Takotsubo syndrome (TTS), once considered a benign self-limiting disease, is now recognized to have substantial short-term morbidity and mortality. During the acute phase, it can result in severe heart failure, cardiogenic shock, arrhythmias, cardiac rupture, ventricular septal perforation (VSP), and thromboembolic events, with in-hospital mortality rates comparable to those observed in acute coronary syndrome. Although VSP is rare, it represents a potentially lethal complication of TTS. Herein, we present a case of VSP associated with TTS and discuss a mechanism for the development of VSP in TTS. A 69-year-old female presented with dyspnea. The diagnosis of TTS was established based on the presence of apical ballooning of the left ventricle (LV), hyperkinesis of the LV basal walls, normal coronary arteries, and apical defect in myocardial scintigraphy. Additionally, a VSP was identified, and given the stabilization of hemodynamics with an intra-aortic balloon pump and medical treatment, it was deemed preferable to delay surgical treatment. Approximately 1 month later, after the LV wall motion abnormality had been normalized, the VSP was successfully closed. Histopathological examination of the ventricular septum revealed contraction band necrosis along with fibrosis and focal cardiomyocyte necrosis. While VSP is a potentially lethal complication of TTS, recovery of LV function can be anticipated, suggesting that surgical treatment could be deferred, provided that hemodynamic stability is maintained. This case demonstrates that focal myocardial necrosis can occur in TTS. Furthermore, increased wall tension occurs in the ballooning segments during systole, as the LV radius increases and the ventricular wall fails to thicken, in accordance with Laplace's law. Both myocardial fragility resulting from focal myocardial necrosis and increased LV wall tension due to systolic ballooning are considered to be key mechanisms underlying the development of VSP in TTS.

Occlusion of the left main coronary artery (LMCA) is a highly lethal cause of myocardial infarction (MI), often referred to as the "widowmaker" due to its rapid progression and high mortality rate. Prompt diagnosis and intervention are crucial, although frequently delayed, particularly in females who tend to present with atypical symptoms. We report the case of a 57-year-old woman who arrived at the emergency department with severe epigastric pain and distress that progressed into altered mental status, initially prompting evaluation for gastrointestinal pathology. Her condition rapidly progressed to cardiogenic shock, with persistent hypotension, tachycardia, and new-onset atrial fibrillation with rapid ventricular response, despite no prior history of arrhythmia. Initial laboratory testing revealed elevated cardiac biomarkers and metabolic acidosis, and electrocardiogram (ECG) findings concerning for ST-elevation myocardial infarction (STEMI). Emergent coronary angiography revealed a 99% thrombotic occlusion of the LMCA. The patient underwent successful placement of a drug-eluting stent and initiation of intra-aortic balloon pump (IABP) support, leading to hemodynamic stabilization and transfer to a tertiary care center for advanced cardiac management. Despite these interventions, the patient expired due to complications of her acute MI. This case highlights the diagnostic and clinical challenges associated with LMCA occlusion, particularly in females whose symptoms often deviate from classical presentations. It emphasizes the importance of maintaining a high index of suspicion for acute coronary syndrome (ACS) even in the absence of chest pain, especially when patients exhibit signs of hemodynamic instability or arrhythmia. The presence of atrial fibrillation further complicated both the clinical picture and management strategy. Timely recognition, rapid activation of a STEMI protocol, and emergent percutaneous coronary intervention (PCI) were instrumental in stabilizing this patient for transport. More broadly, this case underscores the ongoing need for sex-specific approaches in cardiovascular medicine and reinforces the importance of early, personalized intervention strategies in high-risk presentations.

Recent advances in dose-delivery techniques have led to a reduction in normal tissue complications in radiotherapy patients. However, significant early and late cardiovascular (CV) effects may result when the heart is included in the radiation field and exposed to doses commonly used to treat several types of malignancies, or during total-body irradiation (TBI) prior to hematopoietic stem cell transplantation. Moreover, a radiological or nuclear (RAD/NUC) incident in which thousands of people are exposed to potentially lethal doses of ionizing radiation could result in the development of delayed effects of acute radiation exposure (DEARE) in survivors; several life-threatening cardiac DEARE-related pathologies would be observed months to years after TBI doses that trigger the hematopoietic acute radiation syndrome (H-ARS). While mitigators are available to treat acute symptoms in individuals that received radiation doses high enough to trigger the H-ARS, there are no drugs or strategies for mitigating early or late cardiovascular effects in radiotherapy patients, or late cardiac pathologies that would subsequently manifest in H-ARS survivors; while some drugs have shown promise, toxicity, limited efficacy or logistical issues regarding administration precludes their clinical use. Thus, there is great interest in the development of mitigators of cardiovascular dysfunction. We previously identified a novel non-pharmacological strategy that is effective in mitigating the lethal effects of TBI in mice when administered after exposure. Our approach involved the creation of a small subcutaneous (SC) incision postirradiation. We found that subcutaneous wounding several minutes after a high-dose TBI greatly protected against lethality, and that mitigation of the resulting H-ARS was likely mediated by enhanced recovery of hematopoiesis. We refer to this approach as "protective wounding." We now show that a subcutaneous cut preserves cardiac function, specifically, pumping capacity as measured by the Langendorff technique, in mice when assessed 30 days after a single dose or fractionated TBI. For example, left ventricular developed pressure (LVDP) at end diastolic pressure (EDP) 30-39 was 22.5% greater in mice that received a cut after a TBI dose of 6.5 Gy, compared to sham-cut mice. We propose that "protective wounding" may be used as a novel model for interrogating the proteins and pathways involved in reducing cardiotoxicity after irradiation and ultimately guiding development of pharmacological mitigators of cardiotoxicity in radiotherapy patients or victims of RAD/NUC incidents.

We present a male patient born at 38-wk gestation with rhizomelic shortening of extremities, hepatomegaly, ventriculomegaly, heart failure, severely depressed left ventricular function, biventricular hypertrophy, and biatrial enlargement. Additional physical findings included anteriorly displaced anus, vertebral anomalies, and brachydactyly. The patient's cardiac malformations led to persistent hypotension, sinus tachycardia, and multiorgan failure in the absence of arrhythmias. Rapid whole-exome sequencing was ordered on day of life (DOL) 8. The patient's family elected to withdraw supportive care, and he passed away that evening. Whole-exome sequencing returned posthumously and identified a variant in NAA10, E100K. The genotype-phenotype was closest to Ogden syndrome or amino-terminal acetyltransferase deficiency. Typical features of this rare X-linked syndrome include progeroid appearance, failure to thrive, developmental delays, hypotonia, and cardiac arrhythmias. Other family members were tested and the patient's mother, who has a history of mild intellectual disability, as well as a daughter born later, were identified as carriers. All carriers showed no cardiac findings. The carrier sister has manifested developmental delay and cortical atrophy. Protein modeling, evolution, dynamics, population variant assessments, and immunoprecipitation depict the deleterious nature of the variant on the interactions of NAA10 with NAA15 These findings had subsequent implications for posthumous diagnosis of the index patient, for female carriers, and regarding family planning. We highlight how these rapid genetic tests and variant characterization can potentially lead to informed decision-making between health-care providers and family members of patients with critical or lethal conditions when treatment options are limited.

A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations. We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents. We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity. Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.