Prognostic Implications of Blunted Feature-Tracking Global Longitudinal Strain During Vasodilator Cardiovascular Magnetic Resonance Stress Imaging.

OBJECTIVES: The purpose of this study was to determine the prognostic value of feature-tracking global longitudinal strain (GLS) measured during vasodilator stress cardiac magnetic resonance (CMR) imaging. BACKGROUND: Prior studies have suggested that blunted myocardial strain during dobutamine stress echocardiography may be associated with adverse prognosis. Recent developments in CMR feature-tracking techniques now allow assessment of strain in clinical practice using standard cine images without specialized pulse sequences or complex post-processing. Whether feature-tracking GLS measured during vasodilator stress provides independent and incremental prognostic data is unclear. METHODS: Consecutive patients undergoing stress perfusion CMR were prospectively enrolled (n = 535). Feature-tracking stress GLS was measured immediately after regadenoson perfusion. Patients were followed for major adverse cardiac events (MACE): death, nonfatal myocardial infarction, heart failure hospitalization, sustained ventricular tachycardia, and late revascularization. Cox proportional hazards regression modeling was used to examine the association between stress GLS and MACE. The incremental prognostic value of stress GLS was assessed in nested models. RESULTS: Over a median follow-up of 1.5 years, 82 patients experienced MACE. By Kaplan-Meier analysis, patients with stress GLS ≥ median (-19%) had significantly reduced event-free survival compared with those with stress GLS < median (log-rank p < 0.001). Stress GLS was significantly associated with risk of MACE after adjustment for clinical and imaging risk factors including ischemia, ejection fraction, and late gadolinium enhancement (hazard ratio: 1.267; p < 0.001). Addition of stress GLS into a model with clinical and imaging predictors resulted in significant increase in the C-index (from 0.80 to 0.85; p = 0.031) and a continuous net reclassification improvement of 0.898 (95% confidence interval: 0.565 to 1.124). CONCLUSIONS: Feature-tracking stress GLS measured during vasodilator stress CMR is an independent predictor of MACE in patients with known or suspected coronary artery disease, incremental to common clinical and imaging risk factors. These findings suggest a role for feature-tracking derived stress GLS in identifying patients at highest risk of adverse events following stress CMR.

Feature-Tracking Global Longitudinal Strain Predicts Mortality in Patients With Preserved Ejection Fraction: A Multicenter Study.

OBJECTIVES: The goal of this study was to evaluate the prognostic value of global longitudinal strain (GLS) derived from cardiac magnetic resonance (CMR) feature-tracking in a large multicenter population of patients with preserved ejection fraction. BACKGROUND: Ejection fraction is the principal parameter used clinically to assess cardiac mechanics and provides prognostic information. However, significant abnormalities of myocardial deformation can be present despite preserved ejection fraction. CMR feature-tracking techniques now allow assessment of strain from routine cine images, without specialized pulse sequences. Whether abnormalities of strain measured by using CMR feature-tracking have prognostic value in patients with preserved ejection fraction is unknown. METHODS: Consecutive patients with preserved ejection fraction (≥50%) and a clinical indication for CMR at 4 U.S. medical centers were included in this retrospective study. Feature-tracking GLS was calculated from 3 long-axis cine views. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the independent association between GLS and death. The incremental prognostic value of GLS was assessed in nested models. RESULTS: Of the 1,274 patients in this study, 115 died during a median follow-up of 6.2 years. By Kaplan-Meier analysis, patients with GLS ≥ median (-20%) had significantly reduced event-free survival compared with those with GLS < median (log-rank test, p < 0.001). By Cox multivariable regression modeling, each 1% worsening in GLS was associated with a 22.8% increased risk of death after adjustment for clinical and imaging risk factors (hazard ratio: 1.228 per percent; p < 0.001). Addition of GLS in this model resulted in significant improvement in the global chi-square test (94 to 183; p < 0.001) and Harrell's C-statistic (0.75 to 0.83; p < 0.001). CONCLUSIONS: GLS derived from CMR feature-tracking is a powerful independent predictor of mortality in patients with preserved ejection fraction, incremental to common clinical and imaging risk factors.

Impacts of environmental complexity on respiratory and gut microbiome community structure and diversity in growing pigs.

The limited understanding of the interaction between rearing environment of the growing pig and the pig's microbial community impedes efforts to identify the optimal housing system to maximize animal health and production. Accordingly, we characterized the impact of housing complexity on shaping the respiratory and gut microbiota of growing pig. A total of 175 weaned pigs from 25 litters were randomly assigned within liter to either simple slatted-floor (S) or complex straw-based rearing ecosystem (C). Beside the floor swabs samples, fecal swabs and mucosal scraping samples from bronchus, ileum, and colon were collected approximately 164 days post-weaning at the time of slaughter. The S ecosystem seems to increase the α-diversity of respiratory and gut microbiota. Moreover, the C-raised pigs showed 35.4, 89.2, and 60.0% reduction in the Firmicutes/Bacteroidetes ratio than the S-raised pigs at bronchus, ileum, and colon, respectively. The unfavorable taxa Psychrobacter, Corynebacterium, Actinobacteria, and Neisseria were the signature taxa of C environment-associated microbial community. Therefore, the microbiota of S-raised pigs seems to show higher density of the most essential and beneficial taxa than the C-raised pigs. We preliminarily conclude that increasing the physical complexity of rearing environment seems to provide suboptimal conditions for establishing a healthy microbial community in the growing pigs.

Genetics of heart rate in heart failure patients (GenHRate).

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction < 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant "hits" (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 × 10-8). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts.

Prognostic Implications of Mitral Annular Plane Systolic Excursion in Patients with Hypertension and a Clinical Indication for Cardiac Magnetic Resonance Imaging: A Multicenter Study.

OBJECTIVES: This study sought to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived mitral annular plane systolic excursion (MAPSE) in a large multicenter population of patients with hypertension. BACKGROUND: In patients with hypertension, cardiac abnormalities are powerful predictors of adverse outcomes. Long-axis mitral annular movement plays a fundamental role in cardiac mechanics and is an early marker for a number of pathological processes. Given the adverse consequences of cardiac involvement in hypertension, the authors hypothesized that lateral MAPSE may provide incremental prognostic information in these patients. METHODS: Consecutive patients with hypertension and a clinical indication for CMR at 4 U.S. medical centers were included in this study (n = 1,735). Lateral MAPSE was measured in the 4-chamber cine view. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the association between lateral MAPSE and death. The incremental prognostic value of lateral MAPSE was assessed in nested models. RESULTS: Over a median follow-up period of 5.1 years, 235 patients died. By Kaplan-Meier analysis, risk of death was significantly higher in patients with a lateral MAPSE < median (10 mm) (log-rank; p < 0.0001). Lateral MAPSE was associated with risk of death after adjustment for clinical and imaging risk factors (hazard ratio [HR]: 1.402-per-millimeter decrease; p < 0.001). Addition of lateral MAPSE in this model resulted in significant improvement in the C-statistic (0.735 to 0.815; p < 0.0001). Continuous net reclassification improvement was 0.739 (95% confidence interval: 0.601 to 0.902). Lateral MAPSE remained significantly associated with death even after adjustment for feature tracking global longitudinal strain (HR: 1.192-per-millimeter decrease; p < 0.001). Lateral MAPSE was independently associated with death among the subgroups of patients with preserved ejection fraction (HR = 1.339; p < 0.001) and in those without history of myocardial infarction (HR: 1.390; p < 0.001). CONCLUSIONS: CMR-derived lateral MAPSE is a powerful, independent predictor of mortality in patients with hypertension and a clinical indication for CMR, incremental to common clinical and CMR risk factors. These findings may suggest a role for CMR-derived lateral MAPSE in identifying hypertensive patients at highest risk of death.

Global Coronary Flow Reserve Measured During Stress Cardiac Magnetic Resonance Imaging Is an Independent Predictor of Adverse Cardiovascular Events.

OBJECTIVES: The aim of this study was to evaluate the incremental prognostic value of global coronary flow reserve (CFR) in patients with known or suspected coronary artery disease who were undergoing stress cardiac magnetic resonance (CMR) imaging. BACKGROUND: Coronary microvascular dysfunction results in impaired global CFR and is implicated in the development of both atherosclerosis and heart failure. Although noninvasive assessment of CFR with positron emission tomography provides independent prognostic information, the incremental prognostic value of CMR-derived CFR remains unclear. METHODS: Consecutive patients undergoing stress perfusion CMR were prospectively enrolled (n = 507). Coronary sinus flow was measured using phase-contrast imaging at baseline (pre) and immediately after stress (peak) perfusion. CFR was calculated as the ratio of peak to pre-flow. Patients were followed for major adverse cardiac events (MACE): death, nonfatal myocardial infarction, heart failure hospitalization, sustained ventricular tachycardia, and late revascularization. Cox proportional hazards regression modeling was used to examine the association between CFR and MACE. The incremental prognostic value of CFR was assessed in nested models. RESULTS: Over a median follow-up of 2.1 years, 80 patients experienced MACE. By Kaplan-Meier analysis, the risk of MACE was significantly higher in patients with CFR lower than the median (2.2) (log-rank p < 0.001); this remained significant after adjustment for the presence of ischemia and late gadolinium enhancement (LGE) (log-rank p < 0.001). CFR was significantly associated with the risk of MACE after adjustment for clinical and imaging risk factors, including ischemia extent, ejection fraction, and LGE size (hazard ratio: 1.238; p = 0.018). Addition of CFR in this model resulted in significant improvement in the C-index (from 0.70 to 0.75; p = 0.0087) and a continuous net reclassification improvement of 0.198 (95% confidence interval: 0.120 to 0.288). CONCLUSIONS: CMR-derived CFR is an independent predictor of MACE in patients with known or suspected coronary artery disease, incremental to common clinical and CMR risk factors. These findings suggest a role for CMR-derived CFR in identifying patients at risk of adverse events following stress CMR, even in the absence of ischemia and LGE.

Henry Ford HEART Score Randomized Trial: Rapid Discharge of Patients Evaluated for Possible Myocardial Infarction.

BACKGROUND: Hospital evaluation of patients with chest pain is common and costly. The HEART score risk stratification tool that merges troponin testing into a clinical risk model for evaluation emergency department patients with possible acute myocardial infarction (AMI) has been shown to effectively identify a substantial low-risk subset of patients possibly safe for early discharge without stress testing, a strategy that could have tremendous healthcare savings implications. METHOD AND RESULTS: A total of 105 patients evaluated for AMI in the emergency departments of 2 teaching hospitals in the Henry Ford Health System (Detroit and West Bloomfield, MI), between February 2014 and May 2015, with a modified HEART score ≤3 (which includes cardiac troponin I <0.04 ng/mL at 0 and 3 hours) were randomized to immediate discharge (n=53) versus management in an observation unit with stress testing (n=52). The primary end points were 30-day total charges and length of stay. Secondary end points were all-cause death, nonfatal AMI, rehospitalization for evaluation of possible AMI, and coronary revascularization at 30 days. Patients randomized to early discharge, compared with those who were admitted for observation and cardiac testing, spent less time in the hospital (median 6.3 hours versus 25.9 hours; P<0.001) with an associated reduction in median total charges of care ($2953 versus $9616; P<0.001). There were no deaths, AMIs, or coronary revascularizations in either group. One patient in each group was lost to follow-up. CONCLUSIONS: Among patients evaluated for possible AMI in the emergency department with a modified HEART score ≤3, early discharge without stress testing as compared with transfer to an observation unit for stress testing was associated with significant reductions in length of stay and total charges, a finding that has tremendous potential national healthcare expenditure implications. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03058120.

Prognostic Utility of a Modified HEART Score in Chest Pain Patients in the Emergency Department.

BACKGROUND: The TRAPID-AMI trial study (High-Sensitivity Troponin-T Assay for Rapid Rule-Out of Acute Myocardial Infarction) evaluated high-sensitivity cardiac troponin-T (hs-cTnT) in a 1-hour acute myocardial infarction (AMI) exclusion algorithm. Our study objective was to evaluate the prognostic utility of a modified HEART score (m-HS) within this trial. METHODS AND RESULTS: Twelve centers evaluated 1282 patients in the emergency department for possible AMI from 2011 to 2013. Measurements of hs-cTnT (99th percentile, 14 ng/L) were performed at 0, 1, 2, and 4 to 14 hours. Evaluation for major adverse cardiac events (MACEs) occurred at 30 days (death or AMI). Low-risk patients had an m-HS≤3 and had either hs-cTnT<14 ng/L over serial testing or had AMI excluded by the 1-hour protocol. By the 1-hour protocol, 777 (60%) patients had an AMI excluded. Of those 777 patients, 515 (66.3%) patients had an m-HS≤3, with 1 (0.2%) patient having a MACE, and 262 (33.7%) patients had an m-HS≥4, with 6 (2.3%) patients having MACEs (P=0.007). Over 4 to 14 hours, 661 patients had a hs-cTnT<14 ng/L. Of those 661 patients, 413 (62.5%) patients had an m-HS≤3, with 1 (0.2%) patient having a MACE, and 248 (37.5%) patients had an m-HS≥4, with 5 (2.0%) patients having MACEs (P=0.03). CONCLUSIONS: Serial testing of hs-cTnT over 1 hour along with application of an m-HS identified a low-risk population that might be able to be directly discharged from the emergency department.

Regional and physician specialty-associated variations in the medical management of atherosclerotic renal-artery stenosis.

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis.

Endovascular versus medical therapy for atherosclerotic renovascular disease.

The diagnosis of renal artery stenosis (RAS) has become increasingly common in part due to greater awareness of ischemic renal disease and increased use of diagnostic techniques. Over 90 % of RAS cases are caused by atherosclerotic renovascular disease (ARVD). Patients with ARVD are at high risk for fatal and nonfatal cardiovascular and renal events. The mortality rate in patients with ARVD is high, especially with other cardiovascular or renal comorbidities. Recent clinical studies have provided substantial evidence concerning medical therapy and endovascular interventional therapeutic approaches for ARVD. Despite previous randomized clinical trials, the optimal therapy for ARVD remained uncertain until the results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial were released recently. CORAL demonstrated that optimal medical therapy was equally effective to endovascular therapy in the treatment of ARVD. Clinicians can now practice with more evidence-based medicine to treat ARVD and potentially decrease mortality in patients with ARVD using optimal medical therapy.

Use of renin-angiotensin inhibitors in people with renal artery stenosis.

BACKGROUND AND OBJECTIVES: People with atherosclerotic renal artery stenosis may benefit from renin-angiotensin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers, but little is known about the factors associated with their use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions study (ClinicalTrials.gov identified: NCT00081731) is a prospective, international, multicenter clinical trial that randomly assigned participants with atherosclerotic renal artery stenosis who received optimal medical therapy to stenting versus no stenting from May 2005 through January 2010. At baseline, medication information was available from 853 of 931 randomly assigned participants. Kidney function was measured by serum creatinine-based eGFR at a core laboratory. RESULTS: Before randomization, renin-angiotensin inhibitors were used in 419 (49%) of the 853 participants. Renin-angiotensin inhibitor use was lower in those with CKD (eGFR<60 ml/min per 1.73 m(2)) (58% versus 68%; P=0.004) and higher in individuals with diabetes (41% versus 27%; P<0.001). Presence of bilateral renal artery stenosis or congestive heart failure was not associated with renin-angiotensin inhibitor use. Although therapy with renin-angiotensin inhibitors varied by study site, differences in rates of use were not related to the characteristics of the site participants. Participants receiving a renin-angiotensin inhibitor had lower systolic BP (mean ± SD, 148 ± 23 versus 152 ± 23 mmHg; P=0.003) and more often had BP at goal (30% versus 22%; P=0.01). CONCLUSIONS: Kidney function and diabetes were associated with renin-angiotensin inhibitor use. However, these or other clinical characteristics did not explain variability among study sites. Patients with renal artery stenosis who received renin-angiotensin inhibitor treatment had lower BP and were more likely to be at treatment goal.

Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation.

Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) differentiation capacity. BMSCs were isolated from male Sprague-Dawley rats and cultured in minimal essential medium alpha (MEM-α) supplemented with 15% Fetal Bovine serum (FBS). The results showed that marinobufagenin (MBG), a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα) protein expression through activation of an extracellular regulated kinase (ERK) signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2) expression, which resulted in the inhibition of osteogenesis induced by ß-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.

Reduction of Na/K-ATPase affects cardiac remodeling and increases c-kit cell abundance in partial nephrectomized mice.

The current study examined the role of Na/K-ATPase α1-subunit in animals subjected to 5/6th partial nephrectomy (PNx) using Na/K-ATPase α1-heterozygous (α1(+/-)) mice and their wild-type (WT) littermates. After PNx, both WT and α1(+/-) animals displayed diastolic dimension increases, increased blood pressure, and increased cardiac hypertrophy. However, in the α1(+/-) animals we detected significant increases in cardiac cell death in PNx animals. Given that reduction of α1 elicited increased cardiac cell death with PNx, while at the same time these animals developed cardiac hypertrophy, an examination of cardiac cell number, and proliferative capabilities of those cells was carried out. Cardiac tissues were probed for the progenitor cell marker c-kit and the proliferation marker ki-67. The results revealed that α1(+/-) mice had significantly higher numbers of c-kit-positive and ki-67-positive cells, especially in the PNx group. We also found that α1(+/-) mice express higher levels of stem cell factor, a c-kit ligand, in their heart tissue and had higher circulating levels of stem cell factor than WT animals. In addition, PNx induced significant enlargement of cardiac myocytes in WT mice but has much less effect in α1(+/-) mice. However, the total cell number determined by nuclear counting is higher in α1(+/-) mice with PNx compared with WT mice. We conclude that PNx induces hypertrophic growth and high blood pressure regardless of Na/K-ATPase content change. However, total cardiac cell number as well as c-kit-positive cell number is increased in α1(+/-) mice with PNx.

Mechanisms and treatments for renal artery stenosis.

Atherosclerotic renal artery stenosis (ARAS) is a common and complicated disease, which can result in high blood pressure and loss of kidney function. Although progress has been made in the understanding and treatment of hypertension in relation to ARAS, much less progress has been made in the area of renal function. Here we discuss current treatment options in regard to medical therapy and revascularization. We also describe the proposed mechanisms leading to renal dysfunction, including the CD40 signaling cascade, which is a particularly attractive signaling mechanism that may provide a mechanistic rationale for the development of renal disease in ARAS.