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Interest in ketones as a cardiac "super fuel" has grown significantly following reports of a marked increase in cardiac output after exogenous ketone administration in heart failure. However, the extent to which this increase in cardiac output is related to changes in cardiac contractility, and dependent on the presence of heart failure, remains incompletely understood. Therefore, we performed a randomized, double-blind, placebo-controlled study of oral ketone ester in young healthy volunteers. Baseline cardiac magnetic resonance imaging was performed and repeated every 15 min for 60 min after ketone and placebo ingestion to assess changes in left ventricular function. As expected, circulating β-hydroxybutyrate increased rapidly after ketone ingestion, but did not change with placebo (interaction: P < 0.001). Consistent with prior investigations, ketone ingestion resulted in an average 1 L/min increase in cardiac output after 60 min that did not occur with placebo (interaction: P = 0.026). This increase in cardiac output was primarily driven by an increase in heart rate after ketone ingestion (interaction: P = 0.018), with only a modest increase in stroke volume (interaction: P = 0.037). Changes in left ventricular strain and twist mechanics were limited. Taken together, the increase in cardiac output following an acute elevation in circulating β-hydroxybutyrate is primarily driven by changes in cardiac chronotropy, with minimal inotropic contribution. NEW & NOTEWORTHY In this randomized, double-blind, placebo-controlled study of oral ketone ester in young healthy volunteers, we show a marked increase in cardiac output (∼1 L/min), driven primarily by changes in chronotropy. The cardiac magnetic resonance imaging data support the limited role for inotropy.

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 V̇o 2 ). 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/m 2 ) 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 V̇o 2 . 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 V̇o 2 ( 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 V̇o 2 , 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 V̇o 2 . In contrast, the data show a much stronger relationship between elevated LV filling pressures and exercise intolerance, refocusing future therapeutic priorities.

Purpose of the Review: This review summarizes sex-related changes in the heart and vasculature that occur with aging, both in the presence and absence of cardiovascular disease (CVD)., Recent Findings: In the presence of CVD risk factors and/or overt CVD, sex-specific changes in the number of cardiomyocytes, extent of the myocardial extracellular matrix, and myocellular hypertrophy promote unique patterns of LV remodeling in men and women. In addition, age- and sex-specific vascular stiffening is also well established, driven by changes in endothelial dysfunction, elastin-collagen content, microvascular dysfunction, and neurohormonal signaling. Together, these changes in LV chamber geometry and morphology, coupled with heightened vascular stiffness, appear to drive both age-related increases in systolic function and declines in diastolic function, particularly in postmenopausal women. Accordingly, estrogen has been implicated as a key mediator, given its direct vasodilating properties, association with nitric oxide excretion, and involvement in myocellular Ca 2+ handling, mitochondrial energy production, and oxidative stress. The culmination of the abovementioned sex-specific cardiac and vascular changes across the lifespan provides important insight into heart failure development, particularly of the preserved ejection fraction variety, while offering promise for future preventive strategies and therapeutic approaches.

Background: The role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients., Methods: We searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients., Results: 18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI -0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF., Conclusions: In clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2018. Published by Elsevier B.V.)

Background: Cycle exercise echocardiography is a useful tool to "unmask" diastolic dysfunction; however, this approach can be limited by respiratory and movement artifacts. Isometric handgrip avoids these issues while reproducibly increasing afterload and myocardial oxygen demand., Hypothesis: Isometric handgrip echocardiography (IHE) can differentiate normal from abnormal diastolic function., Methods: First recruited 19 young healthy individuals (mean age, 24 ± 4 years) to establish the "normal" response. To extend these observations to a more at-risk population, we performed IHE on 17 elderly individuals (mean age, 72 ± 6 years) with age-related diastolic dysfunction. The change in the ratio of mitral valve inflow velocity to lateral wall tissue velocity (E/e'), a surrogate for left ventricular filling pressure, was used to assess the diastolic stress response in each group., Results: In the young subjects, isometric handgrip increased heart rate and mean arterial pressure (25 ± 12 bpm and 26 ± 17 mmHg, respectively), whereas E/e' changed minimally (0.6 ± 0.9). In the elderly subjects, heart rate and mean arterial pressure were similarly increased with isometric handgrip (19 ± 16 bpm and 25 ± 11 mmHg, respectively), whereas E/e' increased more dramatically (2.3 ± 1.7). Remarkably, 11 of the 17 elderly subjects had an abnormal diastolic response (ΔE/e': 3.4 ± 1.1), whereas the remaining 6 elderly subjects showed very little change (ΔE/e': 0.3 ± 0.7), independent of age or the change in myocardial oxygen demand., Conclusions: IHE is a simple, effective tool for evaluating diastolic function during simulated activities of daily living., (© 2017 Wiley Periodicals, Inc.)

Low cardiorespiratory fitness (CRF) and obesity are significant risk factors for heart failure (HF). However, given the inverse association between CRF and obesity, the independent contributions of low CRF and adiposity toward HF risk are not well established. We evaluated the association of CRF and measures of adiposity with left ventricular (LV) peak systolic strain-a subclinical measure of LV dysfunction-among the Dallas Heart Study phase II participants without cardiovascular disease who had CRF estimated using a submaximal treadmill test and LV systolic circumferential strain assessment by tissue-tagged cardiac magnetic resonance imaging. Peak midwall systolic circumferential strain (Ecc) was determined by harmonic phase imaging. Associations of CRF and adiposity measures with Ecc were determined using adjusted linear regression analysis. A total of 1,617 participants were included in the analysis. After adjustment for baseline risk factors, higher waist circumference (WC) and lower CRF were associated with higher Ecc (WC: β = 0.07; p = 0.01; CRF: β = -0.17; p = < 0.0001), whereas % body fat and body mass index were not associated with Ecc. The relationship between WC and Ecc was attenuated completely after additional adjustment for CRF. In contrast, the association between CRF and Ecc did not attenuate after additional adjustment for WC and other measures of LV structure and function (β = -0.18; p = < 0.0001). Taken together, our study findings suggest that lower CRF, but not measures of adiposity, is associated with greater impairment in LV strain independent of LV mass and ejection fraction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Patients with coronary microvascular dysfunction (CMD) often have diastolic dysfunction, representing an important therapeutic target. Ranolazine-a late sodium current inhibitor-improves diastolic function in animal models and subjects with obstructive coronary artery disease (CAD)., Hypothesis: We hypothesized that ranolazine would beneficially alter diastolic function in CMD., Methods: To test this hypothesis, we performed retrospective tissue tracking analysis to evaluate systolic/diastolic strain, using cardiac magnetic resonance imaging cine images acquired in a recently completed, randomized, double-blind, placebo-controlled, crossover trial of short-term ranolazine in subjects with CMD and from 43 healthy reference controls., Results: Diastolic strain rate was impaired in CMD vs controls (circumferential diastolic strain rate: 99.9% ± 2.5%/s vs 120.1% ± 4.0%/s, P = 0.0003; radial diastolic strain rate: -199.5% ± 5.5%/s vs -243.1% ± 9.6%/s, P = 0.0008, case vs control). Moreover, peak systolic circumferential strain (CS) and radial strain (RS) were also impaired in cases vs controls (CS: -18.8% ± 0.3% vs -20.7% ± 0.3%; RS: 35.8% ± 0.7% vs 41.4% ± 0.9%; respectively; both P < 0.0001), despite similar and preserved ejection fraction. In contrast to our hypothesis, however, we observed no significant changes in left ventricular diastolic function in CMD cases after 2 weeks of ranolazine vs placebo., Conclusions: The case-control comparison both confirms and extends our prior observations of diastolic dysfunction in CMD. That CMD cases were also found to have subclinical systolic dysfunction is a novel finding, highlighting the utility of this retrospective approach. In contrast to previous studies in obstructive CAD, ranolazine did not improve diastolic function in CMD., (© 2016 Wiley Periodicals, Inc.)

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function., (Copyright © 2016 the American Physiological Society.)

The ventricular response to passive heat stress has predominantly been studied in the supine position. It is presently unclear how acute changes in venous return influence ventricular function during heat stress. To address this question, left ventricular (LV) systolic and diastolic function were studied in 17 healthy men (24.3 ± 4.0 yr; mean ± SD), using two-dimensional transthoracic echocardiography with Doppler ultrasound, during tilt-table positioning (supine, 30° head-up tilt, and 30° head-down tilt), under normothermic and passive heat stress (core temperature 0.8 ± 0.1°C above baseline) conditions. The supine heat stress LV volumetric and functional response was consistent with previous reports. Combining head-up tilt with heat stress reduced end-diastolic (25.2 ± 4.1%) and end-systolic (65.4 ± 10.5%) volume from baseline, whereas heart rate (37.7 ± 2.0%), ejection fraction (9.4 ± 2.4%), and LV elastance (37.7 ± 3.6%) increased, and stroke volume (-28.6 ± 9.4%) and early diastolic inflow (-17.5 ± 6.5%) and annular tissue (-35.6 ± 7.0%) velocities were reduced. Combining head-down tilt with heat stress restored end-diastolic volume, whereas LV elastance (16.8 ± 3.2%), ejection fraction (7.2 ± 2.1%), and systolic annular tissue velocities (22.4 ± 5.0%) remained elevated above baseline, and end-systolic volume was reduced (-15.3 ± 3.9%). Stroke volume and the early and late diastolic inflow and annular tissue velocities were unchanged from baseline. This investigation extends previous work by demonstrating increased LV systolic function with heat stress, under varied levels of venous return, and highlights the preload dependency of early diastolic function during passive heat stress.

We examined biventricular function during passive heat stress in endurance trained (ET) and untrained (UT) men to evaluate whether aerobic fitness alters the volumetric response. Body temperature was elevated ~0.8°C above baseline in 20 healthy men (10 ET, 64.4 ± 3.0 ml·kg(-1)·min(-1); and 10 UT, 46.3 ± 6.2 ml·kg(-1)·min(-1)) by circulating warm water (50°C) throughout a tube-lined suit. Cardiac magnetic resonance imaging was used to measure biventricular volumes, function, filling velocities, volumetric flow rates, and left ventricular (LV) twist and circumferential strain at baseline (BL) and after 45 min of heat stress. In both groups, passive heat stress reduced biventricular end-diastolic (ET, -19.5 ± 24.0 ml; UT, -25.1 ± 23.8 ml) and end-systolic (ET, -15.9 ± 8.8 ml; UT, -17.6 ± 7.9 ml) volumes and left atrial volume (ET, -19.2 ± 11.6 ml; UT, -15.0 ± 12.7 ml) and significantly increased heart rate (ET, 29.3 ± 9.0 beats/min; UT, 31.7 ± 10.4 beats/min) and cardiac output (ET, 3.8 ± 2.2 l/min; UT, 3.2 ± 1.4 l/min) similarly, while biventricular stroke volume was unchanged. There were no between-group differences in any parameter. Heat stress increased (P < 0.05), as a percentage of baseline values, biventricular ejection fraction (ET, 3.4 ± 5.3%; UT, 4.4 ± 3.7%), annular systolic tissue velocities (ET, 32.5 ± 34.9%; UT, 44.0 ± 38.1%), and peak LV twist (ET, 51.6 ± 59.7%; UT, 59.7 ± 54.2%) and untwisting rates (ET, 45.5 ± 42.3%; UT, 51.8 ± 55.0%) similarly in both groups. Early LV diastolic tissue and blood velocities, volumetric flow rates, and strain rates (diastole) were unchanged with heat stress in both groups. The present findings indicate that aerobic fitness does not influence the biventricular response to passive heat stress.

The purpose of this study was to examine the effects of the self-contained breathing apparatus (SCBA) on left-ventricular (LV) function at rest and during mild- to moderate-intensity exercise, using 2-dimensional echocardiography. Twenty-three healthy male volunteers exercised on a stair-climber at work rates equivalent to 50%, 60%, 70%, and 80% of peak oxygen consumption. Esophageal pressure LV diastolic and systolic cavity areas, and myocardial areas were acquired during the final minute of each stage of exercise. As expected, the esophageal pressure response during SCBA breathing revealed significantly lower (more negative) inspiratory pressures and higher (more positive) expiratory pressures and, consequently, higher pressure swings, than free breathing (FB). End-diastolic cavity area (EDCA) and end-systolic cavity area (ESCA) were lower with the SCBA than with FB. LV contractility was higher (p < 0.05) with the SCBA, which can partially be explained by decreases in end-systolic wall stress. Therefore, the SCBA was found to decrease LV preload during moderate-intensity exercise, but did not negatively affect stroke area because of a similar reduction in ESCA.

The purpose of this study was to investigate left-ventricular function during strenuous exercise with the self-contained breathing apparatus (SCBA). With the use of two-dimensional echocardiography, images of the left ventricle (LV) were acquired during sustained exercise (3 x 10 min) under two conditions: 1) SCBA, or 2) low resistance breathing valve. Twenty healthy men volunteered for the study, and in each condition subjects wore fire protective equipment. Heart rate, systolic blood pressure, cavity areas during systole and diastole (ESCA and EDCA, respectively), esophageal pressure, ventilation rate, oxygen consumption, perceived physical, thermal and respiratory distress, and core temperature were measured at regular intervals. Urine specific gravity (<1.020 g/ml) and hematological variables were used to infer hydration status. All subjects began both trials in a euhydrated state. No differences were found between conditions for heart rate, systolic blood pressure, ventilation rate, oxygen consumption, perceived distress, or any hematological variables. Peak expiratory esophageal pressure was always higher (P < 0.05), while EDCA and stroke area (SA) were significantly lower (P < 0.05) with the SCBA. ESCA, end-systolic transmural pressure (ESTMP), and LV contractility (ESTMP/ESCA) were similar between conditions. Sustained exercise with fire protective equipment resulted in significant reductions in EDCA, ESCA, and SA from the start of exercise, which was associated with a 6.3 +/- 0.8% reduction in plasma volume, an increase in core temperature (37.0 +/- 0.4 to 38.8 +/- 0.3 degrees C), and a significant increase in heart rate (146.9 +/- 2.1 to 181.7 +/- 2.4 beats/min) throughout exercise. The results from this study support research by others showing that increased intrathoracic pressure reduces LV preload (EDCA); however, the novelty of the present study is that when venous return is compromised by sustained exercise and heat stress, SA cannot be maintained.