Cognitive and physical fatigue: the experience and consequences of 'brain fog' after Spontaneous Coronary Artery Dissection (SCAD), a qualitative study.

AIMS: Brain fog and fatigue are common issues after acute coronary syndrome. However, little is known about the nature and impact of these experiences in spontaneous coronary artery dissection (SCAD) survivors. The aims of this study were to understand the experiences of brain fog and the coping strategies used after SCAD. METHODS AND RESULTS: Participants were recruited from the Victor Chang Cardiac Research Institute Genetics Study database and were considered eligible if their event occurred within 12-months. Seven semi-structured online focus groups were conducted between December to January 2021-2022, with this study reporting findings related to brain fog and fatigue. Interviews were transcribed and thematically analysed using an iterative approach. Participants (N=30) were a mean age of 52.2 ((9.5) and mostly female (n=27, 90%). The overarching theme of brain fog after SCAD included four main themes: how brain fog is experienced, perceived causes, impacts, and how people cope. Experiences included memory lapses, difficulty concentrating and impaired judgement, and perceived causes included medication, fatigue and tiredness, and menopause and hormonal changes. Impacts of brain fog included rumination, changes in self-perception, disruption to hobbies/pastimes, and limitations at work. Coping mechanisms included setting reminders and expectations, being one's own advocate, lifestyle and self-determined medication adjustments, and support from peers. CONCLUSION: Brain fog is experienced by SCAD survivors and the impacts are varied and numerous, including capacity to work. SCAD survivors reported difficulty understanding causes and found their own path to coping. Recommendations for clinicians are provided.

Prevalence and correlates of anxiety and depressive symptoms after Spontaneous Coronary Artery Dissection (SCAD): a cross-sectional study.

AIMS: Spontaneous coronary artery dissection (SCAD) is recognised as a particularly stressful cause of heart attack. However few studies have documented the prevalence of post-SCAD anxiety and depressive symptoms, or identified patients most at risk. This study documents the prevalence and correlates of post-SCAD anxiety and depressive symptoms. METHOD AND RESULTS: 310 (95% women) SCAD survivors were recruited by the Victor Chang Cardiac Research Institute from a database of 433 SCAD survivors. Participants completed an online questionnaire to gather demographic, medical and psychosocial information, including the Generalised Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). Bivariate and multivariate analyses were undertaken to identify the significant demographic, psychosocial and medical correlates of post-SCAD anxiety and depressive symptoms. Time between SCAD and questionnaire completion varied from 2 months to 18 years (mean = 5.5 years; SD = 3.5 years). Rates of anxiety and depressive symptoms were 20.7% (GAD-7 ≥ 10) and 20.9% (PHQ-9 ≥ 10) respectively, and did not vary by time since event. In bivariate analyses, correlates (p < .05) of anxiety and depressive symptoms were absence of a close confidante, financial strain, mental health diagnosis pre-SCAD, comorbid obesity, not being in paid employment (anxiety only), younger age (depression only), and not knowing another SCAD survivor (depression only). Variables retained in multivariate models were absence of a close confidante, financial strain, not being in paid employment, mental health diagnosis pre-SCAD (depression only), and younger age (depression only). CONCLUSION: This study demonstrated that over one in four SCAD survivors experience either anxiety or depressive symptoms after SCAD, and identified those who may need additional support in their psychological recovery.

Correction: Psychosocial and lifestyle impacts of spontaneous coronary artery dissection: A quantitative study.

[This corrects the article DOI: 10.1371/journal.pone.0296224.].

Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System.

BACKGROUND: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation. METHOD: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance. RESULTS: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk. CONCLUSIONS: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.

Polygenic Risk in Families With Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases. Objective: To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls. Design, Setting, and Participants: This genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023. Exposures: PRS for SCAD comprised of 7 single-nucleotide variants. Main Outcomes and Measures: Disease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS. Results: A total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted P = 1.96 × 10-4; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted P = 5.69 × 10-4). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted P = .91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted P = .001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted P = .001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes. Conclusions and Relevance: Extreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.

Psychosocial and lifestyle impacts of spontaneous coronary artery dissection: A quantitative study.

INTRODUCTION: Recent studies suggest that acute myocardial infarction due to spontaneous coronary artery dissection (SCAD) carries significant psychosocial burden. This survey-based quantitative study builds on our earlier qualitative investigation of the psychosocial impacts of SCAD in Australian SCAD survivors. The study aimed to document the prevalence and predictors of a broad range of psychosocial and lifestyle impacts of SCAD. METHOD: Australian SCAD survivors currently enrolled in the Victor Chang Cardiac Research Institute genetics study were invited to participate in an online survey to assess the psychosocial impacts of SCAD. Participants completed a questionnaire, developed using findings from our earlier qualitative research, which assessed 48 psychosocial and five lifestyle impacts of SCAD. Participants also provided demographic and medical data and completed validated measures of anxiety and depression. RESULTS: Of 433 SCAD survivors invited to participate, 310 (72%) completed the questionnaire. The most common psychosocial impacts were 'shock about having a heart attack' (experienced by 87% respondents), 'worry about having another SCAD' (81%), 'concern about triggering another SCAD' (77%), 'uncertainty about exercise and physical activity' (73%) and 'confusion about safe levels of activity and exertion' (73.0%) and 'being overly aware of bodily sensations' (73%). In terms of lifestyle impacts, the SCAD had impacted on work capacity for almost two thirds of participants, while one in ten had sought financial assistance. The key predictors of psychosocial impacts were being under 50, current financial strain, and trade-level education. The key predictors of lifestyle impacts were being over 50, SCAD recurrence, trade-level education, and current financial strain. All psychosocial impacts and some lifestyle impacts were associated with increased risk of anxiety and/or depression. CONCLUSION AND IMPLICATIONS: This quantitative study extends our previous qualitative investigation by documenting the prevalence of each of 48 psychosocial and five lifestyle impacts identified in our earlier focus group research, and by providing risk factors for greater SCAD impacts. The findings suggest the need for supports to address initial experiences of shock, as well as fears and uncertainties regarding the future, including SCAD recurrence and exercise resumption. Support could be targeted to those with identified risk factors. Strategies to enable SCAD survivors to remain in or return to the paid workforce are also indicated.

Generation of induced pluripotent stem cell lines from a sister pair who suffered post-partum or recurrent Spontaneous Coronary Artery Dissections.

Spontaneous Coronary Artery Dissection (SCAD) results from a bleed within a coronary artery wall that impairs blood flow as it expands. It is the most common cause of myocardial infarction in pregnant women. Here, peripheral blood mononuclear cells from two sisters who had suffered SCADs were reprogrammed using Sendai Virus. Expression of pluripotency markers, capability to differentiate to the three germ layers, and cellular integrity were confirmed. This is the first report of a SCAD family induced pluripotent stem cell (iPSC) cohort, including a sister who suffered post-partum SCAD, and one who suffered from multiple recurrences.

Patients' perspective of quality-of-care and its correlation to quality-of-life following spontaneous coronary artery dissection.

AIM: Spontaneous coronary artery dissection (SCAD) is an under-recognised cause of myocardial infarction. We aimed to investigate SCAD survivors' perceptions of their quality-of-care and its relationship to quality-of-life. METHODS AND RESULTS: An anonymous survey was distributed online to SCAD survivors involved in Australian SCAD support groups, with 172 (95.3% female, mean age 52.6 ± 9.2 years) participants in the study. The survey involved assessment of quality-of-life using a standardised questionnaire (EQ-5DTM-3L). Respondents rated the quality-of-care received during their hospital admission for SCAD a median 8/10 [interquartile range (IQR) 7-10]. Respondents ≤50 years versus >50 years were more likely to perceive that their symptoms were not treated seriously as a myocardial infarction (χ2 = 4.127, df = 1, p < 0.05). Participants rated clinician's knowledge of SCAD a median 4/10 (IQR 2-8) and 7/10 (IQR 3-9) for Emergency and Cardiology clinicians, respectively (p < 0.05). The internet was the most selected source (45.4%) of useful SCAD information. The mean EQ-5DTM summary index was 0.79 (population norm 0.87). 47.2% of respondents reported a mental health condition diagnosis, with 36% of these diagnosed after their admission with SCAD. Quality-of-life was significantly associated with perceived quality-of-care: EQ-5DTM index/(1-EQ-5DTM index) increased by 13% for each unit increase in quality-of-care after adjusting for age and comorbidities (p < 0.001). CONCLUSION: While SCAD survivors rated their overall hospital care highly, healthcare providers' knowledge of SCAD was perceived to be poor and, the most common source of SCAD information was the internet. Mental health conditions were common, and a significant association was observed between perceived quality-of-care and SCAD survivors' quality-of-life.

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner.

Transglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound healing in a strain-dependent manner. Early healing of in vivo cutaneous wounds and closure of in vitro scratch wounds in murine embryonic fibroblast (MEF) monolayers were delayed in 129, but not B6, TG2 knockouts, relative to their wild-type counterparts, with wound closure in 129 being faster than in B6 wild-types. A single dose of exogenous recombinant wild-type TG2 to 129 TG2-/- mice or MEFs immediately post-wounding accelerated wound closure. Neutrophil and monocyte recruitment to 129 cutaneous wounds was not affected by Tgm2 deletion up to 5 days post-wounding. Tgm2 mRNA and TG2 protein abundance were higher in 129 than in B6 wild-types and increased in abundance following cutaneous and scratch wounding. Tgm1 and factor XIIA (F13A) mRNA abundance increased post-wounding, but there was no compensation by TG family members in TG2-/- relative to TG2+/+ mice in either strain before or after wounding. 129 TG2+/+ MEF adhesion was greater and spreading was faster than that of B6 TG2+/+ MEFs, and was dependent on syndecan binding in the presence, but not absence, of RGD inhibition of integrin binding. Adhesion and spreading of 129, but not B6, TG2-/- MEFs was impaired relative to their wild-type counterparts and was accelerated by exogenous addition or transfection of TG2 protein or cDNA, respectively, and was independent of the transamidase or GTP-binding activity of TG2. Rho-family GTPase activation, central to cytoskeletal organization, was altered in 129 TG2-/- MEFs, with delayed RhoA and earlier Rac1 activation than in TG2+/+ MEFs. These findings indicate that the rate of wound healing is different between 129 and B6 mouse strains, correlating with TG2 abundance, and although not essential for wound healing, TG2 facilitates integrin- and syndecan-mediated RhoA- and Rac1-activation in fibroblasts to promote efficient wound contraction.

A village in a dish model system for population-scale hiPSC studies.

The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and different conditions. Human induced pluripotent stem cells are uniquely suited to study these context-dependent effects but cell lines from hundreds or thousands of individuals are required. Village cultures, where multiple induced pluripotent stem lines are cultured and differentiated in a single dish, provide an elegant solution for scaling induced pluripotent stem experiments to the necessary sample sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned to an induced pluripotent stem line using single-cell sequencing and illustrating that the genetic, epigenetic or induced pluripotent stem line-specific effects explain a large percentage of gene expression variation for many genes. We demonstrate that village methods can effectively detect induced pluripotent stem line-specific effects, including sensitive dynamics of cell states.

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Prevalence of Anxiety, Depression, and Distress in SCAD and Non-SCAD AMI Patients: A Comparative Study.

PURPOSE: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute myocardial infarction (AMI), particularly in younger women without classic cardiac risk factors. Spontaneous coronary artery dissection is considered to be particularly stressful; however, few studies have quantified SCAD survivor stress levels. This study compared anxiety, depression, and distress levels in SCAD and non-SCAD AMI patients. METHOD: A sample of 162 AMI (35 [22%] SCAD) patients was recruited from hospitals and via social media, in Australia and the United States. All had had their AMI in the past 6 mo. Participants completed an online questionnaire comprising the Generalized Anxiety Disorder-2 (GAD2), Patient Health Questionnaire-2 (PHQ2), Kessler-6 (K6), and Cardiac Distress Inventory (CDI). T-tests, χ 2 tests, Mann-Whitney tests, and analysis of covariance were used to compare SCAD and non-SCAD samples. Logistic regression was used to identify the unique predictors of anxiety, depression, and distress, controlling for relevant confounders. RESULTS: Patients with SCAD were more commonly female and significantly younger than non-SCAD patients. Patients with SCAD scored significantly higher on the GAD2, PHQ2, K6, and CDI and a significantly larger proportion was classified as anxious, depressed, or distressed using these instruments. In logistic regression, together with mental health history, having had a SCAD-AMI predicted anxiety, depression, and distress, after controlling for female sex, younger age, and other confounding variables. CONCLUSION: This study supports the view that anxiety, depression, and distress are more common after SCAD-AMI than after traditional AMI. These findings highlight the psychosocial impacts of SCAD and suggest that psychological support should be an important component of cardiac rehabilitation for these patients.

Heritable defects in telomere and mitotic function selectively predispose to sarcomas.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

Arterial dissections: Common features and new perspectives.

Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations - such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-ß signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1, collagen genes, fibrillin and TGF-ß receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state is lost and replaced by a proliferative activated phenotype. Of interest, dissections in various anatomical locations are associated with distinct sex and age predilections, suggesting involvement of gene and environment interactions in disease pathogenesis. Importantly, these cellular mechanisms are potentially therapeutically targetable. Consideration of arterial dissections as a collective pathology allows insight from the better characterized dissection types, such as that involving the thoracic aorta, to be leveraged to inform the less common forms of dissections, including the potential to apply known therapeutic interventions already clinically available for the former.

The Australian New Zealand Spontaneous Coronary Artery Dissection (ANZ-SCAD) Registry - A Multi-Centre Cohort Study: Protocol, Background and Significance.

INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is an under-recognised cause of acute coronary syndrome (ACS) with a strong female predominance. There are currently limited prospective studies and no randomised controlled trials that inform on SCAD's best clinical care. Little is also known about predictors of acute SCAD deterioration or recurrence. We describe the study design of a multi-centre prospective and historical cohort study recruiting patients with SCAD across 15-20 sites in Australia/New Zealand (NZ). The primary aim is to describe the clinical presentation, management and outcomes along with predictors of acute deterioration and recurrence in a large Australian/NZ SCAD cohort, with international data pooling. METHODS AND ANALYSIS: Consented patients diagnosed with SCAD during a hospital admission for an ACS will be prospectively followed at 30 days then yearly, for up to 5 years. Each recruiting site will also retrospectively identify historical cases of SCAD from the proceeding 10 years, with a waiver of consent. For historical cases, data will be collected in a de-identified manner with date of last follow-up or death obtained from the medical records. All cases undergo core laboratory adjudication of coronary angiography and any accompanying imaging to confirm SCAD diagnosis. The primary endpoint will be occurrence of major adverse cardiovascular events; a composite of all-cause mortality, recurrent myocardial infarction (including SCAD recurrence), stroke/transient ischaemic attack, heart failure, cardiogenic shock, cardiac arrest/ventricular arrhythmia, heart transplantation and, repeat/unplanned revascularisation. Secondary endpoints will include each individual primary outcome as well as acute SCAD extension and quality of life/Seattle Angina Score in prospectively recruited participants. Endpoints will be assessed at the end of the hospital admission and at 30-days, 1 year, and median long-term follow-up. ETHICS: Multicentre ethics approval has been granted from the Western Sydney Local Health District Human Research Ethics Committee (2021/ETH00040). DISSEMINATION OF RESULTS: The analysed results will be published in peer-reviewed journals on completion of the historical data collection and then on completion of the prospective data collection. REGISTRATION DETAILS: The ANZ-SCAD registry has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621000824864).

Psychosocial impacts of spontaneous coronary artery dissection: A qualitative study.

Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute myocardial infarction, particularly in younger women without classic cardiac risk factors. While recent quantitative studies have noted high anxiety and depression in SCAD survivors, the full range and extent of psychosocial impacts of SCAD is unknown. The present study used a qualitative approach to investigate the psychosocial impacts of SCAD in Australian SCAD survivors. Focus group participants were recruited as part of a larger study of SCAD survivors currently being undertaken by the Victor Chang Cardiac Research Institute. Thirty SCAD survivors participated in one of seven online focus groups, conducted using a semi-structured format. Focus group duration was 1.5 hours. Each was digitally recorded and transcribed. Data were analyzed thematically according to recommended guidelines. One over-arching theme, five main themes and 26 sub-themes were identified. The over-arching theme related to lack of information, while the five main themes related to emotional impacts, issues with self-management, issues with family, impacts on work life, and the need for psychosocial support. The 'emotional impacts' theme comprised 11 sub-themes, namely shock and disbelief, confusion and uncertainty, unfairness, fear and anxiety, loss and grief, isolation and loneliness, guilt, invalidation and embarrassment, depression, vulnerability, and frustration. Findings are discussed in light of relevant psychological theories. This qualitative study extends previous quantitative investigations of SCAD survivors by providing an in-depth understanding of the complex, inter-related and highly distressing impacts of SCAD. The findings point to the urgent need for a coherent approach to information provision, the development and delivery of SCAD-specific cardiac rehabilitation programs, and the provision of psychosocial support programs for SCAD survivors.

Standardised method for cardiomyocyte isolation and purification from individual murine neonatal, infant, and adult hearts.

Primary cardiomyocytes are invaluable for understanding postnatal heart development. However, a universal method to obtain freshly purified cardiomyocytes without using different age-dependent isolation procedures and cell culture, is lacking. Here, we report the development of a standardised method that allows rapid isolation and purification of high-quality cardiomyocytes from individual neonatal through to adult C57BL/6J murine hearts. Langendorff retrograde perfusion, which is currently limited to adult hearts, was adapted for use in neonatal and infant hearts by developing an easier in situ aortic cannulation technique. Tissue digestion conditions were optimised to achieve efficient digestion of hearts of all ages in a comparable timeframe (<14 min). This resulted in a high yield (1.56-2.2 × 106 cells/heart) and viability (~70-100%) of cardiomyocytes post-isolation. An immunomagnetic cell separation step was then applied to yield highly purified cardiomyocytes (~95%) as confirmed by immunocytochemistry, flow cytometry, and qRT-PCR. For cell type-specific studies, cardiomyocyte DNA, RNA, and protein could be extracted in sufficient yields to conduct molecular experiments. We generated transcriptomic datasets for neonatal cardiomyocytes from individual hearts, for the first time, which revealed nine sex-specific genes (FDR < 0.05) encoded on the sex chromosomes. Finally, we also developed an in situ fixation protocol that preserved the native cytoarchitecture of cardiomyocytes (~94% rod-shaped post-isolation), and used it to evaluate cell morphology during cardiomyocyte maturation, as well as capture spindle-shaped neonatal cells undergoing cytokinesis. Together, these procedures allow molecular and morphological profiling of high-quality cardiomyocytes from individual hearts of any postnatal age.

Metabolic Profiling of Mice with Deletion of the Orphan G Protein-Coupled Receptor, GPR37L1.

Understanding the neurogenic causes of obesity may reveal novel drug targets to counter the obesity crisis and associated sequelae. Here, we investigate whether the deletion of GPR37L1, an astrocyte-specific orphan G protein-coupled receptor, affects whole-body energy homeostasis in mice. We subjected male Gpr37l1-/- mice and littermate wildtype (Gpr37l1+/+, C57BL/6J background) controls to either 12 weeks of high-fat diet (HFD) or chow feeding, or to 1 year of chow diet, with body composition quantified by EchoMRI, glucose handling by glucose tolerance test and metabolic rate by indirect calorimetry. Following an HFD, Gpr37l1-/- mice had similar glucose handling, body weight and fat mass compared with wildtype controls. Interestingly, we observed a significantly elevated respiratory exchange ratio in HFD- and chow-fed Gpr37l1-/- mice during daylight hours. After 1 year of chow feeding, we again saw no differences in glucose and insulin tolerance or body weight between genotypes, nor in energy expenditure or respiratory exchange ratio. However, there was significantly lower fat mass accumulation, and higher ambulatory activity in the Gpr37l1-/- mice during night hours. Overall, these results indicate that while GPR37L1 may play a minor role in whole-body metabolism, it is not a viable clinical target for the treatment of obesity.

Anesthesia and Intubation of Preadolescent Mouse Pups for Cardiothoracic Surgery.

Murine surgical models play an important role in preclinical research. Mechanistic insights into myocardial regeneration after cardiac injury may be gained from cardiothoracic surgery models in 0-14-day-old mice, the cardiomyocytes of which, unlike those of adults, retain proliferative capacity. Mouse pups up to 7 days old are effectively immobilized by hypothermia and do not require intubation for cardiothoracic surgery. Preadolescent (8-14-day-old) mouse pups, however, do require intubation, but this is challenging and there is little information regarding anesthesia to facilitate intubation. Here, we present dosage regimens of ketamine/xylazine/atropine in 10-day-old C57BL/6J mouse pups that allow endotracheal intubation, while minimizing animal mortality. Empirical titration of ketamine/xylazine/atropine dosage regimens to body weight indicated that the response to anesthesia of mouse pups of different weights was non-linear, whereby doses of 20/4/0.12 mg/kg, 30/4/0.12 mg/kg, and 50/6/0.18 mg/kg facilitated intubation of pups weighing between 3.15-4.49 g (n = 22), 4.50-5.49 g (n = 20), and 5.50-8.10 g (n = 20), respectively. Lower-body-weight pups required more intubation attempts than heavier pups (p < 0.001). Survival post-intubation correlated with body weight (59%, 70%, and 80% for low-, mid-, and high-weight groups, respectively, R2 = 0.995). For myocardial infarction surgery after intubation, a surgical plane of anesthesia was induced with 4.5% isoflurane in 100% oxygen and maintained with 2% isoflurane in 100% oxygen. Survival post-surgery was similar for the three weight groups at 92%, 86%, and 88% (p = 0.91). Together with refinements in animal handling practices for intubation and surgery, and minimizing cannibalization by the dam post-surgery, overall survival for the entire procedure (intubation plus surgery) correlated with body weight (55%, 60%, and 70% for low-, mid-, and high-weight groups, respectively, R2 = 0.978). Given the difficulty encountered with intubation of 10-day old pups and the associated high mortality, we recommend cardiothoracic surgery in 10-day-old pups be restricted to pups weighing at least 5.5 g.