Integration of longitudinal and circumferential strain predicts volumetric change across the cardiac cycle and differentiates patients along the heart failure continuum.

BACKGROUND: Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change. METHODS: Cardiac magnetic resonance (CMR) imaging from 229 participants from the Alberta HEART Study (46 healthy controls, 77 individuals at risk for developing heart failure [HF], 70 patients with diagnosed HF with preserved ejection fraction [HFpEF], and 36 patients with diagnosed HF with reduced ejection fraction [HFrEF]) were evaluated. LV volume was assessed by the method of disks and strain/strain rate were assessed by CMR feature tracking. RESULTS: Integrating endocardial circumferential and longitudinal strain provided a close approximation of LV ejection fraction (EFStrain), when compared to gold-standard volumetric assessment (EFVolume: r = 0.94, P < 0.0001). Likewise, integrating circumferential and longitudinal strain rate provided a close approximation of peak ejection and peak filling rates (PERStrain and PFRStrain, respectively) compared to their gold-standard volume-time equivalents (PERVolume, r = 0.73, P < 0.0001 and PFRVolume, r = 0.78, P < 0.0001, respectively). Moreover, each integrated strain measure differentiated patients across the HF continuum (all P < 0.01), with the HFrEF group having worse EFStrain, PERStrain, and PFRStrain compared to all other groups, and HFpEF having less favorable EFStrain and PFRStrain compared to both at-risk and control groups. CONCLUSIONS: The data herein establish the theoretical framework for integrating discrete strain components into volumetric measurements across the cardiac cycle, and highlight the potential benefit of this approach for differentiating patients along the heart failure continuum.

Left Atrial Stiffness Index Independently Predicts Exercise Intolerance and Quality of Life in Older, Obese Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. The primary chronic symptom in HFpEF is exercise intolerance, associated with reduced quality of life. Emerging evidence implicates left atrial (LA) dysfunction as an important pathophysiologic mechanism. Here we extend prior observations by relating LA dysfunction to peak oxygen uptake (peak VO2), physical function (distance walked in 6 minutes [6MWD]) and quality of life (Kansas City Cardiomyopathy Questionnaire). METHODS AND RESULTS: We compared 75 older, obese, patients with HFpEF with 53 healthy age-matched controls. LA strain was assessed by magnetic resonance cine imaging using feature tracking. LA function was defined according to its 3 distinct phases, with the LA serving as a reservoir during systole, as a conduit during early diastole, and as a booster pump at the end of diastole. The LA stiffness index was calculated as the ratio of early mitral inflow velocity-to-early annular tissue velocity (E/e', by Doppler ultrasound examination) and LA reservoir strain. HFpEF had a decreased reservoir strain (16.4 ± 4.4% vs 18.2 ± 3.5%, P = .018), lower conduit strain (7.7 ± 3.3% vs 9.1 ± 3.4%, P = .028), and increased stiffness index (0.86 ± 0.39 vs 0.53 ± 0.18, P < .001), as well as decreased peak VO2, 6MWD, and lower quality of life. Increased LA stiffness was independently associated with impaired peak VO2 (ß = 9.0 ± 1.6, P < .001), 6MWD (ß = 117 ± 22, P = .003), and Kansas City Cardiomyopathy Questionnaire score (ß = -23 ± 5, P = .001), even after adjusting for clinical covariates. CONCLUSIONS: LA stiffness is independently associated with impaired exercise tolerance and quality of life and may be an important therapeutic target in obese HFpEF. REGISTRATION: NCT00959660.

Left ventricular diastolic dysfunction and exercise intolerance in obese heart failure with preserved ejection fraction.

This study tested the hypothesis that early left ventricular (LV) relaxation is impaired in older obese patients with heart failure with preserved ejection fraction (HFpEF), and related to decreased peak exercise oxygen uptake (peak V̇o2). LV strain and strain rate were measured by feature tracking of magnetic resonance cine images in 79 older obese patients with HFpEF (mean age: 66 yr; mean body mass index: 38 kg/m2) and 54 healthy control participants. LV diastolic strain rates were indexed to cardiac preload as estimated by echocardiography derived diastolic filling pressures (E/e'), and correlated to peak V̇o2. LV circumferential early diastolic strain rate was impaired in HFpEF compared with controls (0.93 ± 0.05/s vs. 1.20 ± 0.07/s, P = 0.014); however, we observed no group differences in early LV radial or longitudinal diastolic strain rates. Isolating myocardial relaxation by indexing all three early LV diastolic strain rates (i.e. circumferential, radial, and longitudinal) to E/e' amplified the group difference in early LV diastolic circumferential strain rate (0.08 ± 0.03 vs. 0.13 ± 0.05, P < 0.0001), and unmasked differences in early radial and longitudinal diastolic strain rate. Moreover, when indexing to E/e', early LV diastolic strain rates from all three principal strains, were modestly related with peak V̇o2 (R = 0.36, -0.27, and 0.35, respectively, all P < 0.01); this response, however, was almost entirely driven by E/e' itself, (R = -0.52, P < 0.001). Taken together, we found that although LV relaxation is impaired in older obese patients with HFpEF, and modestly correlates with their severely reduced peak exercise V̇o2, LV filling pressures appear to play a much more important role in determining exercise intolerance.NEW & NOTEWORTHY Using a multimodal imaging approach to uncouple tissue deformation from atrial pressure, we found that left ventricular (LV) relaxation is impaired in older obese patients with HFpEF, but only modestly correlates with their severely reduced peak V̇o2. In contrast, the data show a much stronger relationship between elevated LV filling pressures and exercise intolerance, refocusing future therapeutic priorities.

Exercise cardiac magnetic resonance imaging: a feasibility study and meta-analysis.

Cardiac stress testing improves detection and risk assessment of heart disease. Magnetic resonance imaging (MRI) is the clinical gold-standard for assessing cardiac morphology and function at rest; however, exercise MRI has not been widely adapted for cardiac assessment because of imaging and device limitations. Commercially available magnetic resonance ergometers, together with improved imaging sequences, have overcome many previous limitations, making cardiac stress MRI more feasible. Here, we aimed to demonstrate clinical feasibility and establish the normative, healthy response to supine exercise MRI. Eight young, healthy subjects underwent rest and exercise cinematic imaging to measure left ventricular volumes and ejection fraction. To establish the normative, healthy response to exercise MRI we performed a comprehensive literature review and meta-analysis of existing exercise cardiac MRI studies. Results were pooled using a random effects model to define the left ventricular ejection fraction, end-diastolic, end-systolic, and stroke volume responses. Our proof-of-concept data showed a marked increase in cardiac index with exercise, secondary to an increase in both heart rate and stroke volume. The change in stroke volume was driven by a reduction in end-systolic volume, with no change in end-diastolic volume. These findings were entirely consistent with 17 previous exercise MRI studies (226 individual records), despite differences in imaging approach, ergometer, or exercise type. Taken together, the data herein demonstrate that exercise cardiac MRI is clinically feasible, using commercially available exercise equipment and vendor-provided product sequences and establish the normative, healthy response to exercise MRI.

Adaptation of myocardial twist in the remodelled athlete's heart is not related to cardiac output.

NEW FINDINGS: What is the central question of this study? What is the role of heart muscle function in the increased output of remodelled, larger hearts? What is the main finding and its importance? The greater stroke volume of endurance athletes is not associated with enhanced function of the heart muscle (i.e. left ventricular twist, torsion and twist-to-shortening) in normal and low-oxygen environments. These data indicate that, in the process of cardiac adaptation, left ventricular twist may play an important role that is not related to generating a larger output. Since enlarged hearts with low output can develop in disease, the present findings may influence the future interpretation of heart muscle function in patients. ABSTRACT: Despite increased stroke volume (SV), 'athlete's heart' has been proposed to have a similar left ventricular (LV) muscle function - as represented by LV twist - compared with the untrained state. However, the underpinning mechanisms and the associations between SV/cardiac output and LV twist during exercise are unknown. We hypothesised that endurance athletes would have a significantly lower twist-to-shortening ratio (TwSR, a parameter that relates twist to the shortening of heart muscle layers) at rest, but significantly greater LV muscle function during exercise. Eleven endurance trained male runners and 13 untrained males were tested at rest and during supine cycling exercise in normoxia and hypoxia (increased cardiac output but unaltered SV). Despite the expected cardiac remodelling in endurance athletes, LV twist, torsion, TwSR, strain and strain rate ('LV systolic mechanics') did not differ significantly between groups (P > 0.05). Structural remodelling, as per relative wall thickness, and LV twist did not correlate (r2  = 0.04, P = 0.33). In normoxia and hypoxia, exercise increased LV systolic mechanics in both groups (P < 0.001), but with different relationships to SV and cardiac output. Conversely to our hypothesis, hearts of different size had similar LV systolic mechanics, suggesting that similar twist, torsion and TwSR at rest and during exercise irrespective of cardiac output may be an important mechanism in healthy hearts. We hypothesise that the regulatory 'purpose' of LV twist may be related to the sensing of maximal cardiac myofibre stress, which may act as a biologically purposeful limiter to contraction.

Age-related microvascular dysfunction: novel insight from near-infrared spectroscopy.

NEW FINDINGS: What is the central question of this study? Can near-infrared spectroscopy (NIRS)-derived post-occlusion tissue oxygen saturation recovery kinetics be used to study age-related impairments in microvascular function? What is the main finding and its importance? Using a previously established 5 min cuff occlusion protocol, we found that NIRS-derived indices of microvascular function were markedly reduced in elderly compared with young participants. However, when we controlled for the absolute level of vasodilatory stimulus and matched the tissue desaturation level between groups, we found similar responses in young and elderly participants. Overall, these data highlight the important role NIRS can serve in clinical vascular biology, but also establish the need for assessing tissue ischaemia during cuff occlusion protocols. Near-infrared spectroscopy (NIRS) has emerged as a promising tool to evaluate vascular reactivity in vivo. Whether this approach can be used to assess age-related impairments in microvascular function has not been tested. Tissue oxygen saturation (StO2) post-occlusion recovery kinetics were measured in two distinct age groups (<35 and >65 years of age) using NIRS placed over the flexor digitorum profundus. Key end-points included the following: (i) the desaturation rate during cuff occlusion; (ii) the lowest StO2 value obtained during ischaemia (StO2min); (iii) StO2 reperfusion rate; (iv) the highest StO2 value reached after cuff release (StO2max); and (v) the reactive hyperaemia area under the curve (AUC). At first, using a conventional 5 min cuff occlusion protocol, the elderly participants achieved a much slower rate of oxygen recovery (1.5 ± 0.2 versus 2.5 ± 0.2% s-1 ), lower StO2max (85.2 ± 2.9 versus 92.3 ± 1.5%) and lower reactive hyperaemia AUC (2651.8 ± 307.0 versus 4940.0 ± 375.8% s-1 ). However, owing to a lower skeletal muscle resting metabolic rate, StO2min was also significantly attenuated in the elderly participants compared with the young control subjects (55.7 ± 3.5 versus 41.0 ± 3.4%), resulting in a much lower ischaemic stimulus. To account for this important difference between groups, we then matched the level of tissue ischaemia in a subset of young healthy participants by reducing the cuff occlusion protocol to 3 min. Remarkably, when we controlled for tissue ischaemia, we observed no differences in any of the hyperaemic end-points between the young and elderly participants. These data highlight the important role NIRS can serve in vascular biology, but also establish the need for assessing tissue ischaemia during cuff occlusion protocols.

Performance Limitations in Heart Transplant Recipients.

We hypothesize that the reduced peak aerobic power (peak V˙O2) after heart transplantation is due to impaired cardiovascular and skeletal muscle function, and its improvement with short-term (≤1 yr) exercise training is primarily due to favorable skeletal muscle adaptations. Furthermore, the increased peak V˙O2 with long-term (>2 yr) training is primarily mediated by cardiac (sympathetic) reinnervation.

Diastolic Stress Testing Along the Heart Failure Continuum.

PURPOSE OF REVIEW: This review summarizes recent developments highlighting the clinical utility of diastolic stress testing along the heart failure continuum. RECENT FINDINGS: Invasive hemodynamic assessment of cardiac filling pressures during physiological stress is the gold-standard technique for unmasking diastolic dysfunction. Non-invasive surrogate techniques, such as Doppler ultrasound, have shown excellent agreement with invasive approaches and are now recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. While cycle exercise is often advocated, recent evidence supports the use of isometric handgrip as a viable alternative stressor. Diastolic stress testing is a powerful tool to enhance detection of diastolic dysfunction, is able to differentiate between cardiac and non-cardiac pathology, and should be incorporated into routine clinical assessment.

Correcting Calcium Dysregulation in Chronic Heart Failure Using SERCA2a Gene Therapy.

Chronic heart failure (CHF) is a major contributor to cardiovascular disease and is the leading cause of hospitalization for those over the age of 65, which is estimated to account for close to seventy billion dollars in healthcare costs by 2030 in the US alone. The successful therapies for preventing and reversing CHF progression are urgently required. One strategy under active investigation is to restore dysregulated myocardial calcium (Ca2+), a hallmark of CHF. It is well established that intracellular Ca2+ concentrations are tightly regulated to control efficient myocardial systolic contraction and diastolic relaxation. Among the many cell surface proteins and intracellular organelles that act as the warp and woof of the regulatory network controlling intracellular Ca2+ signals in cardiomyocytes, sarco/endoplasmic reticulum Ca2+ ATPase type 2a (SERCA2a) undoubtedly plays a central role. SERCA2a is responsible for sequestrating cytosolic Ca2+ back into the sarcoplasmic reticulum during diastole, allowing for efficient uncoupling of actin-myosin and subsequent ventricular relaxation. Accumulating evidence has demonstrated that the expression of SERCA2a is downregulated in CHF, which subsequently contributes to severe systolic and diastolic dysfunction. Therefore, restoring SERCA2a expression and improving cardiomyocyte Ca2+ handling provides an excellent alternative to currently used transplantation and mechanical assist devices in the treatment of CHF. Indeed, advancements in safe and effective gene delivery techniques have led to the emergence of SERCA2a gene therapy as a potential therapeutic choice for CHF patients. This mini-review will succinctly detail the progression of SERCA2a gene therapy from its inception in plasmid and animal models, to its clinical trials in CHF patients, highlighting potential avenues for future work along the way.

Athlete's Heart: Is the Morganroth Hypothesis Obsolete?

In 1975, Morganroth and colleagues reported that the increased left ventricular (LV) mass in highly trained endurance athletes versus nonathletes was primarily due to increased end-diastolic volume while the increased LV mass in resistance trained athletes was solely due to an increased LV wall thickness. Based on the divergent remodelling patterns observed, Morganroth and colleagues hypothesised that the increased "volume" load during endurance exercise may be similar to that which occurs in patients with mitral or aortic regurgitation while the "pressure" load associated with performing a Valsalva manoeuvre (VM) during resistance exercise may mimic the stress imposed on the heart by systemic hypertension or aortic stenosis. Despite widespread acceptance of the four-decade old Morganroth hypothesis in sports cardiology, some investigators have questioned whether such a divergent "athlete's heart" phenotype exists. Given this uncertainty, the purpose of this brief review is to re-evaluate the Morganroth hypothesis regarding: i) the acute effects of resistance exercise performed with a brief VM on LV wall stress, and the patterns of LV remodelling in resistance-trained athletes; ii) the acute effects of endurance exercise on biventricular wall stress, and the time course and pattern of LV and right ventricular (RV) remodelling with endurance training; and iii) the value of comparing "loading" conditions between athletes and patients with cardiac pathology.

Myocardial ATP depletion detected noninvasively predicts sudden cardiac death risk in patients with heart failure.

BACKGROUNDSudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies, such as implantable cardioverter defibrillators (ICDs), are based on left ventricular ejection fraction (LVEF), but these guidelines are imprecise: fewer than 5% of ICDs deliver lifesaving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but to our knowledge a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor has the potential for metabolically predicting clinical SCD risk.METHODSWe prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%).RESULTSBy 2 different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over approximately 10 years. Life-threatening arrhythmia risk was approximately 3-fold higher in patients with low ATP and independent of established risk factors, including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings.CONCLUSIONTo the best of our knowledge, these are the first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people, suggesting an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald noninvasive metabolic imaging as a complementary SCD risk stratification tool.TRIAL REGISTRATIONClinicalTrials.gov NCT00181233.FUNDINGThis work was supported by the DW Reynolds Foundation, the NIH (grants HL61912, HL056882, HL103812, HL132181, HL140034), and Russell H. Morgan and Clarence Doodeman endowments at Johns Hopkins.

Cognition and brain oxygen metabolism improves after bariatric surgery-induced weight loss: A pilot study.

Objective: The primary objectives of this pilot study were to assess cognition and cerebral metabolic rate of oxygen (CMRO2) consumption in people with severe obesity before (baseline), and again, 2- and 14-weeks after sleeve gastrectomy bariatric surgery. Methods: Six people with severe/class 3 obesity (52 ± 10 years, five females, body mass index (BMI) = 41.9 ± 3.9 kg/m2), and 10 normal weight sex- and age-matched healthy controls (HC) (48 ± 6 years, eight females, 22.8 ± 1.9 kg/m2). Global CMRO2 was measured non-invasively using MRI and cognition using the Integneuro testing battery. Results: Following a sleeve gastrectomy induced weight loss of 6.4 ± 2.5 kg (% total-body-weight-lost = 5.4) over two-weeks, cognition total scores improved by 0.8 ± 0.5 T-scores (p=0.03, 15.8% improvement from baseline). Weight loss over 14-weeks post-surgery was 15.4 ± 3.6 kg (% total-body-weight-lost = 13.0%) and cognition improved by 1.1 ± 0.4 (p=0.003, 20.6% improvement from baseline). At 14-weeks, cognition was 6.4 ± 0.7, comparable to 6.0 ± 0.6 observed in the HC group. Baseline CMRO2 was significantly higher compared to the HC (230.4 ± 32.9 vs. 177.9 ± 33.9 µmol O2/100 g/min, p=0.02). Compared to baseline, CMRO2 was 234.3 ± 16.2 µmol O2/100 g/min at 2-weeks after surgery (p=0.8, 1.7% higher) and 217.3 ± 50.4 at 14-weeks (p=0.5, 5.7% lower) after surgery. 14-weeks following surgery, CMRO2 was similar to HC (p=0.17). Conclusion: Sleeve gastrectomy induced weight loss was associated with an increase in cognition and a decrease in CMRO2 observed 14-weeks after surgery. The association between weight loss, improved cognition and CMRO2 decrease should be evaluated in larger future studies.

Reduced myocardial perfusion is common among subjects with ischemia and no obstructive coronary artery disease and heart failure with preserved ejection fraction: a report from the WISE-CVD continuation study.

Aim: Women with evidence of ischemia and no obstructive coronary artery disease (INOCA) have an increased risk of major adverse cardiac events, including heart failure with preserved ejection fraction (HFpEF). To investigate potential links between INOCA and HFpEF, we examined pathophysiological findings present in both INOCA and HFpEF. Methods: We performed adenosine stress cardiac magnetic resonance imaging (CMRI) in 56 participants, including 35 women with suspected INOCA, 13 women with HFpEF, and 8 reference control women. Myocardial perfusion imaging was performed at rest and with vasodilator stress with intravenous adenosine. Myocardial perfusion reserve index was quantified as the ratio of the upslope of increase in myocardial contrast at stress vs. rest. All CMRI measures were quantified using CVI42 software (Circle Cardiovascular Imaging Inc). Statistical analysis was performed using linear regression models, Fisher's exact tests, ANOVA, or Kruskal-Wallis tests. Results: Age (P = 0.007), Body surface area (0.05) were higher in the HFpEF group. Left ventricular ejection fraction (P = 0.02) was lower among the INOCA and HFpEF groups than reference controls after age adjustment. In addition, there was a graded reduction in myocardial perfusion reserve index in HFpEF vs. INOCA vs. reference controls (1.5 ± 0.3, 1.8 ± 0.3, 1.9 ± 0.3, P = 0.02), which was attenuated with age-adjustment. Conclusion: Reduced myocardial perfusion reserve appears to be a common pathophysiologic feature in INOCA and HFpEF patients.

The Potential Role of Exercise Training and Mechanical Loading on Bone-Associated Skeletal Nerves.

The spatial distribution, innervation, and functional role of the bone-associated skeletal nerves have been previously reported in detail. However, studies examining exercise-induced associations between skeletal nerves and bone metabolism are limited. This review introduces a potential relationship between exercise and the skeletal nerves and discusses how it can contribute to exercise-induced bone anabolism. First, the background and current understanding of nerve fiber types and their functions in the skeleton are provided. Next, the influence of exercise and mechanical loading on the skeletal nervous system is elaborated. Effective synthesis of recent studies could serve as an established baseline for the novel discovery of the effects of exercise on skeletal nerve density and bone anabolic activity in the future. Therefore, this review overviews the existing evidence for the neural control of bone metabolism and the potential positive effects of exercise on the peripheral skeletal nervous system. The influence of exercise training models on the relationships of sensory nerve signals with osteoblast-mediated bone formation and the increased bone volume provides the first insight on the potential importance of exercise training in stimulating positive adaptations in the skeletal nerve-bone interaction and its downstream effect on bone metabolism, thereby highlighting its therapeutic potential in a variety of clinical populations.

Diastolic dysfunction in women with ischemia and no obstructive coronary artery disease: Mechanistic insight from magnetic resonance imaging.

BACKGROUND: Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF); however, the mechanism(s) contributing to this progression remains unclear. Given that diastolic dysfunction is common in women with INOCA, defining mechanisms related to diastolic dysfunction in INOCA could identify therapeutic targets to prevent HFpEF. METHODS: Cardiac MRI was performed in 65 women with INOCA and 12 reference controls. Diastolic function was defined by left ventricular early diastolic circumferential strain rate (eCSRd). Contributors to diastolic dysfunction were chosen a priori as coronary vascular dysfunction (myocardial perfusion reserve index [MPRI]), diffuse myocardial fibrosis (extracellular volume [ECV]), and aortic stiffness (aortic pulse wave velocity [aPWV]). RESULTS: Compared to controls, eCSRd was lower in INOCA (1.61 ± 0.33/s vs. 1.36 ± 0.31/s, P = 0.016); however, this difference was not exaggerated when the INOCA group was sub-divided by low and high MPRI (P > 0.05) nor was ECV elevated in INOCA (29.0 ± 1.9% vs. 28.0 ± 3.2%, control vs. INOCA; P = 0.38). However, aPWV was higher in INOCA vs. controls (8.1 ± 3.2 m/s vs. 6.1 ± 1.5 m/s; P = 0.045), and was associated with eCSRd (r = -0.50, P < 0.001). By multivariable linear regression analysis, aPWV was an independent predictor of decreased eCSRd (standardized ß = -0.39, P = 0.003), as was having an elevated left ventricular mass index (standardized ß = -0.25, P = 0.024) and lower ECV (standardized ß = 0.30, P = 0.003). CONCLUSIONS: These data provide mechanistic insight into diastolic dysfunction in women with INOCA, identifying aortic stiffness and ventricular remodeling as putative therapeutic targets.

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project.

AIMS: Women with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction. METHODS AND RESULTS: Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02-1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73-0.96 95%CI] vs. 0.65 [0.60-0.71 95%CI], respectively, P = 0.007). CONCLUSION: The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty.

BACKGROUNDPhysical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.METHODSHere, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2).RESULTSDuring graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.CONCLUSIONSeveral-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.FUNDINGThis work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

Impact of bariatric surgery on cerebral vascular reactivity and cognitive function: a non-randomized pilot study.

BACKGROUND: Bariatric surgery is an effective long-term weight loss strategy yielding improvements in neurocognitive function; however, the mechanism(s) responsible for these improvements remains unclear. Here, we assessed the feasibility of using magnetic resonance imaging (MRI) to evaluate whether cerebral vascular reactivity (CVR) is impaired in severely obese bariatric surgery candidates compared with normal weight healthy controls and whether CVR improves following bariatric surgery. We also investigated whether changes in CVR were associated with changes in cognitive function. METHODS: Bariatric surgery candidates (n = 6) were compared with normal weight healthy controls of a similar age (n = 10) at baseline, and then reassessed 2 weeks and 14 weeks following sleeve gastrectomy bariatric surgery. Young reference controls (n = 7) were also studied at baseline to establish the range of normal for each outcome measure. Microvascular and macrovascular CVR to hypercapnia (5% CO2) were assessed using blood-oxygen-level-dependent (BOLD) MRI, and changes in the middle cerebral artery (MCA) cross-sectional area, respectively. Cognitive function was assessed using a validated neurocognitive software. RESULTS: Compliance with the CVR protocol was high. Both macro- and micro-cerebrovascular function were highest in the young reference controls. Cognitive function was lower in obese bariatric surgery candidates compared with normal weight controls, and improved by 17% at 2 weeks and 21% by 14 weeks following bariatric surgery. To our surprise, whole-brain CVR BOLD did not differ between obese bariatric surgery candidates and normal weight controls of similar age (0.184 ± 0.101 vs. 0.192 ± 0.034 %BOLD/mmHgCO2), and did not change after bariatric surgery. In contrast, we observed vasoconstriction of the MCA during hypercapnia in 60% of the obese patients prior to surgery, which appeared to be abolished following bariatric surgery. Improvements in cognitive function were not associated with improvements in either CVR BOLD or MCA vasodilation after bariatric surgery. CONCLUSIONS: Assessing CVR responses to a hypercapnic challenge with MRI was feasible in severely obese bariatric patients. However, no changes in whole-brain BOLD CVR were observed following bariatric surgery despite improvements in cognitive function. We recommend that future large trials assess CVR responses to cognitive tasks (rather than hypercapnia) to better define the mechanisms responsible for cognitive function improvements following bariatric surgery.

Cardiac Structure and Function in Well-Healed Burn Survivors.

Long-term burn survivors have reduced aerobic capacity, placing them at increased risk for cardiovascular disease, morbidity, and mortality. However, the exact mechanism contributing to a reduced aerobic capacity remains incompletely understood, but may be related to adverse cardiovascular remodeling. Therefore, it was hypothesized that well-healed burn survivors would exhibit adverse left ventricular (LV) remodeling and impaired LV function. To test this hypothesis, 22 well-healed moderately burned individuals (age: 41 ± 14 years; BMI: 27.7 ± 5.4 kg/m2; male/female: 12/10; extent of burn: 37 ± 12 %BSA), 11 well-healed severely burned individuals (age: 43 ± 12 years; BMI: 29.5 ± 5.8 kg/m2; male/female: 8/3; extent of burn: 73 ± 11 %BSA), and 12 healthy, age-matched controls (age: 34 ± 9 years; BMI: 28.6 ± 5.2 kg/m2; male/female: 5/7) were enrolled in the study. All subjects were sedentary, performing less than 30 minutes of aerobic exercise per day, 3 days per week. LV morphology and function were assessed via cardiac magnetic resonance imaging. In contrast to the hypothesis, neither the presence nor severity of burn injury adversely affected LV morphology or function, when compared with equally sedentary nonburned controls. However, of note, LV mass of all three groups was in the lowest 5th percentile compared with normative values. Finally, group differences in LV morphology were largely explained by differences in aerobic capacity. Taken together, these data suggest a prior burn injury itself does not result in pathological remodeling of the LV and support a role for aerobic exercise training to improve cardiac function.