Abstract 9376: TRPM77 Knockdown Prevents Hypomagnesemia-Induced Oxidative Stress and Cardiac Diastolic Dysfunction

Circulation, Volume 146, Issue Suppl_1, Page A9376-A9376, November 8, 2022. Introduction:Our previous study has shown that 6-week low-Mg diet-induced hypomagnesemia results in mitochondrial dysfunction, cardiac diastolic dysfunction, and seizure-related death. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function located in the plasma membrane. We investigated the role of TRPM7 in hypomagnesemia-associated changes.Methods:For cardiac-specific knockdown of TRPM7, pAAV[miR30]-cTnT >EGFP:Scramble-shRNA as control (Con) and pAAV[miR30]-cTnT >EGFP:TRPM7 shRNA as TRPM7 knockdown (T7KD) were injected into mice through the jugular vein at 10 weeks old. One week later, mice were fed with a normal diet (nlMg, 2000 mg/kg Mg) or a low-Mg diet (HypoMg, 15-30 mg/kg Mg) for 4 weeks.Results:TRPM7 was increased significantly in wild type mouse hearts under the low-Mg diet (1.45±0.18-fold of mice with normal diet, P

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Ottobre 2022

Abstract 13332: Obesity Paradox in Stress Cardiomyopathy When Comparing Outcomes

Circulation, Volume 146, Issue Suppl_1, Page A13332-A13332, November 8, 2022. Introduction:Stress Cardiomyopathy (SCM), is an acute reversible myocardial injury associated with transient left ventricular dysfunction. Risk factors include female sex, post-menopause, anxiety, depression, schizophrenia, asthma and chronic obstructive pulmonary disease, diabetes, and substance use. Obesity has an increased sympathetic tone and state of chronic metabolic stress, both of which are similar in etiology to SCM. We postulate that obesity may have high prevalence in patients with SCM.Methods:We queried the Nationwide Inpatient Sample database (2016-2019) to identify adult patients with SCM with and without obesity, along with other common co-morbidities using ICD-10 codes. We compared the categorical and continuous variables by Pearson χ2 and Student t test.Results:There were 31,725 patients with SCM. The mean age was 67.15+14 years and the population was predominately female, n=26409 (83.2%). Racial distribution consisted of White (n=24713 77.9%), Black (n=24713, 8%), and Hispanic (n=1918, 6%). There were 3816 (12%) who were diagnosed with obesity. When comparing both groups, obese patients were found to be younger than non-obese, 63.3+14 years vs. 67.68+13 years, p

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Ottobre 2022

Abstract 15081: The Viscoelastic Yield Stress of Blood is Negatively Associated With Pulmonary Blood Flow in the Fontan Circulation

Circulation, Volume 146, Issue Suppl_1, Page A15081-A15081, November 8, 2022. Introduction:In the Fontan (FN) circulation pulmonary blood flow (Qp) is passive, resulting in severely decreased shear rate and velocity in pulmonary arteries to the point of stasis. Yield stress (YS) is the shear stress required for blood to transition from stasis to a moving fluid. Therefore, YS may be a determinant of Qp in FN. We evaluated YS in patients with FN and Glenn (GLN) circulations and whether increased YS is associated with decreased Qp.Methods:We enrolled 20 patients with biventricular (2V) congenital heart disease (CHD) and 41 patients with single ventricle CHD (19 FN and 22 GLN) who were undergoing a clinically indicated cardiac catheterization. Two patients were excluded due to pulmonary vascular disease. We obtained blood samples at the time of catheterization and measured blood viscosity across shear rates 1 s-1to 1000 s-1using a Rheolog viscometer We calculated YS by curve-fitting of the viscosity measurements to a Casson fluid model.Hypothesis:We hypothesize that higher yield stress will be associated with lower pulmonary blood flow in Fontan circulation.Results:The FN group was the oldest and had the largest BSA (FN >2V >GLN; pFN >2V; p

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Ottobre 2022

Abstract 14606: Accurate Detection of Acute Psychological Stress Events Using Single Lead ECG Data

Circulation, Volume 146, Issue Suppl_1, Page A14606-A14606, November 8, 2022. Introduction:Stress has been linked to numerous health conditions, including heart disease, diabetes, and mental health issues. By monitoring changes in physiological signals, such as heart rate (HR) and heart rate variability (HRV), wearable biosensing technology allows acute stress to be non-invasively tracked over long periods, providing valuable insights for preventative healthcare.Methods:This two-phase study comprised several protocols designed to induce varying levels of psychological stress in participants (N=39). HR and HRV metrics, derived from electrocardiogram (ECG) data collected throughout the protocol on the single lead HeartKey®Chest Module, were used by the HeartKey Stress algorithm to generate a relative stress score (0-100), which was validated against two clinically recognized methodologies for assessing patient stress: i) state-trait anxiety index (STAI), a questionnaire that subjectively measured the individual’s perceptual stress after each stage of the protocol, and ii) electrodermal activity (EDA), which continuously monitored conductive changes at the skin’s surface with an Empatica®E4 wrist wearable.Results:Over both phases, participant STAI scores increased significantly during stress protocols (49.9 ± 23.3) relative to the baseline (30.0 ± 10.0). Mean HR showed a similar significant increase (p< 0.001), and HRV gradually decreased throughout the testing protocol. HeartKey Stress scores derived from HR and HRV data showed a strong correlation to STAI scores. Furthermore, the HeartKey Stress trend closely replicated that of the EDA data.Conclusions:HeartKey Stress algorithm consistently generated accurate and reliable stress scores in response to events of induced, acute psychological stress. The results suggest that the algorithm has potential utility for continuous clinical monitoring of patients with stress-related illnesses.

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Ottobre 2022

Abstract 14447: Multi-Center Evaluation of Stress Myocardial Blood Flow by Cardiac Magnetic Resonance in Known and Suspected Ischemic Heart Disease: Preliminary Findings From the AQUA-MBF Initiative

Circulation, Volume 146, Issue Suppl_1, Page A14447-A14447, November 8, 2022. Introduction:Quantitative myocardial blood flow (MBF) analysis using stress cardiac magnetic resonance (CMR) has been shown to detect obstructive coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) in several mostly small, single-center studies. The AQUA-MBF (Assessment ofQUAntitativeMBF) study is a multicenter initiative involving 16 centers.Hypothesis:The goal of this sub-study is to determine if MBF can differentiate CAD, CMD, and normal volunteers in this multicenter setting.Methods:We present data from 53 subjects (15 with CAD, 20 at risk for CMD and 18 controls) who underwent vasodilator stress CMR (Figure) using 1.5T and 3.0T MR scanners (General Electric). At risk for CMD was defined as having diabetes and 2 other risk factors in absence of ≥50% stenosis based on coronary CT. CAD was defined as the presence of stenosis ≥70% based on invasive coronary angiography. Stress perfusion images were acquired using the dual sequence technique. Stress MBF was measured in each of the 16 AHA segments using Fermi deconvolution (Circle Cvi42). In the CAD group, each segment was further classified as having late gadolinium enhancement (LGE), supplied by CAD, or a normal remote territory. The means of the 5 groups were compared using one-way analysis of variance.Results:The segmental stress MBF (ml/g/min) for the 5 groups are shown in figure. Compared to the normal group, segmental stress MBF in 4 disease groups were significantly lower (p

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Ottobre 2022

Abstract 10098: Assessment of a Rate Pressure Product Target During Stress Echocardiograms in Patients With Advanced Cirrhosis

Circulation, Volume 146, Issue Suppl_1, Page A10098-A10098, November 8, 2022. Introduction:Dobutamine and exercise stress echo are routinely performed on patients with advanced cirrhosis though have low sensitivity in this patient population, even when target heart rate is achieved. This is in part due to their unique cardiovascular physiology which is frequently marked by reduced peripheral vascular resistance with low blood pressure, impaired chronotropic response to stress, hyperdynamic left ventricular systolic function and elevated cardiac output. In the general population, achieving a rate pressure product (RPP), defined as peak systolic blood pressure multiplied by peak heart rate, > 25,000 is typically considered a high level of stress and is an adequate workload to detect ischemia, however this has not been validated in patients with advanced cirrhosis. We aimed to assess the impact of achieving a RPP > 25,000 on the ability of stress echo to detect obstructive coronary artery disease (CAD) in patients with advanced cirrhosis.Methods:We performed a case-control study on patients with advanced cirrhosis where 88 had and 97 did not have CAD based on invasive coronary angiography. A total of 159 patients (85.9%, 77 with CAD and 82 without) had dobutamine and 26 (14.1%, 11 with CAD and 15 without) had exercise as their stress modality. Continuous variables were compared by means of Wilcoxon Rank Sum test. Categorical variables were expressed as numbers and percentages and compared by means of chi-square and Fisher exact tests.Results:The average maximum RPP was 19,999 ± 4,969.4 with 32 patients (17.3%) achieving a RPP > 25,000 (14 with and 18 without CAD, P = 0.63). The average percent of maximum predicted HR (MPHR) achieved was 86.7 ± 9.2% with 136 patients (73.5%) achieving > 85% of MPHR. Achieving a maximum RPP > 25,000 (OR 0.83, 95% CI 0.39 – 1.79, P = 0.63) or a MPHR > 85% (OR 1.04, 95% CI 0.54 – 1.99, P = 0.92) did not improve the ability of stress echo to detect obstructive CAD.Conclusions:Achieving a maximum RPP > 25,000 did not improve the ability of stress echo to detect obstructive CAD in patients with advanced cirrhosis.

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Ottobre 2022

Abstract 10199: Increased Aortic Wall Shear Stress in Marfan Patients Long-Term After Proximal Grafting Assessed by 4D Flow Cardiac Magnetic Resonance

Circulation, Volume 146, Issue Suppl_1, Page A10199-A10199, November 8, 2022. Introduction:For Marfan syndrome patients (MFS) with thoracic aortic aneurysms (TAA), prosthetic graft surgery provides lifesaving benefits, but adverse event risk persists in the native aorta for which mechanism is unclear. Sustained impact of proximal grafts on biomechanics within and distal to grafts is unknown.Methods:MFS patients with chronic ( > 6 month) proximal grafts were compared to non-surgical MFS (nsMFS) and age/sex matched controls: Wall shear stress (WSS) on 4D flow cardiac MRI and size (diameter) were quantified at aortic landmarks (ascending, arch, descending, thoracoabdominal).Results:34 subjects were studied including MFS late (7.3±6.7 years) after graft implantation (n=12). Post-surgical MFS were of similar age (p=0.93) and sex (p=0.64) to controls but older than non-surgical MFS (45±10 vs 33±11 yo, p=0.01): In the ascending aorta (grafted territory), post-surgical MFS had higher WSS (1.17±0.55 Pa) than nsMFS (0.74±0.17 Pa) and controls (0.60±0.17 Pa; p=0.002 for trend). Similarly, in the (native) descending aorta, WSS was higher in post-surgical (1.06±0.24 Pa) than nsMFS (0.97±0.11) and controls (0.83±0.16; p=0.02) (Figure) paralleling results in the arch (p=0.06) and a similar trend in the thoracoabdominal aorta (p=0.12). Among the overall MFS cohort (n=23), proximal graft implantation associated with increased WSS in the ascending and descending aorta (both p

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Ottobre 2022

Abstract 10218: Differences in Treadmill Exercise Stress Testing Parameters Among Electronic Cigarette Vapers, Combustible Cigarette Smokers, and Controls: The Clues Study

Circulation, Volume 146, Issue Suppl_1, Page A10218-A10218, November 8, 2022. Background:Use of electronic nicotine delivery devices is increasing but their effects on exercise function are not well-characterized. We hypothesized that treadmill stress test outcomes would differ between chronic electronic cigarette users (“vapers”), combustible cigarette users (“smokers”), and non-smoking/non-vaping controls.Methods:CLUES (HL1393301) was a cross-sectional study of 395 individuals: 164 exclusive vapers (exhaled carbon monoxide [CO] 5 ppm, positive urine NicCheck I), and 114 non-vaping/non-smoking controls (CO

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Ottobre 2022

Abstract 9504: Endothelial Shear Stress Metrics Correlate With Inflammatory Markers at the Culprit Site of Erosion in Patients With an Acute Coronary Syndrome: An OPTICO-ACS Substudy

Circulation, Volume 146, Issue Suppl_1, Page A9504-A9504, November 8, 2022. Introduction:The pathobiological mechanisms of coronary plaque erosion are unclear. Low endothelial shear stress (ESS) is a proinflammatory/proatherogenic stimulus associated with coronary plaque progression/destabilization. Intravascular imaging studies suggest that high ESS gradient (low ESS areas adjacent to high ESS areas), and steepness of plaque upslope/downslope correlate with plaque erosion. We investigated the relationship of local fluid hemodynamics to the inflammatory microenvironment at the culprit site of erosion in patients with an acute coronary syndrome.Hypothesis:ESS metrics associate with proinflammatory/proatherogenic cells and cytokines, and contribute to plaque erosion.Methods:We studied 30 patients with erosion from the OPTIcal-COherence Tomography in Acute Coronary Syndrome study (OPTICO-ACS). OCT images were segmented, co-registered with the angiogram to create a 3D-reconstruction of the coronary artery. ESS metrics were calculated by Computational Fluid Dynamics. Systemic and local blood samples and thrombectomy specimens were collected at the culprit lesion and analyzed by flow cytometry-based immunophenotyping and plasma cytokine and chemokine profiling, and statistically tested for correlations of continuous variables using Spearman rank correlation (r).Results:Proinflammatory cytokines (IL6, MIP-1, IL1β, IL2) and local concentration of T-cells, including subsets of T-cells (CD4+, CD8+, and NKT-cells), were significantly higher at the culprit site of erosion and correlate with local adverse ESS metrics (Min ESS, Max ESS, Plaque Topographical Slope) (Table).Conclusion:Biomechanical features likely trigger activation of the adaptive immune system, including T-lymphocytes and their cytotoxic effector molecules. These results provide novel insights into the links between fluid hemodynamics, inflammatory activation, and mechanisms involved in the pathogenesis of coronary plaque erosion.

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Ottobre 2022

Abstract 10014: Work-Related Stress and Ideal Cardiovascular Health: The Multi-Ethnic Study of Atherosclerosis

Circulation, Volume 146, Issue Suppl_1, Page A10014-A10014, November 8, 2022. Background:Work-related stress is a psychosocial risk factor linked to a higher risk of adverse health outcomes, especially cardiovascular disease (CVD). However, the association between work-related stress and ideal cardiovascular health (CVH) is not well established. We examined whether work-related stress was negatively associated with favorable CVH in a multi-ethnic population of adults free of CVD at baseline.Methods:We analyzed cross-sectional data of 6,486 men and women aged 45-84 years. Work-related stress was assessed by the presence or absence of ongoing job difficulty and ongoing job difficulty for >6 months. CVH was measured by a scoring system that assigned points to 7 metrics (smoking, physical activity, body mass index, diet, total cholesterol, blood pressure and blood glucose). Each metric had 3 categories: poor (0 points), intermediate (1 point) and ideal (2 points). The total score attainable was 14 points, categorized as inadequate (0-8 points), average (9-10 points) and optimal (11-14 points). We used polytomous logistic regression to examine the association of work-related stress with the CVH score and number of ideal metrics, adjusted for sociodemographic factors.Results:The mean age (SD) was 62 (10) years and 53% were women. Ongoing job difficulty was reported by 14% of participants while 13% reported ongoing job difficulty for >6 months. Participants who reported ongoing job difficulty had 21% and 24% lower odds of having average and optimal CVH scores, respectively(Table).Additionally, the presence of ongoing job difficulty for >6 months was associated with 23% and 24% lower odds of having average and optimal CVH scores, respectively. A similar trend was observed for the association of work-related stress with the number of ideal metrics.Conclusion:Work-related stress was negatively associated with favorable CVH. Stress reduction and CVH promotion programs in the workplace may decrease the incidence of CVD.

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Ottobre 2022

Abstract 13156: The Location of Combined High-Risk Low Endothelial Shear Stress and High Plaque Structural Stress is Distant From the Minimal Lumen Area in the Majority of Coronary Plaques Responsible for Major Adverse Cardiac Events

Circulation, Volume 146, Issue Suppl_1, Page A13156-A13156, November 8, 2022. Introduction:The presence of multiple high-risk prognostic features enhances risk-stratification of plaques prone to destabilization and major adverse cardiac events (MACE). Spatial superimposition of high-risk features (concordance) likely amplifies local risk. Local endothelial shear stress (ESS) and plaque structural stress (PSS) metrics predict MACE, but their spatial concordance and their location relative to the minimal lumen area (MLA) is unknown. If the highest-risk plaque area is distant from the MLA, then PCI of the MLA alone will leave high-risk plaque areas untreated.Purpose:To identify the site of high-risk features of low ESS and high PSS heterogeneity (HI) along the course of a plaque in patients who develop MACE, and the site of their spatial concordance relative to the MLA.Methods:We examined ESS, PSS, and PSS HI in 22 non-culprit lesions (NCL) leading to MACE, and 64 randomly selected control NCLs without MACE from the PROSPECT study. ESS was calculated by computational fluid dynamics and PSS by finite element analysis on co-registered lesions. We examined high-risk plaques with empirically-derived (ROC curve) ESS < 1.3 Pa and PSS HI > 0.29 in 16 lesions leading to future MACE, and 11 control lesions without MACE.Results:MACE outcomes were significantly more frequent in plaques with combined low ESS+high PSS HI vs plaques with low ESS alone (72.7% vs 27.3%, p

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Ottobre 2022

Abstract 13105: The Effect of Mechanical Stress on Cardiac Fibroblasts in Pulmonary Arterial Hypertension

Circulation, Volume 146, Issue Suppl_1, Page A13105-A13105, November 8, 2022. Introduction:Pulmonary arterial hypertension (PAH) is a rare fatal disease with vascular remodeling leading to increased right ventricular pressure followed by fibrosis. To study PAH-induced cardiac fibrosis we develop anin vitromodel of the failing right ventricle, for which cardiac fibroblasts (cFBs) were generated from healthy subjects’ and PAH patients’ induced pluripotent stem cells (iPSC).Methods:Confluent iPSC were induced to differentiate by adding 12 μM CHIR99021 for 24h to RPMI supplemented with B27 without insulin. Next, cells recovered for 24 h in RPMI supplemented with B27 without insulin, followed by stimulation with 75 ng/ml FGF2 up to day 20. Finally, the differentiated cells were reseeded and submitted to 10% cyclic stretch at 1 Hz for 4 days using the Flexcell FX-6000 system. Control and PAH cFBs were characterized at gene and protein levels.Results:The differentiated cells had a spindle morphology typical of FBs. Furthermore, the presence of cardiac (GATA4, TCF21) and fibroblast (VIM, PDGFRα, COL1A1) markers at gene and protein levels confirmed the cFB identity. Comparable expression of fibroblast related genes was observed in PAH cFBs as well as controls. Over 4 weeks of culture, iPSC-cFBs increasingly expressed markers of activated FBs (ACTA2andPOSTN)over time, similar to in vitro adult cFBs. When exposed to mechanical stretch, cell aligned to the stretch direction. Surprisingly, no increase in gene expression of extracellular matrix (COL1A1, COL3A1) or activated fibroblasts (ACTA2, POSTN) markers was observed.Interestingly, under static and stretch conditions expression of these genes was increased in PAH cFBs compared to healthy cells.Conclusion:The cellular morphology after differentiation as well as the gene and protein analyses indicate that cFBs were successfully generated. Furthermore, cyclic stretch induced alignment of the cells but was not sufficient to stimulate fibroblast activation in either PAH or healthy cFBs.

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Ottobre 2022

Abstract 12932: Should We Screen For Radiotherapy-Induced Heart Disease With Exercise Stress Echocardiography? Emphasis on Major Adverse Cardiac Events

Circulation, Volume 146, Issue Suppl_1, Page A12932-A12932, November 8, 2022. Introduction:Exercise Stress Echocardiography (ESE) is recommended as a screening tool for the evaluation of Coronary Artery Disease (CAD) in patients with suspected Radiation-Induced Heart Disease (RIHD). Up to now, studies have only evaluated its association with the extent of CAD.HypothesisCancer survivors treated with chest Radiotherapy (RT) that undergo an ESE and have a +ESE develop more MACE than those who have -ESE.Methods:A retrospective, descriptive, cohort study was conducted. Patients who had chest RT and underwent ESE with Treadmill Bruce Stress Protocol, from 2000 to 2012, at Mayo Clinic Rochester and Mayo Clinic Health System were included. A univariate analysis was performed to characterize the population. An analysis including Kruskal Wallis and Pearson Chi-Squared tests was completed to identify variables associated with + SE (Table 1). Multivariable Cox Model for MACE was conducted and is shown in Table 2. A time-to-event curve using Kaplan-Meier estimates is shown in Figure 1.Results:We identified 113 patients, with a mean age of 67 years and a median follow-up of 15.1 years. Of those, 99% were female, 98% were breast cancer survivors, 59% had HTN, 14% DM, 11% AFib, 2% COPD, and 12% had a history of MI. All the patients received >3000cGy of Photon RT, and 57% were treated with systemic cancer therapies. A +ESE was seen in 20.3% of the patients with no significant difference in METS achieved compared with patients who had a -ESE. COPD, RT dose, and systemic therapies, specifically doxorubicin, were associated with a +ESE. The cumulative incidence of MACE was higher in the group of +ESE (p=0.029). After adjustment for HTN, DM, smoking history, hyperlipidemia, and prior MI, the HR for MACE associated with a +ESE was 1.97 (1.09-3.59).Conclusion:MACE was more frequent in patients with a +ESE who received chest RT and doxorubicin versus -ESE. These results support the usefulness of ESE in cancer survivors after RT as a cardiovascular screening tool.

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Ottobre 2022

Abstract 14139: Differential Benefit of Non-Invasive Cardiac Stress Testing by HEART Score Risk Stratification

Circulation, Volume 146, Issue Suppl_1, Page A14139-A14139, November 8, 2022. Introduction:AHA guidelines recommend non-invasive cardiac testing (NIT) within 72 hours after an emergency department (ED) evaluation for suspected acute coronary syndrome (ACS), after acute myocardial infarction (AMI) has been excluded. However, the effectiveness of this strategy to reduce the risk of future AMI or death, in low-risk patients is contested.Hypothesis:We hypothesized that in patients with low risk based on history, electrocardiogram, age, risk factors and troponin (HEART) based scoring, early NIT may not be beneficial compared to higher risk.Methods:We compared the effectiveness of early NIT vs. no early testing, in a retrospective cohort of adult (age ≥18) members of the Kaiser Permanente Southern California health system from 05/2016-12/2020. We included all adults presenting at EDs with suspected ACS and who had data to compute HEART score. We stratified the cohort into low risk (score 0-3); intermediate risk (score 4-6) and high-risk (score ≥7) based on HEART score. Within each group, confounder adjusted instrumental variables models were used to evaluate the marginal effect of early NIT, and the number needed to treat (NNT) was calculated as the inverse of the absolute composite risk reduction in death/AMI within 30 days of ED discharge.Results:The cohort included 174,936 patients [61% Low risk (mean age 53; female 58%; early NIT 5%), 36% intermediate risk (mean age 71; female 72%; early NIT 18%), and 3% high risk (mean age 74, female 45%; early NIT 23%)]. The risk reduction in 30-day death/AMI due to early NIT increased progressively through the intermediate-risk (NNT = 59) and high-risk groups (NNT = 24) (Table 1). Risk reduction in the low-risk group was not statistically significant.Conclusions:HEART score based high risk patients may benefit the most from early NIT. However, the majority of the suspected ACS cohort was classified as low risk and the benefit of early NIT on 30-day death/AMI was uncertain in this low-risk group.

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Ottobre 2022

Abstract 11298: Bioenergetics-Independent Stress Response to Mitochondrial Protein Import Clogging in the Heart

Circulation, Volume 146, Issue Suppl_1, Page A11298-A11298, November 8, 2022. Mitochondria are double-membraned organelles indispensable in metabolically active organs such as the heart. Much of the mitochondrial proteome is encoded by the nuclear genome and requires import into mitochondria via channels present on the outer and inner mitochondrial membranes. If protein import goes awry at any step, it can cause unimported mitochondrial proteins to accumulate in the cytosol, leading to mitochondrial Precursor Overaccumulation Stress (mPOS). Defects in mitochondrial protein import have been linked to many forms of heart disease such as Senger’s syndrome, cardiac arrhythmia, and chronic atrial fibrillation. The A123D mutation in adenine nucleotide translocase 1 (Ant1), an ATP/ADP antiporter present on the mitochondrial inner membrane, has been shown to cause hypertrophic cardiomyopathy, while other mutations inAnt1(A114P, A90D, V289M, L98P) have been shown to cause Autosomal Dominant Progressive External Ophthalmoplegia. Our studies suggested that the mutant ANT1 can cause mitochondrial protein import clogging. To characterize the pathophysiology induced by mitochondrial protein import clogging, we developed a mouse model (the “clogger mouse”) expressing two clinically relevant mutations inAnt1, namelyA114PandA123D. While prior work on this model revealed a low-penetrant neurodegenerative and mild myopathic phenotype, the impact of this mutation on the heart has not been studied. In the current study, we show that expression of Ant1A114P, A123Dhas little effect on mitochondrial respiration and heart function. This is consistent with the rapid degradation of Ant1A114P, A123Din the heart. Interestingly, transcriptomic analysis revealed an altered expression of circadian regulator and output genes such asClock,Ciart, Per1-3, CebpbandHlfin the clogger mouse relative to wild type. These data suggest that mitochondrial protein import clogging can induce a stress response independent of bioenergetics. It also led us to hypothesize that the circadian pathway plays a role in adapting to mitochondria-induced proteostatic stress in the heart. Our current experiments focused on testing this hypothesis are anticipated to help us understand how the heart can uniquely adapt to mitochondrial protein import clogging.

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Ottobre 2022

Abstract 11938: Novel Approach for Optimal Assessment of Cardiovascular Risk of Blood Pressure in Asymptomatic Subjects Utilizing Mild Exercise Stress Test Protocol

Circulation, Volume 146, Issue Suppl_1, Page A11938-A11938, November 8, 2022. Background:BP risk class assessment has been relying on resting BP (rBP) measurements by healthcare providers. Often, this measurement does not correlate with 24-hour ambulatory BP monitoring nor with at-home measurements.Purpose:To assess whether abnormal rise in BP post-mild exercise protocol (PMEP), which resembles most of the activities subjects are under all day, will be more physiologic and informative for risk stratification, beyond the rBP measurements.Methods:We screened 2,924 subjects, ages 20-79, for CVD risk using the Early Cardiovascular Disease Risk Scoring System, also known as the Rasmussen Risk Score, which consists of 10 tests: 7 vascular and 3 cardiac (published previously). The vascular tests include rBP, BP PMEP (2.4 mi/hr and 7% elevation for 3 minutes), small (C2) artery stiffness, and CIMT. Out of the total subjects, 1094 (37%) were asymptomatic and on no medications. These were divided into four BP classes according to the current ACC/AHA guidelines.Results:In the table, normotension with an abnormal rise in BP PMEP has significant cardiovascular structural and functional abnormalities (CVSFA) than those without. Also noted, the higher the BP class, the higher the CVSFA with and without an abnormal rise in BP PMEP.Conclusions:Abnormal rise in BP PMEP in normotensive subjects is associated with significant CVSFA. This may represent a “masked hypertension” cohort. These findings mandate early diagnosis, follow-up, and optimal treatment. Additionally, an abnormal rise in BP PMEP in other classes is more pronounced with stepwise increases in BP class. Hence, we advocate for PMEP for BP classification and treatment. Early detect to protect.

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Ottobre 2022