NADPH oxidase overexpression and mitochondrial OxPhos impairment are more profound in human hearts donated after circulatory death than brain death.

This study investigated cardiac stress and mitochondrial oxidative phosphorylation (OxPhos) in human donation after circulatory death (DCD) hearts regarding warm ischemic time (WIT) and subsequent cold storage and compared them with that of human brain death donor (DBD) hearts. A total of 24 human hearts were procured for the research study-6 in the DBD group and 18 in the DCD group. DCD group was divided into three groups (n = 6) based on different WITs (20, 40, and 60 min). All hearts received del Nido cardioplegia before being placed in normal saline cold storage for 6 h. Left ventricular biopsies were performed at hours 0, 2, 4, and 6. Cardiac stress [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits: 47-kDa protein of phagocyte oxidase (p47phox), 91-kDa glycoprotein of phagocyte oxidase (gp91phox)] and mitochondrial oxidative phosphorylation [OxPhos, complex I (NADH dehydrogenase) subunit of ETC (CI)-complex V (ATP synthase) subunit of ETC (CV)] proteins were measured in cardiac tissue and mitochondria respectively. Modulation of cardiac stress and mitochondrial dysfunction were observed in both DCD and DBD hearts. However, DCD hearts suffered more cardiac stress (overexpressed NADPH oxidase subunits) and diminished mitochondrial OxPhos than DBD hearts. The severity of cardiac stress and impaired oxidative phosphorylation in DCD hearts correlated with the longer WIT and subsequent cold storage time. More drastic changes were evident in DCD hearts with a WIT of 60 min or more. Activation of NADPH oxidase via overproduction of p47phox and gp91phox proteins in cardiac tissue may be responsible for cardiac stress leading to diminished mitochondrial oxidative phosphorylation. These protein changes can be used as biomarkers for myocardium damage and might help assess DCD and DBD heart transplant suitability.NEW & NOTEWORTHY First human DCD heart research studied cardiac stress and mitochondrial dysfunction concerning WIT and the efficacy of del Nido cardioplegia as an organ procurement solution and subsequent cold storage. Mild to moderate cardiac stress and mitochondrial dysfunction were noticed in DCD hearts with WIT 20 and 40 min and cold storage for 4 and 2 h, respectively. These changes can serve as biomarkers, allowing interventions to preserve mitochondria and extend WIT in DCD hearts.

Comparative predictors of mortality among patients referred for stress single-photon emission computed tomography versus positron emission tomography myocardial perfusion imaging.

BACKGROUND: There is currently little information regarding the usage and comparative predictors of mortality among patients referred for single-photon emission computed tomography (SPECT) versus positron emission tomography (PET) myocardial perfusion imaging (MPI) within multimodality imaging laboratories. METHODS: We compared the clinical characteristics and mortality outcomes among 15,718 patients referred for SPECT-MPI and 6202 patients referred for PET-MPI between 2008 and 2017. RESULTS: Approximately two-thirds of MPI studies were performed using SPECT-MPI. The PET-MPI group was substantially older and included more patients with known coronary artery disease (CAD), hypertension, diabetes, and myocardial ischemia. The annualized mortality rate was also higher in the PET-MPI group, and this difference persisted after propensity matching 3615 SPECT-MPI and 3615 PET-MPI patients to have similar clinical profiles. Among the SPECT-MPI patients, the most potent predictor of mortality was exercise ability and performance, including consideration of patients' mode of stress testing and exercise duration. Among the PET-MPI patients, myocardial flow reserve (MFR) was the most potent predictor of mortality. CONCLUSIONS: In our real-world setting, PET-MPI was more commonly employed among older patients with more cardiac risk factors than SPECT-MPI patients. The most potent predictors of mortality in our SPECT and PET-MPI groups were variables exclusive to each test: exercise ability/capacity for SPECT-MPI patients and MFR for PET-MPI patients.

Inferior Vena Cava-Balloon Occlusion and Its Effect on the Myocardium During Endograft Deployment in the Arch.

PURPOSE: To evaluate the impact of cava balloon occlusion on the myocardium during endovascular repair of thoracic aortic pathologies. MATERIAL AND METHODS: A prospective observational cohort study of 21 patients who underwent endovascular repair of aortic arch and thoracic aorta in a single tertiary referral center with use of inferior vena cava (IVC) balloon occlusion as a method of intraoperative cardiac output reduction. Pre-, intra-, and postoperative measurements of heart rate, blood pressure, stroke volume index, and central venous oxygen saturation were noted. High-sensitive serum troponin levels were also analyzed according to a pre-established protocol. Endpoints were cardiac troponin T levels after induced hypotension and left ventricular ejection fraction during follow-up. Secondary endpoints were procedure technical success and overall survival. RESULTS: Twenty-one patients (18 male, median age 69, (62-75, IQR)) enrolled in the study between May 2015 and January 2019. Indication for endovascular treatment was an aortic arch aneurysm (n=10), descending aortic aneurysm (n=8), lusorian artery aneurysm (n=2), and thoracoabdominal aortic aneurysm (n=1). Median time to reach half mean arterial pressure was 60 seconds while median recovery time of blood pressure was 135 seconds. In 5 (24%) cases, we observed a > 50% change of Troponin T on the reference level. Technical success was achieved in all cases. Two (10%) patients developed new and persistent atrial fibrillation and 1 (5%) suffered a peri-operative ST-elevation myocardial infarction. CONCLUSION: The use of IVC balloon occlusion is a feasible technique for cardiac output reduction during endovascular repair of thoracic aortic pathologies. One fourth of the patients develop significant troponin leakage but the significance of the finding needs further studies.

Increasing frequency of dyspnea among patients referred for cardiac stress testing.

OBJECTIVE: To assess the frequency, change in prevalence, and prognostic significance of dyspnea among contemporary patients referred for cardiac stress testing. PATIENTS AND METHODS: We evaluated the prevalence of dyspnea and its relationship to all-cause mortality among 33,564 patients undergoing stress/rest SPECT-MPI between January 1, 2002 and December 31, 2017. Dyspnea was assessed as a single-item question. Patients were divided into three temporal groups. RESULTS: The overall prevalence of dyspnea in our cohort was 30.2%. However, there was a stepwise increase in the temporal prevalence of dyspnea, which was present in 25.6% of patients studied between 2002 and 2006, 30.5% of patients studied between 2007 and 2011, and 38.7% of patients studied between 2012 and 2017. There was a temporal increase in the prevalence of dyspnea in each age, symptom, and risk factor subgroup. The adjusted hazard ratio for mortality was higher among patients with dyspnea vs those without dyspnea both among all patients, and within each chest pain subgroup. CONCLUSIONS: Dyspnea has become increasingly prevalent among patients referred for cardiac stress testing and is now present among nearly two-fifths of contemporary cohorts referred for stress-rest SPECT-MPI. Prospective study is needed to standardize the assessment of dyspnea and evaluate the reasons for its increasing prevalence.

Development and validation of ischemia risk scores.

BACKGROUND: The likelihood of ischemia on myocardial perfusion imaging is central to physician decisions regarding test selection, but dedicated risk scores are lacking. We derived and validated two novel ischemia risk scores to support physician decision making. METHODS: Risk scores were derived using 15,186 patients and validated with 2,995 patients from a different center. Logistic regression was used to assess associations with ischemia to derive point-based and calculated ischemia scores. Predictive performance for ischemia was assessed using area under the receiver operating characteristic curve (AUC) and compared with the CAD consortium basic and clinical models. RESULTS: During derivation, the calculated ischemia risk score (0.801) had higher AUC compared to the point-based score (0.786, p < 0.001). During validation, the calculated ischemia score (0.716, 95% CI 0.684- 0.748) had higher AUC compared to the point-based ischemia score (0.699, 95% CI 0.666- 0.732, p = 0.016) and the clinical CAD model (AUC 0.667, 95% CI 0.633- 0.701, p = 0.002). Calibration for both ischemia scores was good in both populations (Brier score  < 0.100). CONCLUSIONS: We developed two novel risk scores for predicting probability of ischemia on MPI which demonstrated high accuracy during model derivation and in external testing. These scores could support physician decisions regarding diagnostic testing strategies.

Prevalence and predictors of automatically quantified myocardial ischemia within a multicenter international registry.

BACKGROUND: The utility of cardiac stress testing depends on the prevalence of myocardial ischemia within candidate populations. However, a comprehensive assessment of the factors influencing frequency of myocardial ischemia within contemporary populations referred for stress testing has not been performed. METHODS: We assessed 19,690 patients undergoing nuclear stress testing from a multicenter registry. The chi-square test was used to assess the relative importance of features for predicting myocardial ischemia. RESULTS: In the overall cohort, LVEF, male gender, and rest total perfusion deficit (TPD) were the top three predictors of ischemia, followed by CAD status, age, typical angina, and CAD risk factors. Myocardial ischemia was observed in 13.6 % of patients with LVEF > 55 %, in 26.2 % of patients with LVEF 45 %-54 %, and in 48.3% among patients with LVEF < 45 % (P < 0.001). A similar pattern was noted for rest TPD (P < 0.001). Men had a threefold higher frequency of ischemia versus women (25.8 % vs. 8.4%, P < 0.001). Although the relative ranking of ischemia predictors varied among centers, LVEF and/or rest TPD were among the two most potent predictors of myocardial ischemia within each center. CONCLUSION: The prevalence of myocardial ischemia varied markedly according to clinical and imaging characteristics. LVEF and rest TPD are robust predictors of myocardial ischemia.

The prevalence and predictors of inducible myocardial ischemia among patients referred for radionuclide stress testing.

BACKGROUND: The frequency of inducible myocardial ischemia has declined in contemporary stress test cohorts, suggesting a need to re-evaluate its optimal use. To-date, however, a comprehensive analysis of the most potent predictors of myocardial ischemia among cardiac stress test patients has not been conducted. METHODS: We assessed 27,615 patients referred for stress-rest SPECT myocardial perfusion imaging between January 1, 2004 and December 31, 2017. Chi-square analysis was used to ascertain the most potent predictors of ischemia. RESULTS: Among our cohort, CAD status (presence/absence of known CAD), rest left ventricular ejection fraction (LVEF), and typical angina were the most potent predictors of ischemia. The frequency of ischemia was only 6.6% among patients with an LVEF > 55% but 38.1% for patients with LVEF < 45% (P < 0.001). The frequency of myocardial ischemia was fourfold higher among patients with known CAD vs no known CAD (28.0% vs 6.5%, P < 0.001) and approximately threefold higher among patients with typical angina vs patients with atypical symptoms (P < 0.001). CONCLUSIONS: The frequency of myocardial ischemia varies markedly according to the common clinical parameters and is particularly high among patients with known CAD, low LVEF, and typical angina. These observations may be used to develop more cost-effective strategies for referring patients for cardiac stress testing.

Psychological factors of suspect coronary microvascular dysfunction in patients undergoing SPECT imaging.

BACKGROUND: Patients with myocardial ischemia in the absence of obstructive coronary artery disease (CAD) often experience anginal complaints and are at risk of cardiac events. Stress-related psychological factors and acute negative emotions might play a role in these patients with suspect coronary microvascular dysfunction (CMD). METHODS AND RESULTS: 295 Patients (66.9 ± 8.7 years, 46% women) undergoing myocardial perfusion single-photon-emission computed tomography (MPI-SPECT), were divided as follows: (1) a non-ischemic reference group (n = 136); (2) patients without inducible ischemia, but with a history of CAD (n = 62); (3) ischemia and documented CAD (n = 52); and (4) ischemia and suspect CMD (n = 45). These four groups were compared with regard to psychological factors and acute emotions. Results revealed no differences between the groups in psychological factors (all P > .646, all effect sizes d < .015). State sadness was higher for patients with suspect CMD (16%) versus the other groups (P = .029). The groups did not differ in the association of psychological factors or emotions with anginal complaints (all P values > .448). CONCLUSION: Suspect CMD was not associated with more negative psychological factors compared to other groups. State sadness was significantly higher for patients with suspect CMD, whereas no differences in state anxiety and other psychological factors were found.

Anxiety and hemodynamic reactivity during cardiac stress testing: The role of gender and age in myocardial ischemia.

BACKGROUND: The prevalence of myocardial ischemia is associated with anxiety. State and trait anxiety are more common in younger women compared to men, and high anxiety levels could affect hemodynamic reactivity during cardiac stress testing. The aim is to examine whether anxiety plays a role in gender differences in patients ≤ 65 and > 65 years in hemodynamic reactivity and ischemia during cardiac stress testing. METHODS AND RESULTS: Included were 291 patients (66.8 ± 8.7 years, 45% women) with suspect ischemia undergoing myocardial perfusion single-photon emission computed tomography (MPI-SPECT). Primary outcomes were semi-quantitative summed difference score (SDS) and summed stress score (SSS), as continuous indicators of myocardial ischemia. Analyses were stratified by age. Trait anxiety was measured using a validated questionnaire (GAD-7) and state anxiety using facial expression analyses software. Overall, trait and state anxiety were not associated with the prevalence of ischemia (N = 107, 36%). A significant interaction was found between gender and trait anxiety in women ≤ 65 years for SDS (F(1,4) = 5.73, P = .019) and SSS (F(1,10) = 6.50, P = .012). This was not found for state anxiety. CONCLUSION: SDS and SSS were significantly higher in women younger than 65 years with high trait anxiety. This interaction was not found in men and women over 65 years.

Circulating microRNAs after a 24-h ultramarathon run in relation to muscle damage markers in elite athletes.

Ultra-endurance sports are growing in popularity but can be associated with adverse health effects, such as exercise-induced muscle damage (EIMD), which can lead to exertional rhabdomyolysis. Circulating microRNAs (miRNAs) may be useful to approach the degree of EIMD. We aimed to (1) investigate the relevance of circulating miRNAs as biomarkers of muscle damage and (2) examine the acute response of skeletal/cardiac muscle and kidney biomarkers to a 24-h run in elite athletes. Eleven elite athletes participated in the 24-h run World Championships. Counter-movement jump (CMJ), creatine kinase (CK), myoglobin (Mb), creatinine (Cr), high-sensitive cardiac troponin T (hs-cTnT), and muscle-specific miRNA (myomiR) levels were measured before, immediately after, and 24 and 48h after the race. CMJ height was reduced immediately after the race (-84.0 ± 25.2%, p < 0.001) and remained low at 24 h (-43.6 ± 20.4%, p = 0.002). We observed high CK activity (53 239 ± 63 608 U/L, p < 0.001) immediately after the race, and it remained elevated 24h after (p < 0.01). Circulating myomiR levels (miR-1-3p, miR-133a-3p, miR-133b, miR-208a-3p, miR-208b-3p, and miR-499a-5p) were elevated immediately after the 24-h run (fold changes: 18-124,723, p<0.001) and significantly (p < 0.05) correlated or tended to significantly (p < 0.07) correlate with the reduction in CMJ height at 24 h. We found no significant correlation between CMJ height loss at 24 h and CK (p = 0.23) or Mb (p = 0.41) values. All elite ultramarathon runners included in our study were diagnosed with exertional rhabdomyolysis after the 24-h ultramarathon race. MyomiR levels may be useful to approach the degree of muscle damage.

Facial Expressions of Emotions During Pharmacological and Exercise Stress Testing: the Role of Myocardial Ischemia and Cardiac Symptoms.

BACKGROUND: Negative emotions have been linked to ischemic heart disease, but existing research typically involves self-report methods and little is known about non-verbal facial emotion expression. The role of ischemia and anginal symptoms in emotion expression was examined. METHODS: Patients undergoing cardiac stress testing (CST) using bicycle exercise or adenosine with myocardial perfusion imaging were included (N = 256, mean age 66.8 ± 8.7 year., 43% women). Video images and emotion expression (sadness, anxiety, anger, and happiness) were analyzed at baseline, initial CST , maximal CST, recovery. Nuclear images were evaluated using SPECT. RESULTS: Ischemia (N = 89; 35%) was associated with higher levels of sadness (p = .017, d = 0.34) and lower happiness (p = .015, d = 0.30). During recovery, patients with both ischemia and anginal symptoms had the highest sadness expression (F (3,254) = 3.67, p = .013, eta2 = 0.042) and the lowest happiness expression (F (3, 254) = 4.19, p = .006, eta2 = .048). CONCLUSION: Sadness and reduced happiness were more common in patients with ischemia. Also, anginal symptoms were associated with more negative emotions.

Transient recovery of epicardial and torso ST-segment ischemic signals during cardiac stress tests: A possible physiological mechanism.

BACKGROUND: Acute myocardial ischemia has several characteristic ECG findings, including clinically detectable ST-segment deviations. However, the sensitivity and specificity of diagnosis based on ST-segment changes are low. Furthermore, ST-segment deviations have been shown to be transient and spontaneously recover without any indication the ischemic event has subsided. OBJECTIVE: Assess the transient recovery of ST-segment deviations on remote recording electrodes during a partial occlusion cardiac stress test and compare them to intramyocardial ST-segment deviations. METHODS: We used a previously validated porcine experimental model of acute myocardial ischemia with controllable ischemic load and simultaneous electrical measurements within the heart wall, on the epicardial surface, and on the torso surface. Simulated cardiac stress tests were induced by occluding a coronary artery while simultaneously pacing rapidly or infusing dobutamine to stimulate cardiac function. Postexperimental imaging created anatomical models for data visualization and quantification. Markers of ischemia were identified as deviations in the potentials measured at 40% of the ST-segment. Intramural cardiac conduction speed was also determined using the inverse gradient method. We assessed changes in intramyocardial ischemic volume proportion, conduction speed, clinical presence of ischemia on remote recording arrays, and regional changes to intramyocardial ischemia. We defined the peak deviation response time as the time interval after onset of ischemia at which maximum ST-segment deviation was achieved, and ST-recovery time was the interval when ST deviation returned to below thresholded of ST elevation. RESULTS: In both epicardial and torso recordings, the peak ST-segment deviation response time was 4.9±1.1 min and the ST-recovery time was approximately 7.9±2.5 min, both well before the termination of the ischemic stress. At peak response time, conduction speed was reduced by 50% and returned to near baseline at ST-recovery. The overall ischemic volume proportion initially increased, on average, to 37% at peak response time; however, it recovered to only 30% at the ST-recovery time. By contrast, the subepicardial region of the myocardial wall showed 40% ischemic volume at peak response time and recovered much more strongly to 25% as epicardial ST-segment deviations returned to baseline. CONCLUSION: Our data show that remote ischemic signal recovery correlates with a recovery of the subepicardial myocardium, whereas subendocardial ischemic development persists.

Pharmacological and simulated exercise cardiac stress tests produce different ischemic signatures in high-resolution experimental mapping studies.

OBJECTIVE: Test the hypothesis that exercise and pharmacological cardiac stressors create different electrical ischemic signatures. INTRODUCTION: Current clinical stress tests for detecting ischemia lack sensitivity and specificity. One unexplored source of the poor detection is whether pharmacological stimulation and regulated exercise produce identical cardiac stress. METHODS: We used a porcine model of acute myocardial ischemia in which animals were instrumented with transmural plunge-needle electrodes, an epicardial sock array, and torso arrays to simultaneously measure cardiac electrical signals within the heart wall, the epicardial surface, and the torso surface, respectively. Ischemic stress via simulated exercise and pharmacological stimulation were created with rapid electrical pacing and dobutamine infusion, respectively, and mimicked clinical stress tests of five 3-minute stages. Perfusion to the myocardium was regulated by a hydraulic occluder around the left anterior descending coronary artery. Ischemia was measured as deflections to the ST-segment on ECGs and electrograms. RESULTS: Across eight experiments with 30 (14 simulated exercise and 16 dobutamine) ischemic interventions, the spatial correlations between exercise and pharmacological stress diverged at stage three or four during interventions (p<0.05). We found more detectable ST-segment changes on the epicardial surface during simulated exercise than with dobutamine (p<0.05). The intramyocardial ischemia formed during simulated exercise had larger ST40 potential gradient magnitudes (p<0.05). CONCLUSION: We found significant differences on the epicardium between cardiac stress types using our experimental model, which became more pronounced at the end stages of each test. A possible mechanism for these differences was the larger ST40 potential gradient magnitudes within the myocardium during exercise. The presence of microvascular dysfunction during exercise and its absence during dobutamine stress may explain these differences.

The Argument for Abolishing Cardiac Screening of Asymptomatic Kidney Transplant Candidates.

Cardiovascular disease is the leading cause of death for individuals with end-stage renal disease. Due to concern about cardiac fitness, international guidelines support screening algorithms based on clinical risk factors for people with kidney failure who wish to consider kidney transplantation surgery. The stated aim of cardiac screening is to identify asymptomatic kidney transplantation candidates with potentially significant pathology that either allows risk stratification or facilitates intervention. This will enable some to proceed toward kidney transplant listing while others will be denied kidney transplantation due to perceived risks. The ultimate aim is to attenuate the risk for peri- or early postoperative cardiovascular mortality after kidney transplantation while maximizing the utility of scarce donor organs. However, heterogeneous recommendations for cardiac screening from international professional and/or society guidelines reflect the lack of evidence base to support published advice. Currently established screening strategies lack evidence for efficacy, incur substantial expense, and can be associated with significant risk for harm. In this Perspective article, the argument is made that current cardiac screening algorithms for asymptomatic kidney transplantation candidates are overzealous, counterproductive, and not in the best interests of the majority of people living with kidney failure and should be abolished.

Associations of cardiac stress biomarkers with incident type 2 diabetes and changes in glucose metabolism: KORA F4/FF4 study.

BACKGROUND: High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism. METHODS: We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates. RESULTS: During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors. CONCLUSIONS: High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

Quantification of regional myocardial mean intracellular water lifetime: A nonhuman primate study in myocardial stress.

Heart failure with preserved ejection fraction (HFpEF) is typically associated with early metabolic remodeling. Noninvasive imaging biomarkers that reflect these changes will be crucial in determining responses to early drug interventions in these patients. Mean intracellular water lifetime (τi ) has been shown to be partially inversely related to Na, K-ATPase transporter activity and may thus provide insight into the metabolic status in HFpEF patients. Here, we aim to perform regional quantification of τi using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in the nonhuman primate (NHP) heart and evaluate its region-specific variations under conditions of myocardial stress in the context of perturbed myocardial function. Cardiac stress was induced in seven naïve cynomolgus macaques using a dobutamine stepwise infusion protocol. All animals underwent 3 T cardiac dual-bolus DCE and tagging MRI experiments. The shutter-speed model was employed to quantify regional τi from the DCE-MR images. Additionally, τi values were correlated with myocardial strains. During cardiac stress, there was a significant decrease in global τi (192.9 ± 76.3 ms vs 321.6 ± 70 ms at rest, P < 0.05) in the left ventricle, together with an increase in global peak circumferential strain (-15.4% ± 2.7% vs -10.1% ± 2.9% at rest, P < 0.05). Specifically, slice-level analysis further revealed that a greater significant decrease in mean τi was observed in the apical region (ΔτI = 182.4 ms) compared with the basal (Δτi = 113.2 ms) and midventricular regions (Δτi = 108.4 ms). Regional analysis revealed that there was a greater significant decrease in mean τi in the anterior (Δτi = 243.9 ms) and antero-lateral (Δτi = 177.2 ms) regions. In the inferior and infero-septal regions, although a decrease in τi was observed, it was not significant. Whole heart regional quantification of τi is feasible using DCE-MRI. τi is sensitive to regional changes in metabolic state during cardiac stress, and its value correlates with strain.

Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. We used 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK transiently before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) animals. In contrast to AMPK activities during stress, in unstressed hearts, AICAR induced a mild activation of Akt signaling, and, in SRC-2-CKO mice, partially relieved an NAD+ deficiency and increased antioxidant signaling. These molecular changes translated to a mild hypertrophic response to TAC with decreased maladaptive remodeling, including markedly decreased fibrosis. Additionally, preactivation of AMPK in SRC-2-CKO mice was accompanied by a dramatic improvement in cardiac function compared with saline-treated SRC-2-CKO mice. Our results show that altered molecular signaling before stress onset has extended effects on sustained cardiac stress responses, and prestress modulation of transient growth and metabolism pathways may control those effects.-Nam, D. H., Kim, E., Benham, A., Park, H.-K., Soibam, B., Taffet, G. E., Kaelber, J. T., Suh, J. H., Taegtmeyer, H., Entman, M. L., Reineke, E. L. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

Immediate and 24-h post-marathon cardiac troponin T is associated with relative exercise intensity.

PURPOSE: We aimed at exploring whether cardiopulmonary fitness, echocardiographic measures and relative exercise intensity were associated with high-sensitivity cardiac troponin T (hs-TNT) rise and normalization following a marathon. METHODS: Nighty-eight participants (83 men, 15 women; 38.72 ± 3.63 years) were subjected to echocardiographic assessment and a cardiopulmonary exercise test (CPET) before the race. hs-TNT was measured before, immediately after and at 24, 48, 96, 144 and 192 h post-race. Speed and mean heart rate (HR) during the race were relativized to CPET values: peak speed (%VVMAX), peak HR (HR%MAX), speed and HR at the second ventilatory threshold (HR%VT2 and %VVT2). RESULTS: Hs-TNT increased from pre- to post-race (5.74 ± 5.29 vs. 50.4 ± 57.04 ng/L; p < 0.001), seeing values above the Upper Reference Limit (URL) in 95% of the participants. At 24 h post-race, 39% of the runners still exceeded the URL (High hs-TNT group). hs-TNT rise was correlated with marathon speed %VVT2 (r = 0.22; p = 0.042), mean HR%VT2 (r = 0.30; p = 0.007), and mean HR%MAX (r = 0.32; p = 0.004). Moreover, the High hs-TNT group performed the marathon at a higher Speed %VVT2 (88.21 ± 6.53 vs. 83.49 ± 6.54%; p = 0.002) and Speed %VVMAX (72 ± 4.25 vs. 69.40 ± 5.53%; p = 0.009). hs-TNT showed no significant associations with cardiopulmonary fitness and echocardiographic measures, except for a slight correlation with left ventricular end systolic diameter (r = 0.26; p = 0.018). CONCLUSION: Post-race hs-TNT was above the URL in barely all runners. Magnitude of hs-TNT rise was correlated with exercise mean HR; whereas, its normalization kept relationship with marathon relative speed.

Feasibility evaluation of non-invasive cardiac function technology during echocardiography-based cardiac stress testing.

Evaluation of cardiac function during periods of stress is of key importance for the perioperative setting. Non-invasive hemodynamic monitors provide markers of cardiac function. This pilot study sought to evaluate the ability of a non-invasive hemodynamic monitor to detect cardiac stress during formal stress echocardiography testing. The primary goal was to compare the change in hemodynamic values during the pre/during/post phases of stress echocardiography testing in patients who had results negative versus positive for myocardial ischemia. Adult patients scheduled for outpatient cardiac stress testing were screened. Only patients scheduled for stress-echocardiography testing were consented. Patients with history of arrhythmias were excluded. During the testing, patients wore a cuff-based hemodynamic sensor (Nexfin system, Edwards Lifesciences). Data from the hemodynamic sensor were compared to the findings of the stress study. A total of 37 patients were enrolled, with 31 patients included for analysis. Five patients had stress studies positive for coronary ischemia. Comparison of the hemodynamic variables between patients who had a positive stress study versus negative showed a significant reduction in the percentage change in dP/dt and stroke volume from baseline (p < 0.05). This pilot study indicates that patients who have abnormal stress echocardiograms also have significantly reduced values from a noninvasive hemodynamic monitor. Further evaluation of the clinical utility of this technology, to assist in the care of patients at risk for cardiac ischemia, should be carried out.

Dynamic palmitoylation regulates trafficking of K channel interacting protein 2 (KChIP2) across multiple subcellular compartments in cardiac myocytes.

BACKGROUND: K channel interacting protein 2 (KChIP2), initially cloned as Kv4 channel modulator, is a multi-tasking protein. In addition to modulating several cardiac ion channels at the plasma membrane, it can also modulate microRNA transcription inside nuclei, and interact with presenilins to modulate Ca release through RyR2 in the cytoplasm. However, the mechanism regulating its subcellular distribution is not clear. OBJECTIVE: We tested whether palmitoylation drives KChIP2 trafficking and distribution in cells, and whether the distribution pattern of KChIP2 in cardiac myocytes is sensitive to cellular milieu. METHOD: We conducted imaging and biochemical experiments on palmitoylatable and unpalmitoylatable KChIP2 variants expressed in COS-7 cells and in cardiomyocytes, and on native KChIP2 in myocytes. RESULTS: In COS-7 cells, palmitoylatable KChIP2 clustered to plasma membrane, while unpalmitoylatable KChIP2 exhibited higher cytoplasmic mobility and faster nuclear entry. The same differences in distribution and mobility were observed when these KChIP2 variants were expressed in cardiac myocytes, indicating that the palmitoylation-dependent distribution and trafficking are intrinsic properties of KChIP2. Importantly, acute stress in a rat model of cardiac arrest/resuscitation induced changes in native KChIP2 resembling those of KChIP2 depalmitoylation, promoting KChIP2 nuclear entry. CONCLUSION: The palmitoylation status of KChIP2 determines its subcellular distribution in cardiac myocytes. Stress promotes nuclear entry of KChIP2, diverting it from ion channel modulation at the plasma membrane to other functions in the nuclear compartment.