Chronic infarct size after spontaneous coronary artery dissection: implications for pathophysiology and clinical management.

AIMS: To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury. METHODS AND RESULTS: One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass]. CONCLUSION: The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

Intra-Aortic Balloon Pump Counterpulsation in the Post-Resuscitation Period is Associated with Improved Functional Outcomes in Patients Surviving an Out-of-Hospital Cardiac Arrest: Insights from a Dedicated Heart Attack Centre.

BACKGROUND: Despite advances in cardiopulmonary resuscitation, functional survival remains low after out-of-hospital cardiac arrest (OOHCA). Intra-aortic balloon pump (IABP) therapy has recently been shown to augment cerebral blood flow. Whether IABP therapy in the post-resuscitation period improves functional outcomes is unknown. METHODS: We analysed 174 consecutive patients who were successfully resuscitated from an OOHCA between 2011-2013 at Harefield Hospital, London. We analysed functional status at discharge and mortality up to one year. RESULTS: A total of 55 patients (32.1%) received IABP therapy. Comparing those receiving IABP with those not receiving IABP, there was no difference in favourable functional status at discharge (49.1% vs. 57.1%, p=0.321); and mortality at one year (45.5% vs. 35.5%, p=0.164). Multivariable analyses identified IABP therapy as a strong independent predictor for favourable functional status at discharge (OR=7.51, 95% CI: 2.15-26.14, p=0.002) and this association was maintained in propensity-score adjusted analyses (OR=9.90, 95% CI: 2.11-46.33, p=0.004) and inverse probability treatment weighted analyses (OR=10.84, 95% CI: 2.75-42.69, p<0.001). However, IABP therapy was not an independent predictor for mortality at one year (HR=0.93, 95% CI: 0.52-1.65, p=0.810) and this was confirmed in both propensity-score adjusted and inverse probability treatment weighted analyses. CONCLUSIONS: In this observational analysis of patients surviving an OOHCA, the use of IABP therapy in the post-resuscitation period was associated with improved functional outcomes. This warrants further evaluation in larger prospective studies.

PHACTR1 modulates vascular compliance but not endothelial function: a translational study.

AIMS: The non-coding locus at 6p24 located in Intron 3 of PHACTR1 has consistently been implicated as a risk allele in myocardial infarction and multiple other vascular diseases. Recent murine studies have identified a role for Phactr1 in the development of atherosclerosis. However, the role of PHACTR1 in vascular tone and in vivo vascular remodelling has yet to be established. The aim of this study was to investigate the role of PHACTR1 in vascular function. METHODS AND RESULTS: Prospectively recruited coronary artery disease (CAD) patients undergoing bypass surgery and retrospectively recruited spontaneous coronary artery dissection (SCAD) patients and matched healthy volunteers were genotyped at the PHACTR1 rs9349379 locus. We observed a significant association between the PHACTR1 loci and changes in distensibility in both the ascending aorta (AA = 0.0053 ± 0.0004, AG = 0.0041 ± 0.003, GG = 0.0034 ± 0.0009, P < 0.05, n = 58, 54, and 7, respectively) and carotid artery (AA = 12.83 ± 0.51, AG = 11.14 ± 0.38, GG = 11.69 ± 0.66, P < 0.05, n = 70, 65, and 18, respectively). This association was not observed in the descending aorta or in SCAD patients. In contrast, the PHACTR1 locus was not associated with changes in endothelial cell function with no association between the rs9349379 locus and in vivo or ex vivo vascular function observed in CAD patients. This finding was confirmed in our murine model where the loss of Phactr1 on the pro-atherosclerosis ApoE-/- background did not alter ex vivo vascular function. CONCLUSION: In conclusion, we have shown a role for PHACTR1 in arterial compliance across multiple vascular beds. Our study suggests that PHACTR1 has a key structural role within the vasculature.

Short Communication: Predictive Value of HIV-Related Versus Traditional Risk Factors for Coronary Atherosclerosis in People Aging with HIV.

Cardiovascular disease (CVD) is an important cause of morbidity in people living with HIV (PLWH). We compared the predictive value of HIV-related and traditional CVD risk factors to assess which factors best predict the presence of subclinical coronary atherosclerosis in PLWH. This is a cross-sectional study in PLWH over 50 years of age who performed computed tomography coronary artery calcium (CAC) scoring between 2009 and 2019 at Chelsea and Westminster Hospital. The following outcomes were analyzed: CAC = 0 (no calcification), CAC >0 (any calcification), CAC >100 (moderate calcification), and CAC >400 (severe calcification). Univariate and multivariate logistic regression analyses were performed to assess predictors of coronary calcification. A total of 744 patients were included (mean age 56 ± 5.7 years, 94.8% male, 84% white). A CAC >0 was found in 392 (52.7%), CAC >100 in 90 (12.1%), and CAC >400 in 42 (5.6%) subjects. CAC >100 was strongly associated with hypertension [odds ratio, OR: 2.91, (95% confidence interval: 1.93-4.36), p < .001], dyslipidemia [2.71 (1.81-4.06), p < .001], and diabetes [2.53 (1.29-4.96), p = .01]. Regarding HIV-specific factors, a significant association was found with exposure (>6 years) to protease inhibitors [1.67 (1.06-2.61), p = .05], whereas exposure to tenofovir (>8 years) was negatively associated with CAC >100 [0.54 (0.30-0.98), p = .05]. Despite the high prevalence of hypertension (45.4%) only 21.5% were on antihypertensives, whereas only 29.2% of eligible candidates were receiving lipid-lowering drugs for primary prevention of CVD. Traditional cardiometabolic risk factors remain the strongest predictors of coronary atherosclerosis in PLWH as in the general population. These results underscore the importance of optimizing treatment of hypertension and promoting primary prevention strategies that may be underused in PLWH.

Prevalence and Disease Spectrum of Extracoronary Arterial Abnormalities in Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD) has been associated with fibromuscular dysplasia (FMD) and other extracoronary arterial abnormalities. However, the prevalence, severity, and clinical relevance of these abnormalities remain unclear. Objective: To assess the prevalence and spectrum of FMD and other extracoronary arterial abnormalities in patients with SCAD vs controls. Design, Setting, and Participants: This case series included 173 patients with angiographically confirmed SCAD enrolled between January 1, 2015, and December 31, 2019. Imaging of extracoronary arterial beds was performed by magnetic resonance angiography (MRA). Forty-one healthy individuals were recruited to serve as controls for blinded interpretation of MRA findings. Patients were recruited from the UK national SCAD registry, which enrolls throughout the UK by referral from the primary care physician or patient self-referral through an online portal. Participants attended the national SCAD referral center for assessment and MRA. Exposures: Both patients with SCAD and healthy controls underwent head-to-pelvis MRA (median time between SCAD event and MRA, 1 [IQR, 1-3] year). Main Outcome and Measures: The diagnosis of FMD, arterial dissections, and aneurysms was established according to the International FMD Consensus. Arterial tortuosity was assessed both qualitatively (presence or absence of an S curve) and quantitatively (number of curves ≥45%; tortuosity index). Results: Of the 173 patients with SCAD, 167 were women (96.5%); mean (SD) age at diagnosis was 44.5 (7.9) years. The prevalence of FMD was 31.8% (55 patients); 16 patients (29.1% of patients with FMD) had involvement of multiple vascular beds. Thirteen patients (7.5%) had extracoronary aneurysms and 3 patients (1.7%) had dissections. The prevalence and degree of arterial tortuosity were similar in patients and controls. In 43 patients imaged with both computed tomographic angiography and MRA, the identification of clinically significant remote arteriopathies was similar. Over a median 5-year follow-up, there were 2 noncardiovascular-associated deaths and 35 recurrent myocardial infarctions, but there were no primary extracoronary vascular events. Conclusions and Relevance: In this case series with blinded analysis of patients with SCAD, severe multivessel FMD, aneurysms, and dissections were infrequent. The findings of this study suggest that, although brain-to-pelvis imaging allows detection of remote arteriopathies that may require follow-up, extracoronary vascular events appear to be rare.

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants. METHODS: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses. RESULTS: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function. CONCLUSIONS: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.

Spontaneous Coronary Artery Dissection: Pathophysiological Insights From Optical Coherence Tomography.

OBJECTIVES: This study used optical coherence tomography to investigate the mechanism of false lumen (FL) formation in spontaneous coronary artery dissection (SCAD) by studying: 1) differences between fenestrated and nonfenestrated SCAD; 2) vasa vasorum density; and 3) light attenuation characteristics of the FL. BACKGROUND: SCAD is an increasingly recognized cause of acute coronary syndromes, characterized by FL formation and compression of the true lumen (TL). The mechanisms underlying FL formation remain poorly understood. METHODS: A total of 65 SCAD patients (68 vessels) who underwent acute OCT imaging as part of routine clinical care were included. Images were classified by the absence or presence of a connection (fenestration) between the TL and FL. Indexed measurements of TL stenosis, external elastic lamina (EEL) area, FL area, and light attenuation of the FL were assessed. Vasa vasorum densities of SCAD cases were compared with those in control non-SCAD myocardial infarction cases. RESULTS: In nonfenestrated cases, there was significantly larger expansion of the EEL area (9.1% vs. -1.9%; p <0.05) and a larger FL area (73.6% vs. 53.2%, respectively; p <0.05) in dissected segments. No significant differences were found between vasa vasorum density in SCAD and those in control subjects. The FL contents were heterogeneous but attenuated less light than whole blood or thrombus (4.28 ± 0.55 mm-1 vs. 5.08 ± 0.56 mm-1; p < 0.05; vs. 4.96 ± 0.56 mm-1; p < 0.05). CONCLUSIONS: These observational data suggest that the absence of a fenestration leads to increased FL pressure and compression of the TL. Although vasa vasorum may still be implicated in pathogenesis, increased vasa vasorum density could be an epiphenomenon of vascular healing.

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Predictors of survival and favorable functional outcomes after an out-of-hospital cardiac arrest in patients systematically brought to a dedicated heart attack center (from the Harefield Cardiac Arrest Study).

Despite advances in cardiopulmonary resuscitation (CPR), survival remains low after out-of-hospital cardiac arrest (OOHCA). Acute coronary ischemia is the predominating precipitant, and prompt delivery of patients to dedicated facilities may improve outcomes. Since 2011, all patients experiencing OOHCA in London, where a cardiac etiology is suspected, are systematically brought to heart attack centers (HACs). We determined the predictors for survival and favorable functional outcomes in this setting. We analyzed 174 consecutive patients experiencing OOHCA from 2011 to 2013 brought to Harefield Hospital-a designated HAC in London. We analyzed (1) all-cause mortality and (2) functional status using a modified Rankin scale (mRS 0 to 6, where mRS0-3(+) = favorable functional status). The overall survival rates were 66.7% (30 days) and 62.1% (1 year); and 54.5% had mRS0-3(+) at discharge. Patients with mRS0-3(+) had reduced mortality compared to mRS0-3(-): 30 days (1.2% vs 72.2%, p <0.001) and 1 year (5.3% vs 77.2%, p <0.001). Multivariate analyses identified lower patient comorbidity, absence of cardiogenic shock, bystander CPR, ventricular tachycardia/ventricullar fibrillation as initial rhythm, shorter duration of resuscitation, prehospital advanced airway, absence of adrenaline and inotrope use, and intra-aortic balloon pump use as predictors of mRS0-3(+). Consistent predictors of increased mortality were the presence of cardiogenic shock, advanced airway use, increased duration of resuscitation, and absence of therapeutic hypothermia. A streamlined delivery of patients experiencing OOHCA to dedicated facilities is associated with improved functional status and survival. Our study supports the standardization of care for such patients with the widespread adoption of HACs.

The South Asian genome.

The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.

"CURB" your enthusiasm and consider HIV.

We present the case of a 40-year old female who was initially seen by her GP and the Emergency Department with pneumonia failing to respond to oral antibiotics. Her severity assessment score categorised her as being in a low risk group and she was discharged. Subsequent admission and further investigations diagnosed Human Immunodeficiency Virus infection and Pneumocystis jeruvici pneumonia. It is important for emergency departments and acute physicians to apply risk validation tools appropriately and to be alert to underlying immunosuppression.