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Background: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited.Objectives: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI).Methods: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake).Results: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001).Conclusions: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318). [ABSTRACT FROM AUTHOR]

Background: Sleep duration and quality have been associated with increased cardiovascular risk. However, large studies linking objectively measured sleep and subclinical atherosclerosis assessed in multiple vascular sites are lacking.Objectives: The purpose of this study was to evaluate the association of actigraphy-measured sleep parameters with subclinical atherosclerosis in an asymptomatic middle-aged population, and investigate interactions among sleep, conventional risk factors, psychosocial factors, dietary habits, and inflammation.Methods: Seven-day actigraphic recording was performed in 3,974 participants (age 45.8 ± 4.3 years; 62.6% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study. Four groups were defined: very short sleep duration <6 h, short sleep duration 6 to 7 h, reference sleep duration 7 to 8 h, and long sleep duration >8 h. Sleep fragmentation index was defined as the sum of the movement index and fragmentation index. Carotid and femoral 3-dimensional vascular ultrasound and cardiac computed tomography were performed to quantify noncoronary atherosclerosis and coronary calcification.Results: When adjusted for conventional risk factors, very short sleep duration was independently associated with a higher atherosclerotic burden with 3-dimensional vascular ultrasound compared to the reference group (odds ratio: 1.27; 95% confidence interval: 1.06 to 1.52; p = 0.008). Participants within the highest quintile of sleep fragmentation presented a higher prevalence of multiple affected noncoronary territories (odds ratio: 1.34; 95% confidence interval: 1.09 to 1.64; p = 0.006). No differences were observed regarding coronary artery calcification score in the different sleep groups.Conclusions: Lower sleeping times and fragmented sleep are independently associated with an increased risk of subclinical multiterritory atherosclerosis. These results highlight the importance of healthy sleep habits for the prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events.Objectives: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals.Methods: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used.Results: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [×10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels.Conclusions: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318). [ABSTRACT FROM AUTHOR]

Background: The ideal cardiovascular health score (ICHS) is recommended for use in primary prevention. Simpler tools not requiring laboratory tests, such as the Fuster-BEWAT (blood pressure [B], exercise [E], weight [W], alimentation [A], and tobacco [T]) score (FBS), are also available.Objectives: The purpose of this study was to compare the effectiveness of ICHS and FBS in predicting the presence and extent of subclinical atherosclerosis.Methods: A total of 3,983 participants 40 to 54 years of age were enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) cohort. Subclinical atherosclerosis was measured in right and left carotids, abdominal aorta, right and left iliofemoral arteries, and coronary arteries. Subjects were classified as having poor, intermediate, or ideal cardiovascular health based on the number of favorable ICHS or FBS.Results: With poor ICHS and FBS as references, individuals with ideal ICHS and FBS showed lower adjusted odds of having atherosclerotic plaques (ICHS odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.31 to 0.55 vs.Fbs or: 0.49; 95% CI: 0.36 to 0.66), coronary artery calcium (CACS) ≥1 (CACS OR: 0.41; 95% CI: 0.28 to 0.60 vs.Cacs or: 0.53; 95% CI: 0.38 to 0.74), higher number of affected territories (OR: 0.32; 95% CI: 0.26 to 0.41 vs. OR: 0.39; 95% CI: 0.31 to 0.50), and higher CACS level (OR: 0.40; 95% CI: 0.28 to 0.58 vs. OR: 0.52; 95% CI: 0.38 to 0.72). Similar levels of significantly discriminating accuracy were found for ICHS and FBS with respect to the presence of plaques (C-statistic: 0.694; 95% CI: 0.678 to 0.711 vs. 0.692; 95% CI: 0.676 to 0.709, respectively) and for CACS ≥1 (C-statistic: 0.782; 95% CI: 0.765 to 0.800 vs. 0.780; 95% CI: 0.762 to 0.798, respectively).Conclusions: Both scores predict the presence and extent of subclinical atherosclerosis with similar accuracy, highlighting the value of the FBS as a simpler and more affordable score for evaluating the risk of subclinical disease. [ABSTRACT FROM AUTHOR]

Background: Daily habits, including the number and quality of eating occasions, are potential targets for primary prevention strategies with large health impacts. Skipping breakfast is considered a frequent and unhealthy habit associated with an increased cardiovascular (CV) risk.Objectives: The study sought to explore the association between different breakfast patterns and CV risk factors and the presence, distribution, and extension of subclinical atherosclerosis.Methods: Cross-sectional analysis was performed within the PESA (Progression of Early Subclinical Atherosclerosis) study, a prospective cohort of asymptomatic (free of CV events at baseline) adults 40 to 54 years of age. Lifestyle and multivascular imaging data along with clinical covariates were collected from 4,052 participants. Multivariate logistic regression models were used in the analysis.Results: Three patterns of breakfast consumption were studied: high-energy breakfast, when contributing to >20% of total daily energy intake (27% of the population); low-energy breakfast, when contributing between 5% and 20% of total daily energy intake (70% of the population); and skipping breakfast, when consuming <5% of total daily energy (3% of the population). Independent of the presence of traditional and dietary CV risk factors, and compared with high-energy breakfast, habitual skipping breakfast was associated with a higher prevalence of noncoronary (odds ratio: 1.55; 95% confidence interval: 0.97 to 2.46) and generalized (odds ratio: 2.57; 95% confidence interval: 1.54 to 4.31) atherosclerosis.Conclusion: Skipping breakfast is associated with an increased odds of prevalent noncoronary and generalized atherosclerosis independently of the presence of conventional CV risk factors. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318). [ABSTRACT FROM AUTHOR]

Background: Clinical practice guidelines recommend assessment of subclinical atherosclerosis using imaging techniques in individuals with intermediate atherosclerotic cardiovascular risk according to standard risk prediction tools.Objectives: The purpose of this study was to develop a machine-learning model based on routine, quantitative, and easily measured variables to predict the presence and extent of subclinical atherosclerosis (SA) in young, asymptomatic individuals. The risk of having SA estimated by this model could be used to refine risk estimation and optimize the use of imaging for risk assessment.Methods: The Elastic Net (EN) model was built to predict SA extent, defined by a combined metric of the coronary artery calcification score and 2-dimensional vascular ultrasound. The performance of the model for the prediction of SA extension and progression was compared with traditional risk scores of cardiovascular disease (CVD). An external independent cohort was used for validation.Results: EN-PESA (Progression of Early Subclinical Atherosclerosis) yielded a c-statistic of 0.88 for the prediction of generalized subclinical atherosclerosis. Moreover, EN-PESA was found to be a predictor of 3-year progression independent of the baseline extension of SA. EN-PESA assigned an intermediate to high cardiovascular risk to 40.1% (n = 1,411) of the PESA individuals, a significantly larger number than atherosclerotic CVD (n = 267) and SCORE (Systematic Coronary Risk Evaluation) (n = 507) risk scores. In total, 86.8% of the individuals with an increased risk based on EN-PESA presented signs of SA at baseline or a significant progression of SA over 3 years.Conclusions: The EN-PESA model uses age, systolic blood pressure, and 10 commonly used blood/urine tests and dietary intake values to identify young, asymptomatic individuals with an increased risk of CVD based on their extension and progression of SA. These individuals are likely to benefit from imaging tests or pharmacological treatment. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318). [ABSTRACT FROM AUTHOR]

Background: Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting.Objectives: The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19-associated ARDS.Methods: A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography.Results: Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17).Conclusions: In this pilot trial, intravenous metoprolol administration to patients with COVID-19-associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19-associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Atherosclerosis starts early in life and progresses silently for decades. Considering atherosclerosis as a "systemic disease" invites the use of noninvasive methodologies to detect disease in various regions before symptoms appear. The PESA-(Progression of Early Subclinical Atherosclerosis) CNIC-SANTANDER study is an ongoing prospective cohort study examining imaging, biological, and behavioral parameters associated with the presence and progression of early subclinical atherosclerosis. Between 2010 and 2014, PESA enrolled 4,184 asymptomatic middle-aged participants who undergo serial 3-yearly follow-up examinations including clinical interviews, lifestyle questionnaires, sampling, and noninvasive imaging assessment of multiterritorial subclinical atherosclerosis (carotids, iliofemorals, aorta, and coronaries). PESA tracks the trajectories of atherosclerosis and associated disorders from early stages to the transition to symptomatic phases. A joint venture between the CNIC and the Santander Bank, PESA is expected to run until at least 2029, and its significant contributions to date are presented in this review paper. [ABSTRACT FROM AUTHOR]

Background: Left ventricular (LV) hypertrabeculation fulfilling noncompaction cardiomyopathy criteria has been detected in athletes. However, the association between LV noncompaction (LVNC) phenotype and vigorous physical activity (VPA) in the general population is disputed.Objectives: The aim of this study was to assess the relationship between LVNC phenotype on cardiac magnetic resonance (CMR) imaging and accelerometer-measured physical activity (PA) in a cohort of middle-aged nonathlete participants in the PESA (Progression of Early Subclinical Atherosclerosis) study.Methods: In PESA participants (n = 4,184 subjects free of cardiovascular disease), PA was measured by waist-secured accelerometers. CMR was performed in 705 subjects (mean age 48 ± 4 years, 16% women). VPA was recorded as total minutes per week. The study population was divided into 6 groups: no VPA and 5 sex-specific quintiles of VPA rate (Q1 to Q5). The Petersen criterion for LVNC was evaluated in all subjects undergoing CMR. For participants meeting this criterion (noncompacted-to-compacted ratio ≥2.3), 3 more restrictive LVNC criteria were also evaluated (Jacquier, Grothoff, and Stacey).Results: LVNC phenotype prevalence according to the Petersen criterion was significantly higher among participants in the highest VPA quintile (Q5 = 30.5%) than in participants with no VPA (14.2%). The Jacquier and Grothoff criteria were also more frequently fulfilled in participants in the highest VPA quintile (Jacquier Q5 = 27.4% vs. no VPA = 12.8% and Grothoff Q5 = 15.8% vs. no VPA = 7.1%). The prevalence of the systolic Stacey LVNC criterion was low (3.6%) and did not differ significantly between no VPA and Q5.Conclusions: In a community-based study, VPA was associated with a higher prevalence of CMR-detected LVNC phenotype according to diverse established criteria. The association between VPA and LVNC phenotype was independent of LV volumes. According to these data, vigorous recreational PA should be considered as a possible but not uncommon determinant of LV hypertrabeculation in asymptomatic subjects. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking.Objectives: The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets.Methods: The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n = 360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n = 394]).Results: Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification.Conclusions: Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood.Objectives: This study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk.Methods: The study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk.Results: Imaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): -1 to 3 plaques] by 2DVUS; 7.6 mm3 [IQR: -32.2 to 57.6 mm3] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk.Conclusions: With this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318). [ABSTRACT FROM AUTHOR]

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic status (SES)-education, income level, and occupation-is associated with cardiovascular risk.Objectives: This study aimed to investigate the association between SES and subclinical atherosclerosis and the potential mechanisms involved.Methods: SES, lifestyle habits (smoking, dietary patterns, physical activity, and hours of sleep), traditional risk factors, and subclinical atherosclerosis extent were prospectively assessed in 4,025 individuals aged 40 to 54 years without known cardiovascular disease enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) study. After factors associated with atherosclerosis were identified, a multiple mediation model was created to quantify the effect of SES on subclinical atherosclerosis as explained by lifestyle behaviors.Results: Although education level was significantly associated with the presence of atherosclerosis, no differences were found according to income level in this population. Participants with lower education presented with a higher risk of generalized atherosclerosis than those with higher education (odds ratio: 1.46; 95% confidence interval: 1.15 to 1.85; p = 0.002). Lifestyle behaviors associated with both education level and atherosclerosis extent were: smoking status, number of cigarettes/day, and dietary pattern, which explained 70.5% of the effect of SES on atherosclerosis. Of these, tobacco habit (smoking status 35% and number of cigarettes/day 32%) accounted for most of the explained differences between groups, whereas dietary pattern did not remain a significant mediator in the multiple mediation model.Conclusions: Despite the relative economic homogeneity of the cohort, lower education level is associated with increased subclinical atherosclerosis, mainly mediated by the higher and more frequent tobacco consumption. Smoking cessation programs are still needed, particularly in populations with lower education level. [ABSTRACT FROM AUTHOR]

Background: Detection of subclinical atherosclerosis improves risk prediction beyond cardiovascular risk factors (CVRFs) and risk scores, but quantification of plaque burden may improve it further. Novel 3-dimensional vascular ultrasound (3DVUS) provides accurate volumetric quantification of plaque burden.Objectives: The authors evaluated associations between 3DVUS-based plaque burden and CVRFs and explored potential added value over simple plaque detection.Methods: The authors included 3,860 (92.2%) PESA (Progression of Early Subclinical Atherosclerosis) study participants (age 45.8 ± 4.3 years; 63% men). Bilateral carotid and femoral territories were explored by 3DVUS to determine the number of plaques and territories affected, and to quantify global plaque burden defined as the sum of all plaque volumes. Linear regression and proportional odds models were used to evaluate associations of plaque burden with CVRFs and estimated 10-year cardiovascular risk.Results: Plaque burden was higher in men (63.4 mm3 [interquartile range (IQR): 23.8 to 144.8 mm3] vs. 25.7 mm3 [IQR: 11.5 to 61.6 mm3] in women; p < 0.001), in the femoral territory (64 mm3 [IQR: 27.6 to 140.5 mm3] vs. 23.1 mm3 [IQR: 9.9 to 48.7 mm3] in the carotid territory; p < 0.001), and with increasing age (p < 0.001). Age, sex, smoking, and dyslipidemia were more strongly associated with femoral than with carotid disease burden, whereas hypertension and diabetes showed no territorial differences. Plaque burden was directly associated with estimated cardiovascular risk independently of the number of plaques or territories affected (p < 0.01).Conclusions: 3DVUS quantifies higher plaque burden in men, in the femoral territory, and with increasing age during midlife. Plaque burden correlates strongly with CVRFs, especially at the femoral level, and reflects estimated cardiovascular risk more closely than plaque detection alone. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318). [ABSTRACT FROM AUTHOR]

Background: Pre-reperfusion administration of intravenous (IV) metoprolol reduces infarct size in ST-segment elevation myocardial infarction (STEMI).Objectives: This study sought to determine how this cardioprotective effect is influenced by the timing of metoprolol therapy having either a long or short metoprolol bolus-to-reperfusion interval.Methods: We performed a post hoc analysis of the METOCARD-CNIC (effect of METOprolol of CARDioproteCtioN during an acute myocardial InfarCtion) trial, which randomized anterior STEMI patients to IV metoprolol or control before mechanical reperfusion. Treated patients were divided into short- and long-interval groups, split by the median time from 15 mg metoprolol bolus to reperfusion. We also performed a controlled validation study in 51 pigs subjected to 45 min ischemia/reperfusion. Pigs were allocated to IV metoprolol with a long (-25 min) or short (-5 min) pre-perfusion interval, IV metoprolol post-reperfusion (+60 min), or IV vehicle. Cardiac magnetic resonance (CMR) was performed in the acute and chronic phases in both clinical and experimental settings.Results: For 218 patients (105 receiving IV metoprolol), the median time from 15 mg metoprolol bolus to reperfusion was 53 min. Compared with patients in the short-interval group, those with longer metoprolol exposure had smaller infarcts (22.9 g vs. 28.1 g; p = 0.06) and higher left ventricular ejection fraction (LVEF) (48.3% vs. 43.9%; p = 0.019) on day 5 CMR. These differences occurred despite total ischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001). There was no between-group difference in the time from symptom onset to metoprolol bolus. In the animal study, the long-interval group (IV metoprolol 25 min before reperfusion) had the smallest infarcts (day 7 CMR) and highest long-term LVEF (day 45 CMR).Conclusions: In anterior STEMI patients undergoing primary angioplasty, the sooner IV metoprolol is administered in the course of infarction, the smaller the infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicated experimental large animal study. [ABSTRACT FROM AUTHOR]

Background Exercise has been proposed as a trigger for arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype manifestation; however, research is hampered by the limited availability of animal models in which disease-associated mutations can be tested. Objectives This study evaluated the impact of exercise on ARVC cardiac manifestations in mice after adeno-associated virus (AAV)–mediated gene delivery of mutant human PKP2 , which encodes the desmosomal protein plakophilin-2. Methods We developed a new model of cardiac tissue–specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype. Results Stable cardiac expression of mutant PKP2 (c.2203C>T), encoding the R735X mutant protein, was achieved 4 weeks after a single AAV9-R735X intravenous injection. High-field cardiac magnetic resonance over a 10-month postinfection follow-up did not detect an overt right ventricular (RV) phenotype in nonexercised (sedentary) mice. In contrast, endurance exercise training (initiated 2 weeks after AAV9-R735X injection) resulted in clear RV dysfunction that resembled the ARVC phenotype (impaired global RV systolic function and RV regional wall motion abnormalities on cardiac magnetic resonance). At the histological level, RV samples from endurance-trained R735X-infected mice displayed connexin 43 delocalization at intercardiomyocyte gap junctions, a change not observed in sedentary mice. Conclusions The introduction of the PKP2 R735X mutation into mice resulted in an exercise-dependent ARVC phenotype. The R735X mutation appears to function as a dominant-negative variant. This novel system for AAV-mediated introduction of a mutation into wild-type mice has broad potential for study of the implication of diverse mutations in complex cardiomyopathies. [ABSTRACT FROM AUTHOR]

Objectives: The study sought to evaluate the ability of cardiac magnetic resonance (CMR) to monitor acute and long-term changes in pulmonary vascular resistance (PVR) noninvasively. Background: PVR monitoring during the follow-up of patients with pulmonary hypertension (PH) and the response to vasodilator testing require invasive right heart catheterization. Methods: An experimental study in pigs was designed to evaluate the ability of CMR to monitor: 1) an acute increase in PVR generated by acute pulmonary embolization (n = 10); 2) serial changes in PVR in chronic PH (n = 22); and 3) changes in PVR during vasodilator testing in chronic PH (n = 10). CMR studies were performed with simultaneous hemodynamic assessment using a CMR-compatible Swan-Ganz catheter. Average flow velocity in the main pulmonary artery (PA) was quantified with phase contrast imaging. Pearson correlation and mixed model analysis were used to correlate changes in PVR with changes in CMR-quantified PA velocity. Additionally, PVR was estimated from CMR data (PA velocity and right ventricular ejection fraction) using a formula previously validated. Results: Changes in PA velocity strongly and inversely correlated with acute increases in PVR induced by pulmonary embolization (r = –0.92), serial PVR fluctuations in chronic PH (r = –0.89), and acute reductions during vasodilator testing (r = –0.89, p ≤ 0.01 for all). CMR-estimated PVR showed adequate agreement with invasive PVR (mean bias –1.1 Wood units,; 95% confidence interval: –5.9 to 3.7) and changes in both indices correlated strongly (r = 0.86, p < 0.01). Conclusions: CMR allows for noninvasive monitoring of acute and chronic changes in PVR in PH. This capability may be valuable in the evaluation and follow-up of patients with PH. [Copyright &y& Elsevier]