AIM:The American College of Cardiology/American Heart Association Scientific Statement, "Clinical Considerations for the Care of the Tactical Athlete With Cardiovascular Abnormalities," was written to provide guidance and education for clinicians caring for the tactical athlete (ie, firefighters, law enforcement officers, military) with cardiovascular disease or risk for cardiovascular disease, and for the organizations overseeing the care and wellness of these athletes. The considerations are shaped by the interaction between occupational demands and fit for full duty assessments, including risk discussions about how a cardiovascular event in a tactical athlete could impact teammates' well-being, community safety, and overall mission success. METHODS:This scientific statement is organized into 11 sections focused on cardiovascular disease processes and other topics that are relevant when considering the potential risks and benefits of performing tasks specific to the tactical athlete. Task forces, comprised of experts in tactical athlete domains, sports cardiology, and the respective topics covered, were assigned to each section, and specific "Clinical Considerations Tables" for clinicians to reference were prepared. Comprehensive literature reviews and an emphasis on tactical athlete-focused data, as available, were integral in the writing of all clinical considerations presented. The framework mirrors that of the recently published, "Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology." STRUCTURE:The specific sections in this document include: Section 1: Tactical Tasks Classification; Section 2: The Tactical Athlete Preparticipation Cardiac Evaluation; Section 3: Ethical and Legal Aspects of Tactical Clinical Management; Section 4: Genetic Cardiomyopathies; Section 5: Myocarditis and Other Acquired Cardiac Conditions; Section 6: Congenital Heart Disease; Section 7: Aortopathy, Bicuspid Aortic Valve, and Spontaneous Coronary Artery Dissection; Section 8: Syncope, SCA, Arrhythmias, and Devices; Section 9: Cardiac Channelopathies; Section 10: Older Tactical Athlete; Section 11: Environmental Exposures, PED/S, and Additional Cardiac Conditions and Considerations. Each section provides a summary detailing the rationale for key clinical considerations and the respective Clinical Considerations Table(s).
BACKGROUND:Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in the understanding of the epigenetic pathogenesis of the disease. METHODS:We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of patients with PH using bisulfite-induced deletion sequencing. PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells, the lung tissues of patients with PH, and SU5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, adeno-associated virus serotype-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition with NSC107512. RESULTS:Bisulfite-induced deletion sequencing revealed global Ψ dysregulation in the lung tissues of patients with PH. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic pulmonary artery endothelial cells. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas adeno-associated virus serotype-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of TGFBI (transforming growth factor β-induced protein) mRNA, thereby stabilizing TGFBI and activating phosphatidylinositol 3-kinase-protein kinase B signaling pathway. Furthermore, hypoxia-inducible factor 2α bound directly to the PUS7 promoter, establishing a hypoxia-inducible factor 2α/PUS7/TGFBI/phosphatidylinositol 3-kinase-protein kinase B positive feedback loop that drives PH pathogenesis. CONCLUSIONS:PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH through the hypoxia-inducible factor 2α/PUS7/TGFBI/phosphatidylinositol 3-kinase-protein kinase B axis, positioning PUS7 as a promising therapeutic target for this devastating disease.
Optimal outcomes for congenital heart surgery depend on the expertise and judgment of an integrated multidisciplinary clinical team. The best outcomes require a comprehensive understanding of the patient's anatomy and physiology, an appropriate therapeutic plan, a meticulously executed operation that is technically optimal and facilitated by lesion-specific anesthesia and perfusion strategies, and skilled perioperative care. A principal factor contributing to adverse outcomes is the presence of important residual lesions after surgery, which may necessitate early unplanned cardiac reinterventions during the index hospitalization. Such reinterventions occur in ≈5% of all pediatric cardiac operations, with a higher incidence in younger patients and more complex procedures. The presence of significant residual lesions and the need for unplanned reinterventions are strongly associated with increased morbidity, mortality, and resource use. Wide center-level variation in the incidence and timing of unplanned reinterventions suggests an opportunity for quality improvement. In this scientific statement, we summarize the incidence, risk factors, and clinical outcomes of important residual lesions and early unplanned cardiac reinterventions. We review postoperative monitoring strategies and clinical indicators suggestive of a residual lesion, and we provide an overview of the noninvasive imaging modalities used for their identification and quantification. The roles of diagnostic and interventional cardiac catheterization in the management of residual lesions are discussed, along with surgical considerations for early reoperation. We highlight the importance of communication with patients and families. Last, key areas for future investigations are identified.
BACKGROUND:Survival to hospital admission for out-of-hospital cardiac arrest is an important resuscitation outcome to gauge emergency medical service (EMS) agency performance. However, its correlation with EMS rates of survival to hospital discharge and favorable neurological survival is unclear. METHODS:Using the Cardiac Arrest Registry to Enhance Survival (CARES), we identified adults with nontraumatic out-of-hospital cardiac arrests during 2 periods: 2015 through 2019 (before the COVID-19 pandemic) and 2022 through 2024 (after the peak pandemic years). Multivariable hierarchical logistic regression was used to derive EMS agency-level risk-standardized survival rates for hospital admission, hospital discharge, and favorable neurological survival during each period. We then assessed the correlation between EMS agency rates of survival to admission versus discharge and favorable neurological survival using weighted linear regression, and whether the correlations differed by neighborhood income (above versus below median household income) and race and ethnicity (categorized as predominantly White [>80% of residents], majority Black or Hispanic [>50% of residents], or integrated). RESULTS:A total of 544 296 events from 1838 EMS agencies met inclusion criteria (252 137 pre-COVID; 292 159 post-COVID). During the period of 2015 to 2019, EMS rates of survival to admission were strongly correlated with survival to discharge (weighted r=0.68 [95% CI, 0.64-0.72]) and favorable neurological survival (weighted r=0.54 [95% CI, 0.43-0.59]). These correlations were similar during the period of 2022 through 2024 (weighted r=0.63 [95% CI, 0.59-0.66] and weighted r=0.48 [95% CI, 0.44-0.53], respectively). Neighborhood racial and ethnic composition modified the correlation between EMS rates of survival to admission and survival outcomes at discharge in both periods (all interactions <0.05), but the correlations remained strong in each neighborhood group. Similar findings were found for the interactions by neighborhood income strata. CONCLUSIONS:EMS agency rates of survival to hospital admission are strongly correlated with their rates of survival to hospital discharge and favorable neurological survival. These findings support the use of survival to hospital admission as a performance metric for EMS systems.
BACKGROUND:The use of anti-programmed cell death-1 (PD-1) antibody increases heart failure (HF) risk in patients with cancer with preexisting cardiovascular conditions. However, the underlying mechanism remains incompletely understood. METHODS:To evaluate the effects of anti-PD-1 antibody on transverse aortic constriction (TAC)-induced cardiac remodeling and HF, anti-PD-1 antibody-treated mice; T cell-, myeloid-, and CD8+ T cell-specific Pdcd1 knockout; C-X-C motif chemokine receptor 3 (Cxcr3) knockout; and granzyme B (Gzmb) knockout mice combined with flow cytometry, Western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used. RESULTS:Administration of anti-PD-1 antibody, T cell-, or CD8+ T cell-specific Pdcd1 deletion, but not myeloid-specific Pdcd1 knockout, aggravated TAC-induced cardiomyopathy and HF in mice. Mechanistically, PD-1 blockade or deletion increased myocardial infiltration of CXCR3+ CD8+ T cells, leading to granzyme B/perforin-mediated impairment of cardiomyocyte mitochondrial complex I to exacerbate TAC-induced cardiac injury and HF. TAC-enhanced chemotaxis, between cardiac fibroblast-derived CXCL9/CXCL10 and CXCR3+ CD8+ T cells, was a driving force for recruiting CXCR3+ CD8+ T cells under the conditions of PD-1 blockade or deletion. The worsened TAC-induced cardiomyopathy caused by anti-PD-1 antibody or T cell-specific Pdcd1 deletion was rescued by genetic deletion or pharmacological blockade of granzyme B and CXCR3. CONCLUSIONS:Anti-PD-1 antibody enhances myocardial infiltration of CXCR3+ CD8+ T cells under TAC condition through CXCL9/CXCL10-mediated chemotaxis. The increased granzyme B and perforin likely derived from CD8+ T cells impair function of mitochondrial respiratory chain complexes to cause cardiomyocyte apoptosis, thereby exacerbating TAC-induced cardiomyopathy and HF. CXCL9/CXCL10-CXCR3+ CD8+ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.
BACKGROUND:Determining the source of thromboembolism in patients with acute ischemic stroke remains challenging because current diagnostic approaches rely largely on circumstantial and inferential associations rather than direct identification of the cause of stroke. Fluorine-18 GP1 ([18F]GP1) is a novel radiotracer that binds with high affinity and specificity to activated glycoprotein IIb/IIIa receptors on activated platelets. We aimed to determine whether hybrid [18F]GP1 positron emission tomography (PET) and computed tomography angiography could identify in vivo cardiovascular thromboembolism in patients with acute ischemic stroke and provide a mechanism-based assessment of stroke etiology. METHODS:In a single-center prospective observational cohort study, 100 patients presenting with acute ischemic stroke underwent hybrid [18F]GP1 PET/computed tomography angiography within 21 days of symptom onset in addition to standard-of-care stroke investigations. Stroke etiology was classified using the causative classification system by an expert stroke physician blinded to [18F]GP1 PET findings. In parallel, [18F]GP1 PET/computed tomography angiography images were analyzed independently by readers who were blinded to all clinical data and causative classification system classification. We assessed whether [18F]GP1 PET/computed tomography angiography could identify the source of in vivo cardiovascular thromboembolism, influence stroke classification, and predict recurrent cerebrovascular events. RESULTS:Cardiovascular [18F]GP1 uptake indicative of thrombosis was identified in nearly two-thirds (n=63) of participants, changing stroke classification in over a quarter (n=26) of patients. In those with stroke of undetermined cause, the source of thrombus was identified in 18 of 41 (44%) participants, which included nonstenotic carotid atherothrombosis, native cardiac valve thrombosis, and paradoxical thromboembolism. During a median follow-up of 613 (interquartile interval, 251-788) days, recurrent stroke or transient ischemic attack occurred in 14 patients, 13 (93%) of whom had cardiovascular [18F]GP1 uptake at baseline. Cardiovascular [18F]GP1 uptake was associated with a 10.4-fold increased risk of recurrent events (95% CI, 1.35-79.40; P=0.024). CONCLUSIONS:Noninvasive thrombosis imaging is a novel technique that enables direct in vivo identification of thrombus formation and frequently reveals the source of thromboembolism in patients with acute ischemic stroke. This approach represents a shift from inference-based to mechanism-based stroke classification with potential implications for targeted prevention strategies and better patient outcomes. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05636748.
BACKGROUND:Spontaneous coronary artery dissection (SCAD) is characterized by a separation of the coronary artery wall, causing myocardial infarction and sudden death. This study is one of the first to clarify the impact of pathological genetic variants in candidate SCAD-related genes on the histopathological and morphological properties of human SCAD lesions. METHODS:A total of 28 SCAD cases were selected from the CVPath Autopsy Registry. Histological differences in collagen and smooth muscle cells were compared among 3 groups: culprit SCAD (C-SCAD), defined as the coronary segment containing a dissection in cases with SCAD; nonculprit SCAD, defined as unaffected coronary segments (ie, healthy arteries) in cases with SCAD; and non-SCAD controls. Whole-exome sequencing was performed, and the identified variants were filtered to isolate pathogenic or likely pathogenic variants. Protein expression corresponding to the identified variants was assessed by immunostaining. RESULTS:Collagen content was significantly reduced in C-SCAD lesions compared with controls, and immunohistochemical staining for smoothelin was reduced in the media of C-SCAD lesions compared with controls, whereas there were no significant differences between C-SCAD and nonculprit SCAD. Further, the nuclear height/width ratio of smooth muscle cells was increased, suggesting smooth muscle cell phenotypic modulation. In whole-exome sequencing analysis, pathogenic or likely pathogenic variants were detected in 25% of cases, which showed a higher frequency of multivessel dissection. In SCAD cases with pathogenic or likely pathogenic variants in COL3A1 (collagen type III alpha 1), FBN1 (fibrillin-1), or FLNA (filamin A), the expression of the corresponding protein was reduced in the media. CONCLUSIONS:Reduced medial collagen and smooth muscle cell phenotypic modulation may be possible predisposing conditions for SCAD, regardless of the presence of pathogenic or likely pathogenic variants. The presence of pathogenic variants in extracellular matrix-related genes may further compromise arterial wall medial integrity, contributing to more severe disease. These findings provide novel pathological and genetic insights into the pathogenesis of SCAD and may inform future diagnostic and therapeutic strategies.
BACKGROUND:Evolocumab, a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor, significantly reduced the risk of cardiovascular events in patients without previous myocardial infarction or stroke in the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke). However, mortality results have yet to be fully characterized. METHODS:VESALIUS-CV was a double-blind study of 12 257 patients (median age, 66 years [interquartile range, 60-71]; 43% women) with qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke, and low-density lipoprotein-cholesterol ≥90 mg/dL (or non-high-density lipoprotein-C ≥120 mg/dL or apolipoprotein B ≥80 mg/dL) who were randomized to evolocumab or placebo. Prespecified mortality outcomes of interest included all-cause mortality, subtypes of death (including cardiovascular [CV] and non-CV), and timing of events. Non-CV mortality was further investigated using multistate modeling to assess the contribution of prevention of nonfatal CV events (myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization) to non-CV mortality. RESULTS:Over a median of 4.6 years (interquartile range, 4.0-5.2), 973 (7.9%) patients died: 351 (36%) of CV causes, 497 (51%) of non-CV causes, and 125 (13%) of undetermined cause. All-cause mortality rates were 20% lower with evolocumab compared with placebo: 434 deaths (5-year Kaplan-Meier rate of 7.9%) with evolocumab versus 539 deaths (9.7%) with placebo (hazard ratio, 0.80, 95% CI, 0.70-0.91; P=0.0005). There was consistency of benefit for CV death (156 deaths [2.8%] versus 195 [3.6%]; hazard ratio, 0.79; 95% CI, 0.64-0.98), non-CV death (229 [4.2%] versus 268 [5.0%]; hazard ratio, 0.85; 95% CI, 0.71-1.01), and deaths of undetermined cause (49 [1.1%] versus 76 [1.4%]; hazard ratio, 0.64; 95% CI, 0.45-0.92). Results were consistent regardless of age, sex, region, race, qualifying atherosclerosis or high-risk diabetes, baseline low-density lipoprotein-cholesterol, or background lipid therapy. Postrandomization nonfatal myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization were associated with increased risk of subsequent non-CV death within the next 4 years, with the majority occurring during the first year after the event. Multistate modeling suggested the observations regarding non-CV death with evolocumab was largely (78%; bootstrap interquartile range, 71-92%) driven by the prevention of antecedent nonfatal CV events. CONCLUSIONS:These results support using evolocumab to improve survival in high-risk patients who have not experienced a previous myocardial infarction or stroke, including those with high-risk diabetes without qualifying atherosclerosis with low-density lipoprotein-cholesterol ≥ 90 mg/dl (or non-high-density lipoprotein-cholesterol ≥ 120 mg/dl or apolipoprotein B ≥ 80 mg/dl). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.
BACKGROUND:High lipoprotein(a) is considered a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD); however, whether the association between lipoprotein(a) and ASCVD is different among older individuals (defined as 70-100 years of age) compared with younger individuals is unclear. We evaluated differences in risk of ASCVD associated with high lipoprotein(a) stratified by age and sex. METHODS:We included 57 899 women and 45 442 men aged 20 to 100 years from the Copenhagen General Population Study, of which 18 322 (18%) were aged 70 to 100 years. Age-stratified incidence rates and hazard ratios for ASCVD were estimated. Secondary analyses were additionally stratified by sex. RESULTS:During a median follow-up of 12.5 years (maximum, 19.1), 9091 individuals were diagnosed with ASCVD. ASCVD incidence increase per 50 mg/dL (105 nmol/L) higher lipoprotein(a) were 0.3 per 1000 person-years (95% CI, 0.2-0.4) for age 20 to 49 years, 0.8 (0.6-0.9) for age 50 to 59 years, 1.5 (1.2-1.7) for age 60 to 69 years, 2.7 (2.2-3.2) for age 70 to 79 years, and 4.5 per 1000 person-years (3.7-5.4) for age 80 to 100 years. For lipoprotein(a) of 70 to 89 mg/dL (148-190 nmol/L), such incidence increases were 2.7 for age 20 to 49 years, 7.1 for age 50 to 59 years, 13.3 for age 60 to 69 years, 24.4 for age 70 to 79 years, and 40.9 for age 80 to 100 years. Corresponding values for lipoprotein(a) of 90 to 426 mg/dL (191-924 nmol/L) were 3.2, 8.3, 15.6, 28.7, and 48, respectively. The above results were similar in women and men, but with the highest incidence increases in men. Hazard ratios per 50 mg/dL higher lipoprotein(a) were similar across all age groups and sexes, ranging from 1.12 to 1.18 (Pinteraction: by age=0.48; by sex=0.74). CONCLUSIONS:In a contemporary primary prevention cohort, the relative risk increase of ASCVD with higher lipoprotein(a) levels was similar for individuals aged older (aged 70-100 years) and younger individuals, with the highest absolute risk in this older age group.
