hoc patients were more frequently prescribed aspirin before (64.7 % vs. 36.4 %, p = 0.007) and after the procedure (66.2 % vs. 39.4 %, p = 0.01). CMD rates were higher for planned procedures (30.3 % vs. 10.3 %, p = 0.01). We observed that CMD referral centers have more planned procedures and a higher rate of positive results over time. CONCLUSION: CMD referral centers' planned procedures, and subsequent positive cases, increased over time. This emphasizes the importance of planned procedures, appropriate patient selection, and increased awareness of CMD among healthcare providers. CLINICAL TRIAL REGISTRATION: Coronary Microvascular Disease (CMD) Registry, NCT05960474, https://clinicaltrials.gov/study/NCT05960474.

Towards more tolerable subcutaneous administration: Review of contributing factors for improving combination product design.

Subcutaneous (SC) injections can be associated with local pain and discomfort that is subjective and may affect treatment adherence and overall patient experience. With innovations increasingly focused on finding ways to deliver higher doses and volumes (≥2 mL), there is a need to better understand the multiple intertwined factors that influence pain upon SC injection. As a priority for the SC Drug Development & Delivery Consortium, this manuscript provides a comprehensive review of known attributes from published literature that contribute to pain/discomfort upon SC injection from three perspectives: (1) device and delivery factors that cause physical pain, (2) formulation factors that trigger pain responses, and (3) human factors impacting pain perception. Leveraging the Consortium's collective expertise, we provide an assessment of the comparative and interdependent factors likely to impact SC injection pain. In addition, we offer expert insights and future perspectives to fill identified gaps in knowledge to help advance the development of patient-centric and well tolerated high-dose/high-volume SC drug delivery solutions.

From chest pain to coronary functional testing: Clinical and economic impact of coronary microvascular dysfunction.

BACKGROUND: Coronary functional testing to formally diagnose coronary microvascular dysfunction (CMD) reduces cardiovascular events and alleviates angina. This study aims to investigate the extensive and complex journey that patients with CMD undergo, from the onset of chest pain to eventual diagnosis. METHODS: Data from the Coronary Microvascular Disease Registry (CMDR) were analyzed, including information on the date of first documentation of chest pain, number of non-invasive and invasive tests the patient underwent, emergency department visits, and hospitalizations. In addition, we estimated the total cost per patient. A total of 61 patients with CMD diagnosis were included in this analysis. RESULTS: Most patients in our cohort were older than 50 years of age. The median time from initial chest pain symptoms to diagnosis was 0.62 (interquartile range [IQR]: 0.06-2.96) years. During this period, patients visited the emergency department a median of 1.0 (IQR: 0.0-2.0) times. Diagnostic tests included 3.0 (IQR: 2.0-6.0) electrocardiograms, 3.0 (IQR: 0.0-6.0) high-sensitivity troponin tests, and 1.0 (IQR: 1.0-2.0) echocardiograms. Prior to diagnosis of CMD, 13 (21.3 %) patients had left heart catheterization without coronary functional testing. Non-invasive testing for ischemia was conducted in 43 (70.5 %) patients. Alternative non-cardiac diagnoses were given to 11 (18.0 %) patients during the diagnostic process, with referrals made to gastroenterology for 16 (26.2 %) and pulmonology for 10 (16.4 %) patients. The cost was almost $2000/patient. CONCLUSION: Timely identification of CMD offers promising opportunities for prompt symptom alleviation, accompanied by reduced visits to the emergency department, cardiovascular testing, invasive medical procedures, and consequently reduced healthcare expenses.

Coronary Microvascular Disease Registry (CMDR): Study design and rationale.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a prevalent condition among patients with cardiovascular risk factors, leading to a reduced quality of life and an increased risk of major adverse cardiovascular events. Novel invasive techniques have emerged to more accurately diagnose CMD. However, CMD's natural history remains poorly understood due to limited data. To address this knowledge gap, the Coronary Microvascular Disease Registry (CMDR) was established with the primary aim of standardizing comprehensive coronary functional testing and understanding of CMD. DESIGN: CMDR is a prospective, multicenter registry enrolling an unlimited number of consecutive subjects who undergo comprehensive invasive hemodynamic assessment of the entire coronary arterial vasculature. Patients undergoing acetylcholine provocation test for coronary vasospasm will also be included. Follow-up assessments will be conducted at 30 days and annually for up to 5 years. The primary endpoint is Canadian Cardiovascular Society angina grade over time. Secondary endpoints, including all-cause mortality, cardiovascular death, acute myocardial infarction, stroke, hospitalizations, medication changes, and subsequent coronary interventions, will be analyzed to establish long-term safety and clinical outcomes in patients undergoing invasive CMD assessment. SUMMARY: CMDR aims to characterize the clinical and physiologic profile of patients undergoing comprehensive invasive coronary functional testing, simultaneously providing crucial longitudinal information on the natural history and outcomes of these patients. This will shed light on CMD's course and clinical implications, which, in turn, holds the potential to significantly improve diagnostic and treatment strategies for CMD patients, ultimately leading to the enhancement of their overall prognosis and quality of life. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT05960474.

Frequency of ventriculography during left heart catheterization for radial vs. femoral access.

BACKGROUND: Radial artery access has been used for left heart catheterization (LHC) and percutaneous coronary intervention (PCI) for over 30 years. This method has gained popularity among operators due to superficial vessel anatomy, allowing for easy accessibility and compressibility, resulting in effective hemostasis. METHODS: We conducted a retrospective analysis of patients who underwent PCI due to ST-elevation myocardial infarction (STEMI), non-ST-elevation acute coronary syndrome (NSTE-ACS), and chest pain (stable angina) from November 2013 to February 2023. RESULTS: We analyzed validated registries and found 7714 PCIs. Of these, 1230 were STEMI patients, 5585 were NSTE-ACS patients, and 899 were stable angina patients, forming the basis of our final analysis. In STEMI patients, there was a trend toward a higher rate of ventriculography with femoral access compared to radial access (53.4 % vs. 47.5 %, p = 0.06), which was also observed in NSTE-ACS patients (34.2 % vs. 31.8 %, p = 0.07). The use of central venous access was more common with femoral access in all three diagnoses, with significantly higher rates seen in STEMI patients (36.2 % vs. 7.6 %, p < 0.001), NSTE-ACS patients (19.3 % vs. 2.8 %, p < 0.001), and chest pain patients (26.4 % vs. 2.7 %, p < 0.001). CONCLUSIONS: The analysis revealed that operators may perform fewer ventriculography and RHC procedures when using radial access as compared to femoral access. While there is discrepancy in performing left ventriculography and RHC when using a radial artery, it is essential to emphasize that routinely performing ventriculography and hemodynamic assessment has not proven to impact outcomes, despite their contributions to proper decision-making and treatment.

A novel approach to saline/contrast delivery in excimer laser coronary atherectomy (ELCA) to enhance efficacy: MAXCon ELCA technique.

The advent of excimer laser coronary atherectomy (ELCA) nearly four decades ago heralded a novel way to treat complex lesions, both coronary and peripheral, which were previously untraversable and thus untreatable. These complex lesions include heavily calcified lesions, ostial lesions, bifurcation lesions, chronic total occlusions, in-stent restenosis (including stent underexpansion), and degenerative saphenous vein grafts. We discuss the technology of ELCA, its indications, applications, and complications, and suggest the "MAXCon ELCA" technique for better outcomes without increased risk. Lastly, we present a case of MAXCon ELCA effectively treating a complex lesion.

Coronary microvascular dysfunction assessment: A comparative analysis of procedural aspects.

BACKGROUND: Full adoption of coronary microvascular dysfunction (CMD) assessment faces challenges due to its invasive nature and concerns about prolonged procedure time and increased contrast and/or radiation exposure. We compared procedural aspects of CMD invasive assessment to diagnostic left heart catheterization (DLHC) in patients with chest pain who were not found to have obstructive coronary artery disease. METHODS: A total of 227 patients in the Coronary Microvascular Disease Registry were compared to 1592 patients who underwent DLHC from August 2021 to November 2023. The two cohorts were compared using propensity-score matching; primary outcomes were fluoroscopy time and total contrast use. RESULTS: The participants' mean age was 64.1 ± 12.6 years. CMD-assessed patients were more likely to be female (66.5% vs. 45.2%, p < 0.001) and have hypertension (80.2% vs. 44.5%, p < 0.001), history of stroke (11.9% vs. 6.3%, p = 0.002), and history of myocardial infarction (20.3% vs. 7.7%, p < 0.001). CMD assessment was safe, without any reported adverse outcomes. A propensity-matched analysis showed that patients who underwent CMD assessment had slightly higher median contrast exposure (50 vs. 40 mL, p < 0.001), and slightly longer fluoroscopy time (6.9 vs. 4.7 min, p < 0.001). However, there was no difference in radiation dose (209.3 vs. 219 mGy, p = 0.58) and overall procedure time (31 vs. 29 min, p = 0.37). CONCLUSION: Compared to DLHC, CMD assessment is safe and requires only slightly additional contrast use (10 mL) and slightly longer fluoroscopy time (2 min) without clinical implications. These findings emphasize the favorable safety and feasibility of invasive CMD assessment.

Angiographic characteristics of patients with STEMI and COVID-19: Insights from NACMI registry.

BACKGROUND: To date, there has been no independent core lab angiographic analysis of patients with COVID-19 and STEMI. The study characterized the angiographic parameters of patients with COVID-19 and STEMI. METHODS: Angiograms of patients with COVID-19 and STEMI from the North American COVID-19 Myocardial Infarction (NACMI) Registry were sent to a Core Laboratory in Vancouver, Canada. Culprit lesion(s), Thrombolysis In Myocardial Infarction (TIMI) flow, Thrombus Grade Burden (TGB), and percutaneous coronary intervention (PCI) outcome were assessed. RESULTS: From 234 patients, 74% had one culprit lesion, 14% had multiple culprits and 12% had no culprit identified. Multivessel thrombotic disease and multivessel CAD were found in 27% and 53% of patients, respectively. Stent thrombosis accounted for 12% of the presentations and occurred in 55% of patients with previous coronary stents. Of the 182 who underwent PCI, 60 (33%) had unsuccessful PCI due to post-PCI TIMI flow <3 (43/60), residual high thrombus burden (41/60) and/or thrombus related complications (27/60). In-hospital mortality for successful, partially successful, and unsuccessful PCI was 14%, 13%, and 27%, respectively. Unsuccessful PCI was associated with increased risk of in-hospital mortality (risk ratio [RR] 1.96; 95% CI: 1.05-3.66, P = .03); in the adjusted model this estimate was attenuated (RR: 1.24; 95% CI: 0.65-2.34, P = .51). CONCLUSION: In patients with COVID-19 and STEMI, thrombus burden was pervasive with notable rates of multivessel thrombotic disease and stent thrombosis. Post-PCI, persistent thrombus and sub-optimal TIMI 3 flow rates led to one-third of the PCI's being unsuccessful, which decreased over time but remained an important predictor of in-hospital mortality.