Structural Valve Deterioration in Transcatheter Aortic Bioprostheses: Diagnosis, Pathogenesis, and Treatment.

Transcatheter aortic valve replacement has emerged as the preferred treatment modality in most patients with severe aortic stenosis. With its global adoption and broader application in younger and healthier patients, the issue of transcatheter bioprosthetic valve degeneration and its impact on valve durability continues to earn clinical relevance. Differences in the pathophysiologic processes that separate native from transcatheter heart valve deterioration remain poorly understood. When compared to surgical aortic bioprostheses, the mechanisms of valve degeneration are similar in transcatheter heart valves, with meaningful differences most noticeably found between the individual constructs of their design. Recognizing the clinical and hemodynamic presentation of structural valve degeneration remains paramount. The recently revised consensus guidelines that incorporate the integration of advanced multimodality imaging with invasive hemodynamics represent a major step forward in our ability to accurately diagnose bioprosthetic valve degeneration, and to identify differences in durability patterns, and to establish treatment recommendations for the lifetime management of patients with aortic stenosis. Parallel efforts to unmask the biomolecular differences in atherosclerotic plaque burden, valve calcification, and thrombotic diathesis, including host immunocompetence, between the different available bioprostheses, will further advance the role of emerging valve tissue technologies to improve durability. As with surgical heart valves, the optimal treatment options for redo-transcatheter aortic valve replacement and surgical explant remain poorly understood. Ongoing translational research in bench testing coupled with prospectively designed core lab-adjudicated clinical trials are much needed. This report provides a contemporary overview of transcatheter structural valve degeneration, including evolving concepts in its pathogenesis, diagnosis, and treatment.

Association of ACEI/ARB and statin prescribing patterns with mortality after Transcatheter Aortic Valve Replacement (TAVR): Findings from real-world claims data.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become the standard of care for most patients with severe aortic stenosis (AS), but the impact of medical therapy prescribing patterns on post-TAVR patients has not been thoroughly investigated. METHODS: We analyzed Optum claims data from 9,012 adults who received TAVR for AS (January 2014-December 2018). Pharmacy claims data were used to identify patients who filled ACEI/ARB and/or statin prescriptions during the study's 90-day landmark period post-TAVR. Kaplan-Meier and adjusted Cox Proportional Hazards models were used to evaluate the association of prescribing patterns with mortality during the 3-year follow-up period. Subgroup analyses were performed to examine the impact of 11 potential confounders on the observed associations. RESULTS: A significantly lower adjusted 3-year mortality was observed for patients with post-TAVR prescription for ACEI/ARBs (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.74-0.91, P = .0003) and statins (HR = 0.85, 95% CI 0.77-0.94, P = .0018) compared to patients who did not fill prescriptions for these medications post-TAVR. Subgroup analyses revealed that the survival benefit associated with ACEI/ARB prescription was not affected by any of the potential confounding variables, except preoperative ACEI/ARB prescription was associated with significantly lower risk of mortality vs postoperative prescription only. No other subgroup variables had significant interactions associated with survival benefits, including preoperative use of statins. CONCLUSIONS: In this large-scale, real-world analysis of patients undergoing TAVR, the prescription of ACEI/ARB and statins was associated with a significantly lower risk of mortality at 3-years, especially in those where the medications were initiated preoperatively.

Intravascular Fluorescence Molecular Imaging of Atherosclerosis.

Optical molecular imaging using near-infrared fluorescence (NIRF) light is an emerging high-resolution imaging approach to image a wide range of molecular and cellular species in vivo. Imaging using NIR wavelengths (650-900 nm) enables deeper photon penetration into tissue and reduced tissue autofluorescence, resulting in higher sensitivity to detect exogenously administered NIR fluorophores (injectable molecular imaging agents). Greater imaging depth of several centimeters is further achievable in the NIR window as blood absorption is as an order of magnitude lower than in the visible range. Furthermore, as optical imaging is routinely performed in the cardiac catheterization laboratory (e.g., optical coherence tomography), intravascular NIRF offers a promising translational approach for clinical coronary and peripheral arterial imaging. To this point, the first human intravascular NIRF imaging study recently demonstrated the ability to detect NIR autofluorescence in patients with coronary atherosclerosis. This study provides a foundation for targeted intravascular NIRF molecular imaging studies in coronary patients. In this chapter, we detail system engineering, imaging agents and translational applications of intravascular NIRF molecular imaging.

Near-Infrared Autofluorescence in Atherosclerosis Associates With Ceroid and Is Generated by Oxidized Lipid-Induced Oxidative Stress.

[Figure: see text].

Clinical practice patterns and ascertainment bias for cardiovascular events in a randomized trial: A survey of investigators in the BEST-CLI trial.

Ascertainment bias is a well-recognized source of bias in research, but few studies have systematically analyzed sources of ascertainment bias in randomized trials in which blinding is not possible and endpoint assessment is not protocolized. In the current study, we sought to evaluate differences in the clinical practice patterns of trial investigators with respect to bias in the ascertainment of pre-revascularization patient risk and the incidence of secondary endpoints post-revascularization. We conducted a cross-sectional survey of active investigators (n = 936) from the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) trial. The total survey response rate was 19.6% (183/936). Vascular surgeons were more likely than nonsurgical interventionalists to order tests for cardiac complications after both surgical bypass (p < 0.001) and endovascular revascularization (p = 0.038). Post-procedure, investigators were more likely to order additional testing for cardiac complications in open surgery versus endovascular cases (7% vs 16% never, 41% vs 65% rarely, 43% vs 17% sometimes, 9% vs 2% always, respectively; p < 0.0001). Significant variation in practice patterns exist in the pre- and post-procedure assessment of cardiac risk and events for patients with CLI undergoing revascularization. Variation in the ascertainment of risk and outcomes according to the type of revascularization procedure and physician specialty should be considered when interpreting the results of clinical studies, such as the BEST-CLI trial. ClinicalTrials.gov Identifier: NCT02060630.

Health Care Utilization Following Inpatient Femoropopliteal Revascularization With Drug-Coated Balloon Angioplasty: A Nationwide Cohort Analysis.

PURPOSE: To examine nationwide variations in inpatient use of drug-coated balloons (DCBs) for treating femoropopliteal segment occlusive disease and whether DCBs are associated with reduced early out-of-hospital health care utilization. MATERIALS AND METHODS: The study included 24,022 patients who survived hospitalization for femoropopliteal revascularization using DCB angioplasty (n=7850) or uncoated balloon angioplasty (n=16,172) in the 2016-2017 Nationwide Readmissions Database. Differences in patient, hospitalization, and institutional characteristics were compared between treatment strategies. Adjusted logistic regression models were used to examine differences in 6-month rates of readmission, amputation, and repeat intervention. Results are presented as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Patients treated with DCBs had a higher prevalence of chronic limb-threatening ischemia, diabetes, hypertension, and tobacco use. Revascularization with a DCB was associated with shorter hospitalizations, lower median hospitalization costs, and fewer inpatient lower extremity amputations. Readmissions at 6 months were decreased in patients treated with DCBs compared with uncoated balloon angioplasty (OR 0.90, 95% CI 0.83 to 0.98, p=0.014). The most common reasons for readmission were complications related to procedures (15.4%) and diabetes (15.4%). Compared to patients treated with DCBs, patients treated with uncoated balloon angioplasty were more often readmitted with early procedure-related complications (13.3% vs 17.5%). There were no between-group differences in readmission for sepsis, myocardial infarction, or congestive heart failure. CONCLUSION: DCBs are less often used compared to uncoated balloons during inpatient femoropopliteal procedures. While DCB utilization is associated with more severe comorbidities and advanced peripheral artery disease, readmission rates are decreased through the first 6 months.

Impact of COVID-19 pandemic on STEMI care: An expanded analysis from the United States.

OBJECTIVE: To evaluate the impact of COVID-19 pandemic migitation measures on of ST-elevation myocardial infarction (STEMI) care. BACKGROUND: We previously reported a 38% decline in cardiac catheterization activations during the early phase of the COVID-19 pandemic mitigation measures. This study extends our early observations using a larger sample of STEMI programs representative of different US regions with the inclusion of more contemporary data. METHODS: Data from 18 hospitals or healthcare systems in the US from January 2019 to April 2020 were collecting including number activations for STEMI, the number of activations leading to angiography and primary percutaneous coronary intervention (PPCI), and average door to balloon (D2B) times. Two periods, January 2019-February 2020 and March-April 2020, were defined to represent periods before (BC) and after (AC) initiation of pandemic mitigation measures, respectively. A generalized estimating equations approach was used to estimate the change in response variables at AC from BC. RESULTS: Compared to BC, the AC period was characterized by a marked reduction in the number of activations for STEMI (29%, 95% CI:18-38, p < .001), number of activations leading to angiography (34%, 95% CI: 12-50, p = .005) and number of activations leading to PPCI (20%, 95% CI: 11-27, p < .001). A decline in STEMI activations drove the reductions in angiography and PPCI volumes. Relative to BC, the D2B times in the AC period increased on average by 20%, 95%CI (-0.2 to 44, p = .05). CONCLUSIONS: The COVID-19 Pandemic has adversely affected many aspects of STEMI care, including timely access to the cardiac catheterization laboratory for PPCI.

Comparative Effectiveness of Reperfusion Strategies in Patients with ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the Acute Coronary Syndrome Quality Improvement in Kerala (ACS QUIK) Trial.

Introduction: Substantial heterogeneity exists in reperfusion strategies for patients with ST-segment myocardial infarction (STEMI) in low- and middle-income countries (LMICs). We sought to compare outcomes associated with primary percutaneous coronary intervention (PPCI) and non-primary percutaneous coronary intervention (nPPCI) reperfusion strategies in patients with STEMI in Kerala, India. Methods: We performed a retrospective analysis of patients with STEMI (n = 8665) from the Acute Coronary Syndrome Quality Improvement in Kerala (ACS QUIK) randomized trial receiving either PPCI (n = 6623) or nPPCI (n = 2042). nPPCI included all PCI strategies implemented when PPCI was not available including all post-fibrinolysis PCI strategies and PCI without fibrinolysis. Clinical outcomes among patients undergoing PPCI and nPPCI were compared after propensity-score matching. The main outcomes were the rates of in-hospital and 30-day major adverse cardiovascular events (MACE), defined as the composite of death, reinfarction, stroke, and major bleeding. Results: In the propensity-score matched cohort (n = 1266 in each group), nPPCI had longer symptom onset to hospital arrival time (347.5 vs. 195.0 minutes, p < 0.001), door to balloon time (108 minutes vs. 75 minutes, p < 0.001), and were less likely to receive a coronary stent (89.4% vs. 95%, p < 0.001), including drug-eluting stents (89.5% vs. 94.4%, p < 0.001). There were no clinically meaningful differences in discharge medical therapy. However, patients treated with nPPCI were less commonly referred for cardiac rehabilitation (20.2% vs. 24.2%; p = 0.019). In-hospital (3.6% vs. 3.3%, p = 0.74%) and 30-day (4.4% vs. 4.6%, p = 0.77) MACE did not differ between nPPCI and PPCI matched groups. Conclusion: In a large, contemporary population of STEMI patients from a LMIC, patients treated with a nPPCI reperfusion strategy had comparable short- and intermediate-term outcomes compared to PPCI despite differences in hospital presentation time and coronary stent use. These findings are reassuring but highlight the need for continued quality improvement in the delivery of STEMI care in resource-limited settings.

Paclitaxel Drug-Coated Balloon Angioplasty Suppresses Progression and Inflammation of Experimental Atherosclerosis in Rabbits.

Paclitaxel drug-coated balloons (DCBs) reduce restenosis, but their overall safety has recently raised concerns. This study hypothesized that DCBs could lessen inflammation and reduce plaque progression. Using 25 rabbits with cholesterol feeding- and balloon injury-induced lesions, DCB-percutaneous transluminal angioplasty (PTA), plain PTA, or sham-PTA (balloon insertion without inflation) was investigated using serial intravascular near-infrared fluorescence-optical coherence tomography and serial intravascular ultrasound. In these experiments, DCB-PTA reduced inflammation and plaque burden in nonobstructive lesions compared with PTA or sham-PTA. These findings indicated the potential for DCBs to serve safely as regional anti-atherosclerosis therapy.

Vascular Positron Emission Tomography and Restenosis in Symptomatic Peripheral Arterial Disease: A Prospective Clinical Study.

OBJECTIVES: This study determined whether in vivo positron emission tomography (PET) of arterial inflammation (18F-fluorodeoxyglucose [18F-FDG]) or microcalcification (18F-sodium fluoride [18F-NaF]) could predict restenosis following PTA. BACKGROUND: Restenosis following lower limb percutaneous transluminal angioplasty (PTA) is common, unpredictable, and challenging to treat. Currently, it is impossible to predict which patient will suffer from restenosis following angioplasty. METHODS: In this prospective observational cohort study, 50 patients with symptomatic peripheral arterial disease underwent 18F-FDG and 18F-NaF PET/computed tomography (CT) imaging of the superficial femoral artery before and 6 weeks after angioplasty. The primary outcome was arterial restenosis at 12 months. RESULTS: Forty subjects completed the study protocol with 14 patients (35%) reaching the primary outcome of restenosis. The baseline activities of femoral arterial inflammation (18F-FDG tissue-to-background ratio [TBR] 2.43 [interquartile range (IQR): 2.29 to 2.61] vs. 1.63 [IQR: 1.52 to 1.78]; p < 0.001) and microcalcification (18F-NaF TBR 2.61 [IQR: 2.50 to 2.77] vs. 1.69 [IQR: 1.54 to 1.77]; p < 0.001) were higher in patients who developed restenosis. The predictive value of both 18F-FDG (cut-off TBRmax value of 1.98) and 18F-NaF (cut-off TBRmax value of 2.11) uptake demonstrated excellent discrimination in predicting 1-year restenosis (Kaplan Meier estimator, log-rank p < 0.001). CONCLUSIONS: Baseline and persistent femoral arterial inflammation and micro-calcification are associated with restenosis following lower limb PTA. For the first time, we describe a method of identifying complex metabolically active plaques and patients at risk of restenosis that has the potential to select patients for intervention and to serve as a biomarker to test novel interventions to prevent restenosis.

Peptide Amphiphile Supramolecular Nanostructures as a Targeted Therapy for Atherosclerosis.

The rising prevalence of cardiovascular disease worldwide necessitates novel therapeutic approaches to manage atherosclerosis. Intravenously administered nanostructures are a promising noninvasive approach to deliver therapeutics that reduce plaque burden. The drug liver X receptor agonist GW3965 (LXR) can reduce atherosclerosis by promoting cholesterol efflux from plaque but causes liver toxicity when administered systemically at effective doses, thus preventing its clinical use. The ability of peptide amphiphile nanofibers containing apolipoprotein A1-derived targeting peptide 4F to serve as nanocarriers for LXR delivery (ApoA1-LXR PA) in vivo is investigated here. These nanostructures are found to successfully target atherosclerotic lesions in a mouse model within 24 h of injection. After 8 weeks of intravenous administration, the nanostructures significantly reduce plaque burden in both male and female mice to a similar extent as LXR alone in comparison to saline-treated controls. Furthermore, they do not cause increased liver toxicity in comparison to LXR treatments, which may be related to more controlled release by the nanostructure. These findings demonstrate the potential of supramolecular nanostructures as safe, effective drug nanocarriers to manage atherosclerosis.

Cardiopulmonary Exercise Testing in Patients Following Massive and Submassive Pulmonary Embolism.

BACKGROUND: Little data exist regarding the functional capacity of patients following acute pulmonary embolism. We sought to characterize the natural history of symptom burden, right ventricular (RV) structure and function, and exercise capacity among survivors of massive and submassive pulmonary embolism. METHODS AND RESULTS: Survivors of submassive or massive pulmonary embolism (n=20, age 57±13.3 years, 8/20 female) underwent clinical evaluation, transthoracic echocardiography, and cardiopulmonary exercise testing at 1 and 6 months following hospital discharge. At 1 month, 9/20 (45%) patients had New York Heart Association II or greater symptoms, 13/20 (65%) demonstrated either persistent RV dilation or systolic dysfunction, and 14/20 (70%) had objective exercise impairment as defined by a peak oxygen consumption (V˙O2) of <80% of age-sex predicted maximal values (16.25 [13.4-20.98] mL/kg per minute). At 6 months, no appreciable improvements in symptom severity, RV structure or function, and peak V˙O2 (17.45 [14.08-22.48] mL/kg per minute, P=NS) were observed. No patients demonstrated an exercise limitation attributable to either RV/pulmonary vascular coupling, as defined by a VE/VCO2 slope >33, or a pulmonary mechanical limit to exercise at either time point. Similarly, persistent RV dilation or dysfunction was not significantly related to symptom burden or peak V˙O2 at either time point. CONCLUSIONS: Persistent symptoms, abnormalities of RV structure and function, and objective exercise limitation are common among survivors of massive and submassive pulmonary embolism. Functional impairment appears to be attributable to general deconditioning rather than intrinsic cardiopulmonary limitation, suggesting an important role for prescribed exercise rehabilitation as a means toward improved patient outcomes and quality of life.

Peptide Amphiphile Nanostructures for Targeting of Atherosclerotic Plaque and Drug Delivery.

Co-assembled peptide amphiphile nanofibers designed to target atherosclerotic plaque and enhance cholesterol efflux are shown to encapsulate and deliver a liver X receptor agonist to increase efflux from murine macrophages in vitro. Fluorescence microscopy reveals that the nanofibers, which display an apolipoprotein-mimetic peptide, localize at plaque sites in LDL receptor knockout mice with or without the encapsulated molecule, while nanofibers displaying a scrambled, non-targeting peptide sequence do not demonstrate comparable binding. These results show that nanofibers functionalized with apolipoprotein-mimetic peptides may be effective vehicles for intravascular targeted drug delivery to treat atherosclerosis.

High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacity Are Not Affected by Supervised Exercise but Are Associated with Baseline Interleukin-6 in Patients with Peripheral Artery Disease.

OBJECTIVE: To quantify the association between high-density lipoprotein (HDL) subfractions, efflux capacity, and inflammatory markers at baseline and the effect of supervised exercise on these HDL parameters in patients with peripheral artery disease (PAD). METHODS: The study to improve leg circulation (SILC) was a randomized trial of supervised treadmill exercise, leg resistance training, or control in individuals with PAD. In a post hoc cross-sectional analysis, we quantified the associations between baseline HDL subfraction concentrations (HDL2 and HDL3), HDL-C efflux capacity, and inflammatory markers [C-reactive protein (CRP) and interleukin-6 (IL-6)]. We then examined the effect of supervised exercise on changes in these lipoprotein parameters and inflammatory markers in 88 patients from SILC. RESULTS: Baseline HDL-C efflux capacity was associated with baseline concentrations of HDL2 (ß = 0.008, p = 0.0106), HDL3 (ß = 0.013, p < 0.0001), and IL-6 (ß = -0.019, p = 0.03). Baseline HDL3 concentration was inversely associated with IL-6 concentration (ß = -0.99, p = 0.008). Compared to control, changes in HDL2, HDL3, normalized HDL-C efflux capacity, CRP, or IL-6 were not significantly different at 6 months following the structured exercise intervention. CONCLUSION: HDL efflux and HDL3 were inversely associated with IL-6 in PAD patients. Structured exercise was not associated with changes in HDL subfractions, HDL-C efflux capacity, CRP, and IL-6 in PAD patients. Our preliminary findings support the theory that inflammation may adversely affect HDL structure and function; however, further studies are needed to evaluate these findings.

A Tailorable In-Situ Light-Activated Biodegradable Vascular Scaffold.

Biodegradable vascular scaffolds (BVS) are novel treatments for obstructive atherosclerotic cardiovascular disease that have been developed to overcome the limitations of traditional metallic drug-eluting stents (DES). The mechanical properties of bioabsorbable polymers used for the production of novel BVS are a key consideration for the clinical translation of this emerging technology. Herein, we describe the engineering of an in situ light-activated vascular scaffold (ILVS) comprised of a biodegradable citric acid-based elastomeric polymer, referred to as methacrylated poly-diol citrate (mPDC), and a diazeniumdiolate chitosan nitric oxide donor (chitoNO). In vitro studies demonstrate that the mechanical properties of the ILVS can be tailored to meet or exceed those of commercially available self-expanding bare metal stents (BMS). The radial compression strength of the ILVS is higher than that of a BMS despite undergoing degradation at physiologic conditions for 7 months. ILVS containing chitoNO provides sustained supraphysiologic levels of NO release. Lastly, ILVS were successfully cast in porcine arteries ex vivo using a custom designed triple balloon catheter, demonstrating translational potential. In conclusion, these data demonstrate the ability of an ILVS to provide tunable mechanical properties and drug-delivery capabilities for the vasculature, and thereby support mPDC as a promising material for the development of novel BVS platforms.

A Natural Language Processing Tool for Large-Scale Data Extraction from Echocardiography Reports.

Large volumes of data are continuously generated from clinical notes and diagnostic studies catalogued in electronic health records (EHRs). Echocardiography is one of the most commonly ordered diagnostic tests in cardiology. This study sought to explore the feasibility and reliability of using natural language processing (NLP) for large-scale and targeted extraction of multiple data elements from echocardiography reports. An NLP tool, EchoInfer, was developed to automatically extract data pertaining to cardiovascular structure and function from heterogeneously formatted echocardiographic data sources. EchoInfer was applied to echocardiography reports (2004 to 2013) available from 3 different on-going clinical research projects. EchoInfer analyzed 15,116 echocardiography reports from 1684 patients, and extracted 59 quantitative and 21 qualitative data elements per report. EchoInfer achieved a precision of 94.06%, a recall of 92.21%, and an F1-score of 93.12% across all 80 data elements in 50 reports. Physician review of 400 reports demonstrated that EchoInfer achieved a recall of 92-99.9% and a precision of >97% in four data elements, including three quantitative and one qualitative data element. Failure of EchoInfer to correctly identify or reject reported parameters was primarily related to non-standardized reporting of echocardiography data. EchoInfer provides a powerful and reliable NLP-based approach for the large-scale, targeted extraction of information from heterogeneous data sources. The use of EchoInfer may have implications for the clinical management and research analysis of patients undergoing echocardiographic evaluation.