Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions.

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) ß-adrenergic (ß-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that ß-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.

A Combined Analysis of Peak and Submaximal Exercise Parameters in Delineating Underlying Mechanisms of Sex Differences in Healthy Adolescents.

Peak exercise parameters are considered the gold standard to quantify cardiac reserve in cardiopulmonary exercise testing (CPET). We studied whether submaximal parameters would add additional values in analyzing sex differences in CPET. We reviewed CPET of age-matched healthy male and female adolescents by cycle ergometer. Besides peak parameters, submaximal CPET parameters, including ventilatory anaerobic threshold (VAT), oxygen uptake efficiency slope (OUES), and submaximal slopes of Δoxygen consumption (ΔVO2)/Δwork rate (ΔWR), Δheart rate (ΔHR)/ΔWR, ΔVO2/ΔHR, and Δminute ventilation (ΔVE)/ΔCO2 production (ΔVCO2), were obtained. We studied 35 male and 40 female healthy adolescents. Peak VO2 (pVO2), peak oxygen pulse (pOP), and VAT were significantly lower in females than males (1.9 ± 0.4 vs. 2.5 ± 0.6 L/min; 10 ± 2.0 vs. 13.2 ± 3.5 ml/beat; 1.23 ± 0.3 vs. 1.52 ± 0.5 L/min, respectively, all p < 0.005). Females showed significantly lower pVO2, VAT, and OUES with the same body weight than males, implying higher skeletal muscle mass in males. When simultaneously examining ΔHR/ΔWR and pOP, females showed higher dependency on increases in HR than in stroke volume. Females demonstrated significantly lower pOP with the same levels of ΔVO2/ΔHR, suggesting more limited exercise persistence than males under an anaerobic condition at peak exercise. Oxygen uptake efficiency in relation to peak VE was significantly higher in males. There was no sex difference in either ΔVO2/ΔWR or ΔVE/ΔVCO2. Combinational assessment of peak and submaximal CPET parameters delineates the multiple mechanisms that contribute to the sex differences in exercise performance.

Exercise as a diagnostic and therapeutic tool for preventing cardiovascular morbidity in breast cancer patients- the BReast cancer EXercise InTervention (BREXIT) trial protocol.

BACKGROUND: Anthracycline chemotherapy (AC) is an efficacious (neo) adjuvant treatment for early-stage breast cancer (BCa), but is associated with an increased risk of cardiac dysfunction and functional disability. Observations suggest that regular exercise may be a useful therapy for the prevention of cardiovascular morbidity but it is yet to be interrogated in a large randomised trial. The primary aims of this study are to: 1) determine if 12-months of ET commenced at the onset of AC can reduce the proportion of BCa patients with functional disability (peak VO2, < 18 ml/kg/min), and 2) compare current standard-of-care for detecting cardiac dysfunction (resting left-ventricular ejection fraction assessed from 3-dimensional echocardiography) to measures of cardiac reserve (peak exercise cardiac output assessed from exercise cardiac magnetic resonance imaging) for predicting the development of functional disability 12-months following AC. Secondary aims are to assess the effects of ET on VO2peak, left ventricular morphology, vascular stiffness, cardiac biomarkers, body composition, bone mineral density, muscle strength, physical function, habitual physical activity, cognitive function, and multidimensional quality of life. METHODS: One hundred women with early-stage BCa (40-75 years) scheduled for AC will be randomized to 12-months of structured exercise training (n = 50) or a usual care control group (n = 50). Participants will be assessed at baseline, 4-weeks following completion of AC (4-months) and at 12-months for all measures. DISCUSSION: Women diagnosed with early-stage BCa have increased cardiac mortality. More sensitive strategies for diagnosing and preventing AC-induced cardiovascular impairment are critical for reducing cardiovascular morbidity and improving long-term health outcomes in BCa survivors. TRIAL REGISTRATION: Australia & New Zealand Clinical Trials Registry (ANZCTR), ID: 12617001408370 . Registered on 5th of October 2017.

Clinical Impact of Changes in Hemodynamic Indices of Contractile Function During Treatment of Acute Decompensated Heart Failure.

BACKGROUND: The objective of this work was to determine the impact of improving right ventricular versus left ventricular stroke work indexes (RVSWI vs LVSWI) during therapy for acute decompensated heart failure (ADHF). METHODS AND RESULTS: Cox proportional hazards regression and logistic regression were used to analyze key factors associated with outcomes in 175 patients (mean age 56.7 ± 13.6 years, 29.1% female) with hemodynamic data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial. In this cohort, 28.6% and 69.7%, respectively, experienced the outcomes of death, transplantation, or ventricular assist device implantatation (DVADTX) and DVADTX or HF rehospitalization (DVADTXHF) during 6 months of follow-up. Increasing RVSWI (ΔRVSWI) from baseline to discharge was associated with a decrease in DVADTXHF (hazard ratio [HR] 0.923, 95% confidence interval [CI] 0.871-0.979) per 0.1 mm Hg⋅L⋅m-2 increase); however, increasing LVSWI (ΔLVSWI) had only a nonsignificant association with decreased DVADTXHF (P = .11) In a multivariable model, patients with ΔRVSWI ≤1.07 mm Hg⋅L⋅m-2 and ΔLVSWI ≤4.57 mm Hg⋅L⋅m-2 had a >2-fold risk of DVADTXHF (HR 2.05, 95% CI 1.23-3.41; P = .006). CONCLUSION: Compared with left ventricular stroke work, increasing right ventricular stroke work during treatment of ADHF was associated with better outcomes. The results promise to inform optimal hemodynamic targets for ADHF.

Left ventricular-arterial coupling is associated with prolonged mechanical ventilation in severe post-cardiac surgery patients: an observational study.

BACKGROUND: Weaning post-cardiac surgery patients from mechanical ventilation (MV) poses a big challenge to these patients. Optimized left ventricular-arterial coupling (VAC) may be crucial for reducing the MV duration of these patients. However, there is no research exploring the relationship between VAC and the duration of MV. We performed this study to investigate the relationship between left ventricular-arterial coupling (VAC) and prolonged mechanical ventilation (MV) in severe post-cardiac surgery patients. METHODS: This was a single-center retrospective study of 56 severe post-cardiac surgery patients from January 2015 to December 2017 at the Department of Critical Care Medicine of Peking Union Medical College Hospital. Patients were divided into two groups according to the duration of MV (PMV group: prolonged mechanical ventilation group, MV > 6 days; Non-PMV group: non-prolonged mechanical ventilation group, MV ≤ 6 days). Hemodynamics and tissue perfusion data were collected or calculated at admission (T0) and 48 h after admission (T1) to the ICU. RESULTS: In terms of hemodynamic and tissue perfusion data, there were no differences between the two groups at admission (T0). Compared with the non-prolonged MV group after 48 h in the ICU (T1), the prolonged MV group had significantly higher values for heart rate (108 ± 13 vs 97 ± 12, P = 0.018), lactate (2.42 ± 1.24 vs.1.46 ± 0.58, P < 0.001), and Ea/Ees (5.93 ± 1.81 vs. 4.05 ± 1.20, P < 0.001). Increased Ea/Ees (odds ratio, 7.305; 95% CI, 1.181-45.168; P = 0.032) and lactate at T1 (odds ratio, 17.796; 95% CI, 1.377-229.988; P = 0.027) were independently associated with prolonged MV. There was a significant relationship between Ea/EesT1 and the duration of MV (r = 0.512, P < 0.01). The area under the receiver operating characteristic (AUC) of the left VAC for predicting prolonged MV was 0.801, and the cutoff value for Ea/Ees was 5.12, with 65.0% sensitivity and 90.0% specificity. CONCLUSIONS: Left ventricular-arterial coupling was associated with prolonged mechanical ventilation in severe post-cardiac surgery patients. The assessment and optimization of left VAC might be helpful in reducing duration of MV in these patients.

Impaired ventricular filling limits cardiac reserve during submaximal exercise in people with type 2 diabetes.

BACKGROUND: Attenuated increases in ventricular stroke volume during exercise are common in type 2 diabetes and contribute to reduced aerobic capacity. The purpose of this study was to determine whether impaired ventricular filling or reduced systolic ejection were responsible for the attenuated stroke volume reserve in people with uncomplicated type 2 diabetes. METHODS: Peak aerobic capacity and total blood volume were measured in 17 people with diabetes and 16 non-diabetic controls with no evidence of cardiovascular disease. Left ventricular volumes and other systolic and diastolic functional parameters were measured with echocardiography at rest and during semi-recumbent cycle ergometry at 40 and 60% of maximal aerobic power and compared between groups. RESULTS: People with diabetes had reduced peak aerobic capacity and heart rate reserve, and worked at lower workloads than non-diabetic controls. Cardiac output, stroke volume and ejection fraction were not different at rest, but increased less in people with diabetes during exercise. Left ventricular end systolic volume was not different between groups in any condition but end diastolic volume, although not different at rest, was smaller in people with diabetes during exercise. Total blood volume was not different between the groups, and was only moderately associated with left ventricular volumes. CONCLUSIONS: People with type 2 diabetes exhibit an attenuated increase in stroke volume during exercise attributed to an inability to maintain/increase left ventricular filling volumes at higher heart rates. This study is the first to determine the role of filling in the blunted cardiac reserve in adults with type 2 diabetes.

Evaluating cardiac physiology through echocardiography in bottlenose dolphins: using stroke volume and cardiac output to estimate systolic left ventricular function during rest and following exercise.

Heart-rate (fH) changes during diving and exercise are well documented for marine mammals, but changes in stroke volume (SV) and cardiac output (CO) are much less known. We hypothesized that both SV and CO are also modified following intense exercise. Using transthoracic ultrasound Doppler at the level of the aortic valve, we compared blood flow velocities in the left ventricle and cardiac frequencies during rest and at 1, 3 and 4 min after a bout of exercise in 13 adult bottlenose dolphins (Tursiops truncatus, six male and seven female, body mass range 143-212 kg). Aortic cross-sectional area and ventricle blood velocity at the aortic valve were used to calculate SV, which together with fH provided estimates of left CO at rest and following exercise. fH and SV stabilized approximately 4-7 s following the post-respiratory tachycardia, so only data after the fH had stabilized were used for analysis and comparison. There were significant increases in fH, SV and CO associated with each breath. At rest, fH, SV and CO were uncorrelated with body mass, and averaged 41±9 beats min(-1), 136±19 ml and 5514±1182 l min(-1), respectively. One minute following high intensity exercise, the cardiac variables had increased by 104±43%, 63±11% and 234±84%, respectively. All variables remained significantly elevated in all animals for at least 4 min after the exercise. These baseline values provide the first data on SV and CO in awake and unrestrained cetaceans in water.

Cardiac function of the naked mole-rat: ecophysiological responses to working underground.

The naked mole-rat (NMR) is a strictly subterranean rodent with a low resting metabolic rate. Nevertheless, it can greatly increase its metabolic activity to meet the high energetic demands associated with digging through compacted soils in its xeric natural habitat where food is patchily distributed. We hypothesized that the NMR heart would naturally have low basal function and exhibit a large cardiac reserve, thereby mirroring the species' low basal metabolism and large metabolic scope. Echocardiography showed that young (2-4 yr old) healthy NMRs have low fractional shortening (28 ± 2%), ejection fraction (43 ± 2%), and cardiac output (6.5 ± 0.4 ml/min), indicating low basal cardiac function. Histology revealed large NMR cardiomyocyte cross-sectional area (216 ± 10 µm(2)) and cardiac collagen deposition of 2.2 ± 0.4%. Neither of these histomorphometric traits was considered pathological, since biaxial tensile testing showed no increase in passive ventricular stiffness. NMR cardiomyocyte fibers showed a low degree of rotation, contributing to the observed low NMR cardiac contractility. Interestingly, when the exercise mimetic dobutamine (3 µg/g ip) was administered, NMRs showed pronounced increases in fractional shortening, ejection fraction, cardiac output, and stroke volume, indicating an increased cardiac reserve. The relatively low basal cardiac function and enhanced cardiac reserve of NMRs are likely to be ecophysiological adaptations to life in an energetically taxing environment.

And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat.

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of >31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP. We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography (3 µg/g ip) revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age. NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening does not occur since there are no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs (P < 0.01). However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related increases in diastolic dysfunction in comparison with other species. Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans.

Impaired Ischemia-Reperfusion Responses in the Hearts of Aged Male and Female Offspring of Obese Rats.

Maternal obesity predisposes offspring (F1) to cardiovascular disease. To evaluate basal heart function and ischemia-reperfusion (IR) responses in F1 males and females of obese mothers, female Wistar rats (F0) were fed chow or an obesogenic (MO) diet from weaning through pregnancy and lactation. Non-sibling F1 males and females were weaned to chow at postnatal day (PND) 21 and euthanized at PND 550. Offspring of MO mothers (MOF1) rarely survive beyond PND 650. Hearts were immediately isolated from euthanized F1s and subjected to 30 min ischemia with 20 min reperfusion. Retroperitoneal fat, serum triglycerides, glucose, insulin, and insulin resistance were measured. Baseline left ventricular developed pressure (LVDP) was lower in male and female MOF1 than in controls. After global ischemia, LVDP in control (C) male and female F1 recovered 78 and 83%, respectively, while recovery in MO male and female F1 was significantly lower at 28 and 52%, respectively. Following the IR challenge, MO hearts showed a higher functional susceptibility to reperfusion injury, resulting in lower cardiac reserve than controls in both sexes. Female hearts were more resistant to IR. Retroperitoneal fat was increased in male MOF1 vs. CF1. Circulating triglycerides and insulin resistance were increased in male and female MOF1 vs. CF1. These data show that MO programming reduces F1 cardiac reserve associated with age-related insulin resistance in a sex-specific manner.

Echocardiographic evaluation of cardiac reserve to detect subtle cardiac dysfunction in mice.

AIMS: Cardiac reserve is a sensitive tool for early detection of cardiac dysfunction. However, cardiac reserve assessment by catecholamine stress echocardiography in mice varied in the doses of ß-adrenergic agonists and the time point for measurements, which may lead to inaccurate readouts. This study aims to establish a standardized protocol for assessing cardiac reserve in mice. MAIN METHODS: C57BL/6J mice under isoflurane anesthesia were intraperitoneally injected with varying doses of isoproterenol (Iso), and subjected to echocardiographic measurements. KEY FINDINGS: Heart rate (HR), ejection fraction (EF), fractional shortening (FS), global longitudinal strain (GLS) and strain rate all reached peak values within 1-3 min after Iso injection at doses higher than 0.2 mg/kg. Compared with 0.1 mg/kg Iso, 0.2 mg/kg Iso resulted in higher HR, EF, FS and GLS, whereas doses higher than 0.2 mg/kg did not yield further increase. Cardiac response of female mice recapitulated main characteristics of those of male mice except that female mice displayed higher maximum HR and were more sensitive to higher doses of Iso. Furthermore, the advantages of present stress protocol over conventional baseline echocardiographic measurements were verified in comparisons of exercised vs. sedentary and aged vs. young mice for cardiac function evaluation. SIGNIFICANCE: We developed a reproducible and sensitive approach to evaluate cardiac reserve by continuously monitoring cardiac function every minute for 3 min after 0.2 mg/kg Iso injection. This approach will enable detection of subtle cardiac dysfunction and accelerate innovative research in cardiac pathophysiology.

Novel insights into diminished cardiac reserve in non-obstructive hypertrophic cardiomyopathy from four-dimensional flow cardiac magnetic resonance component analysis.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and diastolic dysfunction, which alter blood flow haemodynamics and are linked with increased risk of adverse clinical events. Four-dimensional flow cardiac magnetic resonance (4D-flow CMR) enables comprehensive characterization of ventricular blood flow patterns. We characterized flow component changes in non-obstructive HCM and assessed their relationship with phenotypic severity and sudden cardiac death (SCD) risk. METHODS AND RESULTS: Fifty-one participants (37 non-obstructive HCM and 14 matched controls) underwent 4D-flow CMR. Left-ventricular (LV) end-diastolic volume was separated into four components: direct flow (blood transiting the ventricle within one cycle), retained inflow (blood entering the ventricle and retained for one cycle), delayed ejection flow (retained ventricular blood ejected during systole), and residual volume (ventricular blood retained for >two cycles). Flow component distribution and component end-diastolic kinetic energy/mL were estimated. HCM patients demonstrated greater direct flow proportions compared with controls (47.9 ± 9% vs. 39.4 ± 6%, P = 0.002), with reduction in other components. Direct flow proportions correlated with LV mass index (r = 0.40, P = 0.004), end-diastolic volume index (r = -0.40, P = 0.017), and SCD risk (r = 0.34, P = 0.039). In contrast to controls, in HCM, stroke volume decreased with increasing direct flow proportions, indicating diminished volumetric reserve. There was no difference in component end-diastolic kinetic energy/mL. CONCLUSION: Non-obstructive HCM possesses a distinctive flow component distribution pattern characterised by greater direct flow proportions, and direct flow-stroke volume uncoupling indicative of diminished cardiac reserve. The correlation of direct flow proportion with phenotypic severity and SCD risk highlight its potential as a novel and sensitive haemodynamic measure of cardiovascular risk in HCM.

Heart Rate Response Predicts 6-Minutes Walking Distance in Pulmonary Arterial Hypertension.

Because the 6-minute walking test (6MWT) is a self-paced submaximal test, the 6-minute walking distance (6MWD) is substantially influenced by individual effort level and physical condition, which is difficult to quantify. We aimed to explore the optimal indicator reflecting the perceived effort level during 6MWT. We prospectively enrolled 76 patients with pulmonary arterial hypertension and 152 healthy participants; they performed 2 6MWTs at 2 different speeds: (1) at leisurely speed, as performed in daily life without extra effort (leisure 6MWT) and (2) an increased walking speed, walking as the guideline indicated (standard 6MWT). The factors associated with 6MWD during standard 6MWT were investigated using a multiple linear regression analysis. The heart rate (HR) and Borg score increased and oxygen saturation (SpO2) decreased after walking in 2 6MWTs in both groups (all p <0.001). The ratio of difference in HR before and after each test (ΔHR) to HR before walking (HRat rest) and the difference in SpO2 (ΔSpO2) and Borg (ΔBorg) before and after each test were all significantly higher in both groups after standard 6MWT than after leisure 6MWT (all p <0.001). Multiple linear regression analysis revealed that ΔHR/HRat rest was an independent predictor of 6MWD during standard 6MWT in both groups (both p <0.001, adjusted R2 = 0.737 and 0.49, respectively). 6MWD and ΔHR/HRat rest were significantly lower in patients than in healthy participants (both p <0.001) and in patients with cardiac functional class III than in patients with class I/II (both p <0.001). In conclusion, ΔHR/HRat rest is a good reflector of combined physical and effort factors. HR response should be incorporated into 6MWD to better assess a participant's exercise capacity.

Research Update on the Pathophysiological Mechanisms of Heart Failure with Preserved Ejection Fraction.

Heart failure (HF) is a serious clinical syndrome, usually occurs at the advanced stage of various cardiovascular diseases, featured by high mortality and rehospitalization rate. According to left ventricular (LV) ejection fraction (LVEF), HF has been categorized as HF with reduced EF (HFrEF; LVEF<40%), HF with mid-range EF (HFmrEF; LVEF 40-49%), and HF with preserved EF (HFpEF; LVEF ≥50%). HFpEF accounts for about 50% of cases of heart failure and has become the dominant form of heart failure. The mortality of HFpEF is similar to that of HFrEF. There are no welldocumented treatment options that can reduce the morbidity and mortality of HFpEF now. Understanding the underlying pathological mechanisms is essential for the development of novel effective therapy options for HFpEF. In recent years, significant research progress has been achieved on the pathophysiological mechanism of HFpEF. This review aimed to update the research progress on the pathophysiological mechanism of HFpEF.

Ventricular myocardial response to exercise in patients with Fontan circulation.

BACKGROUND: Exercise stress echocardiography has been used to assess myocardial reserve in various heart diseases. This study examined the ventricular myocardial response to exercise in Fontan patients using exercise stress echocardiography. METHODS: Twenty-five Fontan patients and 19 control subjects underwent semi-supine bicycle exercise stress echocardiography in this prospective, single-center, cross-sectional study. Pulsed-wave Doppler tissue imaging peak systolic (s') and diastolic (e') velocities, longitudinal strain and systolic strain rate, and early diastolic strain rate data at rest and at peak exercise were obtained for the systemic ventricle. The myocardial reserve of functional parameters was calculated as the difference between peak exercise and rest. RESULTS: Inter- and intra-observer reliability were both high for exercise stress echocardiography measurements. Compared with controls, Fontan patients had significantly lower s', e', longitudinal systolic strain and strain rate, and early diastolic longitudinal strain rate at rest and at peak exercise as well as reduced myocardial reserve. CONCLUSIONS: Fontan patients have markedly reduced myocardial reserve during exercise. The use of exercise stress echocardiography assessment may improve the clinical management of Fontan patients.

Impaired myocardial reserve underlies reduced exercise capacity and heart rate recovery in preterm-born young adults.

AIMS: We tested the hypothesis that the known reduction in myocardial functional reserve in preterm-born young adults is an independent predictor of exercise capacity (peak VO2) and heart rate recovery (HRR). METHODS AND RESULTS: We recruited 101 normotensive young adults (n = 47 born preterm; 32.8 ± 3.2 weeks' gestation and n = 54 term-born controls). Peak VO2 was determined by cardiopulmonary exercise testing (CPET), and lung function assessed using spirometry. Percentage predicted values were then calculated. HRR was defined as the decrease from peak HR to 1 min (HRR1) and 2 min of recovery (HRR2). Four-chamber echocardiography views were acquired at rest and exercise at 40% and 60% of CPET peak power. Change in left ventricular ejection fraction from rest to each work intensity was calculated (EFΔ40% and EFΔ60%) to estimate myocardial functional reserve. Peak VO2 and per cent of predicted peak VO2 were lower in preterm-born young adults compared with controls (33.6 ± 8.6 vs. 40.1 ± 9.0 mL/kg/min, P = 0.003 and 94% ± 20% vs. 108% ± 25%, P = 0.001). HRR1 was similar between groups. HRR2 decreased less in preterm-born young adults compared with controls (-36 ± 13 vs. -43 ± 11 b.p.m., P = 0.039). In young adults born preterm, but not in controls, EFΔ40% and EFΔ60% correlated with per cent of predicted peak VO2 (r2 = 0.430, P = 0.015 and r2 = 0.345, P = 0.021). Similarly, EFΔ60% correlated with HRR1 and HRR2 only in those born preterm (r2 = 0.611, P = 0.002 and r2 = 0.663, P = 0.001). CONCLUSIONS: Impaired myocardial functional reserve underlies reductions in peak VO2 and HRR in young adults born moderately preterm. Peak VO2 and HRR may aid risk stratification and treatment monitoring in this population.

Reduced cardiac response to the adrenergic system is a key limiting factor for physical capacity in old age.

Ageing is associated with a progressive reduction in physical capacity reducing quality of life. One key physiological limitation of physical capacity that deteriorates in a progressive age-dependent manner is cardiac reserve. Peak cardiac output falls progressively with advancing age such that in extreme old age there is limited ability to enhance cardiac output beyond basal function as is required to support the increased metabolic needs of physical activity. This loss of dynamic range in cardiac output associates with a progressive reduction in the heart's response to adrenergic stimulation. A combination of decreases in the expression and functioning of beta1 adrenergic receptors partially underlies this change. Changes in end effector proteins also have a role to play in this decline. Alterations in the efficiency of excitation-contraction coupling contribute to the reduced chronotropic, inotropic and lusitropic responses of the aged heart. Moderate to vigorous endurance exercise training however has some potential to counter elements of these changes. Further studies are required to fully elucidate the key pivotal mechanisms involved in the age-related loss of response to adrenergic signalling to allow targeted therapeutic strategies to be developed with the aim of preserving physical capacity in advanced old age.

Hemodynamic Heterogeneity of Reduced Cardiac Reserve Unmasked by Volumetric Exercise Echocardiography.

BACKGROUND: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. PURPOSE: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. METHODS: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients (age 59.8 ± 11.4 years; ejection fraction = 63 ± 8%) referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values ≤2.0). Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. RESULTS: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve (odds ratio [OR]: 5.610; 95% confidence intervals [CI]: 4.025 to 7.821), chronotropic incompetence (OR: 3.923, 95% CI: 2.915 to 5.279), and abnormal LVCR (OR: 1.579; 95% CI: 1.105 to 2.259) were independently associated with lowest tertile of cardiac index reserve at peak stress. CONCLUSIONS: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.

The Need for a Physiological Classification of Hemorrhagic Shock.

Classifications mean to conceptualize in a cluster and rapidly summarize the assessment and management of a clinical scenario. In the specific case of a hemorrhagic shock (HS), a classification should serve the purpose of allowing a rapid clinical assessment of the shock level and the earliest or right timing of source control, possibly also on whether to apply damage control surgery (DCS) strategy or not. ATLS® classification of HS is not sensitive and specific enough to help decision-making in reference to the timing of management, based only on the amount of blood loss that may be or may not rightly estimated, for example, blood loss on the floor in penetrating injuries before theatre. Moreover, it focuses also on other parameters, which are taken singularly, instead of the individual generalized physiological response to hemorrhage, which is the core by definition of the derangement we call "shock." It is unhelpful, difficult, and impractical to apply as well. A new classification, which may well be called as the "physiological HS classification" or "therapeutic HS classification," was proposed since 2010, following the new developments on microcirculation and an already going-on sensible praxis among some trauma surgeons. It bases on some physiological considerations such as the significance of fluid-blood resistant hypotension, body natural hemostatic mechanisms, the right definition of shock, and the relevance that hemorrhage-triggered ischemia-reperfusion toxemia and systemic inflammatory response have in critical illness scenarios as secondary insults from ischemia, which is what we mean to prevented with DCS. The key factor remains the persistence of hypotension, following fluid challenge.