Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Intravascular imaging and histological correlates of medial and intimal calcification in peripheral artery disease.

BACKGROUND: In peripheral artery disease, two different types of calcification are frequently observed, i.e., medial and intimal calcification. AIMS: The aim of this study was to determine the ability of intravascular ultrasound (IVUS) imaging and optical frequency domain imaging (OFDI) to detect medial and intimal calcification in human peripheral arteries. METHODS: We performed ex vivo intravascular imaging of cadaveric human peripheral arteries with calcifications. IVUS and OFDI images were co-registered with histology. A total of 12 legs from nine patients were examined, and 438 cross-sectional images were co-registered with histology. RESULTS: OFDI could detect 183 of 231 intimal calcifications by histology, whereas IVUS could detect 194 (OFDI: sensitivity 79%, specificity 86%, area under the curve [AUC] 0.83; IVUS: sensitivity 84%, specificity 85%, AUC 0.85). Of 245 medial calcifications by histology, 160 and 164 were detected by OFDI and IVUS, respectively (OFDI: sensitivity 65%, specificity 85%, AUC 0.75; IVUS: sensitivity 67%, specificity 80%, AUC 0.74). Medial calcification with overlying intimal calcification (overlapped calcification) and an unclear border between intima and media were the main reasons for misdiagnosis. Without those 89 overlapped calcifications, sensitivity in both OFDI and IVUS was improved (OFDI: sensitivity 81%, specificity 85%, AUC 0.83; IVUS: sensitivity 88%, specificity 80%, AUC 0.84). CONCLUSIONS: There are limitations in detecting medial calcification in overlapped intimal calcification and with an unclear border between intima and media by both IVUS and OFDI. It is important to distinguish medial calcification from intimal calcification before proceeding with endovascular therapy since different approaches will be required.

Co-Registration of Peripheral Atherosclerotic Plaques Assessed by Conventional CT Angiography, MicroCT and Histology in Patients with Chronic Limb Threatening Ischaemia.

OBJECTIVE: To co-register conventional computed tomography angiography (CTA), with ex vivo micro-computed tomography (microCT) and histology of popliteal atherosclerotic plaques. Improving the non-invasive imaging capabilities may be valuable to advance patient care with peripheral arterial obstructive disease towards lesion and individual based treatment. METHODS: In this prospective observational study, 12 popliteal arteries from 11 symptomatic patients who had undergone transfemoral amputations for chronic limb threatening ischaemia and who had pre-operative CTA, were analysed ex vivo by microCT and histology. A total of 353 histological cross sections were co-registered with microCT and CTA, and classified as: lipid rich (LP, n = 26), fibrous (FP, n = 80), or calcific (CP, n = 247) plaques. CTA and microCT plaque density was calculated in 791 regions of interest as Hounsfield units (HU). RESULTS: CTA and microCT could identify plaque components that were confirmed by histology such as fibrous tissue (FP), lipid pool/core (LP), and calcification (CP). MicroCT densities were 77.8 HU for FP (IQR 52.8, 129.5 HU), -28.4 HU for LP (IQR -87.1, 13.2 HU), and 3826.0 HU for CP (IQR 2989.0, 4501.0 HU). CTA densities of the three components of the plaque were: 78.0 HU for FP (IQR 59.5, 119.8 HU), 32.5 HU for LP (IQR 15.0, 42 HU), and 641.5 HU for CP (IQR 425.8, 1135 HU). The differences were statistically significant between the HU densitometric characteristics among the three groups (p < .0001) for both imaging modalities. Overall, microCT performed better diagnostically than conventional CTA for the three types of plaques: areas under the receiving operator characteristics curve were greater for microCT than CTA for FP (0.97 vs. 0.90), for LP (0.88 vs. 0.67), and for CP (0.97 vs. 0.90). CONCLUSION: CTA and microCT can be used to identify histological atherosclerotic plaque components, with better diagnostic performance for microCT. This study demonstrates the feasibility of using microCT to assess plaque morphology lesions in a manner that approaches histology thus becoming a useful tool for ex vivo assessment of atherosclerosis and towards lesion based treatment.

Pathology and Multimodality Imaging of Acute and Chronic Femoral Stenting in Humans.

OBJECTIVES: The objective of this study was to comprehensively evaluate the pathology of acute and chronic femoral stenting in symptomatic atherosclerotic patients and to understand the causes of stent failure (SF) using multimodality imaging including micro-computed tomography. BACKGROUND: Although the pathology of coronary stenting has been well studied, the pathology of lower extremity femoral stenting remains poorly understood. METHODS: Twelve stented femoral lesions removed at surgery (n = 10) and at autopsy (n = 2) were obtained from 10 patients (median age 74 years; interquartile range [IQR]: 66 to 82 years) with histories of peripheral artery disease (critical limb ischemia in 7) (7 men and 3 women). All specimens underwent radiography, micro-computed tomography, and histological assessment. RESULTS: The median duration of implantation was 150 days (IQR: 30 to 365 days), the median stent diameter was 5.90 mm (IQR: 5.44 to 7.16 mm), and the median stent length was 39.5 mm (IQR: 27 to 107.5 mm). Of the 12 stented lesions, 2 had drug-eluting stents, and 10 had bare-metal stents. SF was observed in 8 of 12 lesions. The major cause of SF was acute thrombosis (6 of 8), but causes varied (delayed healing, stent underexpansion, false lumen stenting, and fracture), and 2 had restenosis. Stent fractures were observed in 3 cases by micro-computed tomography. Both drug-eluting stents, implanted for >1 year, showed delayed healing with circumferential peristrut fibrin deposition and SF. CONCLUSIONS: This histological study is the first to examine the pathological cause of SF. Stent thrombosis was the major cause of SF. Delayed healing was a common feature of bare-metal stents implanted for <90 days, while all drug-eluting stents, despite implantation duration >1 year, showed delayed healing.

Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing.

AIMS: Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described. METHODS AND RESULTS: From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02). CONCLUSION: Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.

What are the Pathological Concerns and Limitations of Current Drug-coated Balloon Technology?

The use of endovascular therapy for peripheral artery disease and coronary artery disease has increased and spread worldwide and is considered as the foremost, guideline-based invasive treatment. Drug-coated balloons (DCBs) utilise anti-proliferative drugs similar to drug-eluting stents; however, the do not leave any permanent metallic scaffold. Excipients and drug formulations play a crucial role in innovative DCB technologies and allow for treatment of lesions where stents are not suitable. Although the significance of downstream embolic effects after DCB use remains uncertain, several preclinical studies suggest such side effects might pose safety concerns. Recently, a meta-analysis of randomised controlled trials of paclitaxel devices suggested an association between increased mortality and paclitaxel device use. Subsequently, unfavourable criticism of paclitaxel devices attracted much attention and gave rise to a discussion about the safety of such devices. In this review, we will focus on the novel DCB technologies from the standpoint of preclinical studies and clinical trials, as well as discuss current controversies regarding the increase in death rates from paclitaxel-coated DCBs versus control devices seen in a recent meta-analysis of randomised controlled clinical trials.