Effects of Synchronizing Foot Strike and Cardiac Phase on Exercise Hemodynamics in Patients With Cardiac Resynchronization Therapy: A Within-Subjects Pilot Study to Fine-Tune Cardio-Locomotor Coupling for Heart Failure.

BACKGROUND: Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT. METHODS: Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5-3 mph). Participants were randomly assigned to first walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇o2; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples t tests. RESULTS: V̇o2 was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min; P=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL; P=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min; P=0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg; P=0.007). CONCLUSIONS: In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF.

One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. METHODS: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V-V0)}-1], where "P" is transmural pressure (pulmonary capillary wedge pressure - right atrial pressure), "S" is the pressure asymptote of the curve, "V" is the LV end-diastolic volume index, "V0" is equilibrium volume, and "a" is the constant that characterizes LV myocardial stiffness. RESULTS: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min-1·kg-1, P<0.0001, interaction P=0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min-1·kg-1, P=0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P=0.001). CONCLUSIONS: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03476785.

Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF. METHODS: Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. RESULTS: There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P<0.0001). The LV was less distensible in LVH than in controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (pulmonary capillary wedge pressure - right atrial pressure), LV myocardial stiffness was nearly 30% greater in LVH than in controls (LVH stiffness constant, 0.053±0.027 versus controls, 0.042±0.020, P=0.028). CONCLUSIONS: LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03476785 and NCT02039154.

The impact of 2 years of high-intensity exercise training on a model of integrated cardiovascular regulation.

KEY POINTS: Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non-neural control mechanisms may contribute to changes in heart rate variability. We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2 years of high-intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. The dynamic Starling mechanism gain and arterial-cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34-fold larger than that in the control group after the intervention. In these previously sedentary, otherwise healthy, middle-aged adults, 2 years of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity. ABSTRACT: Assessing the effects of exercise training on cardiovascular variability is challenging because of the complexity of multiple mechanisms. In a prospective, parallel-group, randomized controlled study, we examined the effect of 2 years of high-intensity exercise training on integrated cardiovascular function, which incorporates the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. Sixty-one healthy participants (48% male, aged 53 years, range 52-54 years) were randomized to either 2 years of exercise training (exercise group: n = 34) or control/yoga group (controls: n = 27). Before and after 2 years, subjects underwent a 6 min recording of beat-by-beat pulmonary artery diastolic pressure (PAD), stroke volume index (SV index), systolic blood pressure (sBP) and RR interval measurements with controlled respiration at 0.2 Hz. The dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function were calculated by transfer function gain between PAD and SV index; SV index and sBP; and sBP and RR interval, respectively. Fifty-three participants (controls: n = 25; exercise group: n = 28) completed the intervention. After 2 years, the dynamic Starling mechanism gain (Group × Time interaction: P = 0.008) and the arterial-cardiac baroreflex gain (P = 0.005) were significantly increased in the exercise group but remained unchanged in the controls. There was no change in dynamic arterial elastance in either of the two groups. The integrated cardiovascular function gain in the exercise group increased 1.34-fold, whereas there was no change in the controls (P = 0.02). In these previously sedentary, otherwise healthy middle-aged adults, a 2 year programme of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity, without changing dynamic arterial elastance.

Left Atrial Electromechanical Remodeling Following 2 Years of High-Intensity Exercise Training in Sedentary Middle-Aged Adults.

BACKGROUND: Moderate intensity exercise is associated with a decreased incidence of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk. We evaluated the effects of 24 months of high intensity exercise training on left atrial (LA) mechanical and electric remodeling in sedentary, healthy middle-aged adults. METHODS: Sixty-one participants (53±5 years) were randomized to 10 months of exercise training followed by 14 months of maintenance exercise or stretching/balance control. Fourteen Masters athletes were added for comparison. Left ventricular (LV) and LA volumes underwent 3D echocardiographic assessment, and signal-averaged electrocardiographs for filtered P-wave duration and atrial late potentials were completed at 0, 10, and 24 months. Extended ambulatory monitoring was performed at 0 and 24 months. Within and between group differences from baseline were compared using mixed-effects model repeated-measures analysis. RESULTS: Fifty-three participants completed the study (25 control, 28 exercise) with 88±11% adherence to assigned exercise sessions. In the exercise group, both LA and LV end diastolic volumes increased proportionately (19% and 17%, respectively) after 10 months of training (peak training load). However, only LA volumes continued to increase with an additional 14 months of exercise training (LA volumes 55%; LV end diastolic volumes 15% at 24 months versus baseline; P<0.0001 for all). The LA:LV end diastolic volumes ratio did not change from baseline to 10 months, but increased 31% from baseline in the Ex group ( P<0.0001) at 24 months, without a change in controls. There were no between group differences in the LA ejection fraction, filtered P-wave duration, atrial late potentials, and premature atrial contraction burden at 24 months and no atrial fibrillation was detected. Compared with Masters athletes, the exercise group demonstrated lower absolute LA and LV volumes, but had a similar LA:LV ratio after 24 months of training. CONCLUSIONS: Twenty-four months of high intensity exercise training resulted in LA greater than LV mechanical remodeling with no observed electric remodeling. Together, these data suggest different thresholds for electrophysiological and mechanical changes may exist in response to exercise training, and provide evidence supporting a potential mechanism by which high intensity exercise training leads to atrial fibrillation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02039154.

Preload-corrected dynamic Starling mechanism in patients with heart failure with preserved ejection fraction.

The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume (SV) because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. The purpose of this study was to test whether the LVEDP-SV relationship remained impaired in heart failure with preserved ejection fraction (HFpEF) patients after normalization of LVEDP. Right heart catheterization and model-flow analysis of the arterial pressure waveform were performed while preload was manipulated using lower-body negative pressure to alter LVEDP. The DSM was compared at similar levels of LVEDP between HFpEF patients ( n = 10) and age-matched healthy controls ( n = 12) (HFpEF vs. CONTROLS: 10.9 ± 3.8 vs. 11.2 ± 1.3 mmHg, P = 1.00). Transfer function analysis between diastolic pulmonary artery pressure (PAD) representing dynamic changes in LVEDP vs. SV index was applied to obtain gain and coherence of the DSM. The DSM gain was significantly lower in HFpEF patients than in the controls, even at a similar level of LVEDP (0.46 ± 0.19 vs. 0.99 ± 0.39 ml·m-2·mmHg-1, P = 0.0018). Moreover, the power spectral density of PAD, the input variability, was greater in the HFpEF group than the controls (0.75 ± 0.38 vs. 0.28 ± 0.26 mmHg2, P = 0.01). Conversely, the power spectral density of SV index, the output variability, was not different between the groups ( P = 0.97). There was no difference in the coherence, which confirms the reliability of the linear transfer function between the two groups (0.71 ± 0.13 vs. 0.77 ± 0.19, P = 0.87). The DSM gain in HFpEF patients is impaired compared with age-matched controls even at a similar level of LVEDP, which may reflect intrinsic LV diastolic dysfunction and incompetence of ventricular-arterial coupling. NEW & NOTEWORTHY The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. Although the DSM gain is impaired in heart failure with preserved ejection fraction (HFpEF) patients, it is not clear whether this is because of higher LVEDP or left-ventricular diastolic dysfunction. The DSM gain in HFpEF patients is severely impaired, even at a similar level of LVEDP, which may reflect intrinsic left-ventricular diastolic dysfunction.

Effect of pulsatile and nonpulsatile flow on cerebral perfusion in patients with left ventricular assist devices.

BACKGROUND: Insertion of a left ventricular assist device (LVAD) is an accepted therapy for advanced heart failure patients. However, the effects on end-organ perfusion, including cerebral autoregulation, are unclear in the presence of reduced pulsatility. Therefore, the objective of this study was to determine whether cerebral autoregulation is impaired in patients with continuous-flow (CF) LVADs. METHODS: Dynamic cerebral autoregulation was assessed in both time-domain (autoregulatory index) and frequency-domain (transfer function analysis) analyses in 9 CF-LVAD subjects, 5 pulsatile LVAD subjects and 10 healthy controls, by evaluating mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) during a sit-stand maneuver at 0.05 Hz (10-second sit, 10-second stand). The autoregulatory index was calculated as the percent change in mean CBFV per mm Hg change in MAP. RESULTS: The magnitude of oscillation in MAP and CBFV was greater in subjects with pulsatile LVADs than either CF-LVADs or healthy controls (p = 0.065 for MAP, p = 0.004 for CBFV). The autoregulatory index and transfer function gain were similar among groups, indicating that dynamic cerebral autoregulation is preserved among patients with CF-LVADs. CONCLUSIONS: Cerebral blood flow in patients with CF-LVADs is comparable to that of healthy controls across a range of blood pressures. Patients with pulsatile devices have greater oscillations in MAP and CBFV. However, dynamic cerebral autoregulation is preserved among subjects with either type of device. Thus, the reduction in pulsatility afforded by CF-LVADs does not impair normal autoregulatory processes.

Cardiovascular effects of 1 year of alagebrium and endurance exercise training in healthy older individuals.

BACKGROUND: Lifelong exercise training maintains a youthful compliance of the left ventricle (LV), whereas a year of exercise training started later in life fails to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products. Alagebrium breaks advanced glycation end product crosslinks and improves LV stiffness in aged animals. However, it is unclear whether a strategy of exercise combined with alagebrium would improve LV stiffness in sedentary older humans. METHODS AND RESULTS: Sixty-two healthy subjects were randomized into 4 groups: sedentary+placebo; sedentary+alagebrium (200 mg/d); exercise+placebo; and exercise+alagebrium. Subjects underwent right heart catheterization to define LV pressure-volume curves; secondary functional outcomes included cardiopulmonary exercise testing and arterial compliance. A total of 57 of 62 subjects (67 ± 6 years; 37 f/20 m) completed 1 year of intervention followed by repeat measurements. Pulmonary capillary wedge pressure and LV end-diastolic volume were measured at baseline, during decreased and increased cardiac filling. LV stiffness was assessed by the slope of LV pressure-volume curve. After intervention, LV mass and end-diastolic volume increased and exercise capacity improved (by ≈8%) only in the exercise groups. Neither LV mass nor exercise capacity was affected by alagebrium. Exercise training had little impact on LV stiffness (training × time effect, P=0.46), whereas alagebrium showed a modest improvement in LV stiffness compared with placebo (medication × time effect, P=0.04). CONCLUSIONS: Alagebrium had no effect on hemodynamics, LV geometry, or exercise capacity in healthy, previously sedentary seniors. However, it did show a modestly favorable effect on age-associated LV stiffening. CLINICAL TRIAL REGISTRATION- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01014572.

Effects of age and aerobic fitness on myocardial lipid content.

BACKGROUND: Aging and sedentary lifestyles lead to cardiac atrophy, ventricular stiffening, and impaired diastolic function. Both conditions are marked by increased adiposity, which can lead to ectopic fat deposition in nonadipocyte tissues including the myocardium. The effect of excess intramyocardial fat on cardiac function in nonobese individuals is unknown. METHODS AND RESULTS: Cardiac lipid content was measured by magnetic resonance spectroscopy in 153 healthy nonobese subjects with varying fitness levels quantified by peak oxygen uptake during treadmill exercise. Cardiac function (echo) and left ventricular (LV) filling pressures (right heart catheterization) were measured under varying preloads. LV stiffness was calculated from a curve fit of the diastolic portion of the pressure-volume curve. The strongest clinical predictors of lipid content were body mass index (ß=+0.03; 95% confidence interval, 0.001-0.06) and peak oxygen uptake (ß=-0.02; 95% confidence interval, -0.03 to -0.009; R(2)=0.14; P<0.001). Subjects in the highest quintile had smaller LV end-diastolic volumes (68±13 versus 58±12 mL/m(2); P<0.01) and decreased peak early mitral annular and increased peak late mitral inflow velocities. There were no differences in LV stiffness, but a leftward shift in the pressure-volume curve suggested a less distensible ventricle with increasing myocardial lipid levels. After adjusting for age, fitness, and body mass index, echocardiographic and morphometric differences among groups were attenuated and no longer significant. CONCLUSIONS: Body mass index and fitness levels are the strongest predictors of myocardial lipid content in nonobese humans. Cardiac lipid content is associated with decreased ventricular distensibility, and it may provide a causal mechanism linking changes in LV function related to age and fitness.

Cerebral vasomotor reactivity during hypo- and hypercapnia in sedentary elderly and Masters athletes.

Physical activity may influence cerebrovascular function. The objective of this study was to determine the impact of life-long aerobic exercise training on cerebral vasomotor reactivity (CVMR) to changes in end-tidal CO2 (EtCO2) in older adults. Eleven sedentary young (SY, 27±5 years), 10 sedentary elderly (SE, 72±4 years), and 11 Masters athletes (MA, 72±6 years) underwent the measurements of cerebral blood flow velocity (CBFV), arterial blood pressure, and EtCO2 during hypocapnic hyperventilation and hypercapnic rebreathing. Baseline CBFV was lower in SE and MA than in SY while no difference was observed between SE and MA. During hypocapnia, CVMR was lower in SE and MA compared with SY (1.87±0.42 and 1.47±0.21 vs. 2.18±0.28 CBFV%/mm Hg, P<0.05) while being lowest in MA among all groups (P<0.05). In response to hypercapnia, SE and MA exhibited greater CVMR than SY (6.00±0.94 and 6.67±1.09 vs. 3.70±1.08 CBFV1%/mm Hg, P<0.05) while no difference was observed between SE and MA. A negative linear correlation between hypo- and hypercapnic CVMR (R(2)=0.37, P<0.001) was observed across all groups. Advanced age was associated with lower resting CBFV and lower hypocapnic but greater hypercapnic CVMR. However, life-long aerobic exercise training appears to have minimal effects on these age-related differences in cerebral hemodynamics.

The effect of age-related differences in body size and composition on cardiovascular determinants of VO2max.

BACKGROUND: A reduction in maximal stroke volume (SVmax) and total blood volume (TBV) has been hypothesized to contribute to the decline in maximal oxygen uptake (VO2max) with healthy aging. However, these variables have rarely been collected simultaneously in a board age range to support or refute this hypothesis. It is also unclear to what extent scaling size-related cardiovascular determinants of VO2max affects the interpretation of age-related differences. METHODS: A retrospective analysis of VO2max, maximal cardiac output (QCmax), TBV, and body composition including fat-free mass (FFM) in 95 (51% M) healthy adults ranging from 19-86 years. RESULTS: Absolute and indexed VO2max, QCmax, and maximal heart rate decreased in both sexes with age (p ≤ .031). SVmax declined with age when scaled to total body mass or body surface area (p ≤ .047) but not when expressed in absolute levels (p = .120) or relative to FFM (p = .464). Absolute and indexed TBVs (mL/kg; mL/m(2)) were not significantly affected by age but increased with age in both sexes when scaled to FFM (p ≤ .013). A lower arteriovenous oxygen difference (a-vO2diff) contributed to the reduction in VO2max with age in treadmill exercisers (p = .004) but not in the entire cohort (p = .128). CONCLUSION: These results suggest (a) a reduction in absolute SVmax, and TBV do not contribute substantially to the age-related reduction in VO2max, which instead results from a smaller QCmax due to a lower maximal heart rate, and (b) body composition scaling methods should be used to accurately describe the effect of aging on physical function and cardiovascular variables.

Cardiovascular effects of 1 year of progressive endurance exercise training in patients with heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a disease of the elderly with cardiovascular stiffening and reduced exercise capacity. Exercise training appears to improve exercise capacity and cardiovascular function in heart failure with reduced ejection fraction. However, it is unclear whether exercise training could improve cardiovascular stiffness, exercise capacity, and ventricular-arterial coupling in HFpEF. METHODS: Eleven HFpEF patients and 13 healthy controls underwent invasive measurements with right heart catheterization to define Starling and left ventricular (LV) pressure-volume curves; secondary functional outcomes included Doppler echocardiography, arterial stiffness, cardiopulmonary exercise testing with cardiac output measurement, and ventricular-arterial coupling assessed by the dynamic Starling mechanism. Seven of 11 HFpEF patients (74.9 ± 6 years; 3 men/4 women) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline during decreased and increased cardiac filling. LV compliance was assessed by the slope of the pressure-volume curve. Beat-to-beat LV end-diastolic pressure (estimated from pulmonary arterial diastolic pressure) and stroke volume index were obtained, and spectral transfer function analysis was used to assess the dynamic Starling mechanism. RESULTS: Before training, HFpEF patients had reduced exercise capacity, distensibility and dynamic Starling mechanism but similar LV compliance and end-diastolic volumes compared to controls albeit with elevated filling pressure and increased wall stress. One year of training had little effect on LV compliance and volumes, arterial stiffness, exercise capacity or ventricular-arterial coupling. CONCLUSION: Contrary to our hypothesis, 1 year of endurance training failed to impart favorable effects on cardiovascular stiffness or function in HFpEF.

Effect of ageing on left ventricular compliance and distensibility in healthy sedentary humans.

Healthy, but sedentary ageing leads to marked atrophy and stiffening of the heart, with substantially reduced cardiac compliance; but the time course of when this process occurs during normal ageing is unknown. Seventy healthy sedentary subjects (39 female; 21­77 years) were recruited from the Dallas Heart Study, a population-based, random community sample and enriched by a second random sample from employees of Texas Health Resources. Subjects were highly screened for co-morbidities and stratified into four groups according to age: G(21−34): 21­34 years, G(35−49): 35­49 years, G5(0−64): 50­64 years, G(≥65): ≥65 years. All subjects underwent invasive haemodynamic measurements with right heart catheterization to define Starling and left ventricular (LV) pressure­volume curves. LV end-diastolic volumes (EDV) were measured by echocardiography at baseline, −15 and −30 mmHg lower-body negative pressure, and 15 and 30 ml kg(−1) saline infusion with simultaneous measurements of pulmonary capillary wedge pressure. There were no differences in heart rate or blood pressures among the four groups at baseline. Baseline EDV index was smaller in G(≥65) than other groups. LV diastolic pressure­volume curves confirmed a substantially greater LV compliance in G(21−34) compared with G(50−64) and G(≥65), resulting in greater LV volume changes with preload manipulations. Although LV chamber compliance in G(50−64) and G(≥65) appeared identical, pressure­volume curves were shifted leftward, toward a decreased distensibility, with increasing age. These results suggest that LV stiffening in healthy ageing occurs during the transition between youth and middle-age and becomes manifest between the ages of 50 to 64. Thereafter, this LV stiffening is followed by LV volume contraction and remodelling after the age of 65.

Effects of pericardial constraint and ventricular interaction on left ventricular hemodynamics in the unloaded heart.

Pericardial constraint and ventricular interaction influence left ventricular (LV) performance when preload is high. However, it is unclear if these constraining forces modulate LV filling when the heart is unloaded, such as during upright posture, in humans. Fifty healthy individuals underwent right heart catheterization to measure pulmonary capillary wedge (PCWP) and right atrial pressure (RAP). To evaluate the effects of pericardial constraint on hemodynamics, transmural filling pressure (LVTMP) was defined as PCWP-RAP. Beat-to-beat blood pressure (BP) waveforms were recorded, and stroke volume (SV) was derived from the Modelflow method. After measurements at -30 mmHg lower body negative pressure (LBNP), which approximates the upright position, LBNP was released, and beat-to-beat measurements were performed for 15 heartbeats. At -30 mmHg LBNP, RAP and PCWP were significantly decreased. During the first six beats of LBNP release, heart rate (HR) was unchanged, while BP increased from the fourth beat. RAP increased faster than PCWP resulting in an acute decrease in LVTMP from the fourth beat. A corresponding drop in SV by 3% was observed with no change in pulse pressure. From the 7th to 15th beats, LVTMP and SV increased steadily, followed by a decreased HR due to the baroreflex. A decreased TMP, but not PCWP, caused a transient drop in SV with no changes in HR or pulse pressure during LBNP release. These results suggest that the pericardium constrains LV filling during LBNP release, enough to cause a small but significant drop of SV, even at low cardiac filling pressure in healthy humans.

Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age.

BACKGROUND: Healthy but sedentary aging leads to cardiovascular stiffening, whereas life-long endurance training preserves left ventricular (LV) compliance. However, it is unknown whether exercise training started later in life can reverse the effects of sedentary behavior on the heart. METHODS AND RESULTS: Twelve sedentary seniors and 12 Masters athletes were thoroughly screened for comorbidities. Subjects underwent invasive hemodynamic measurements with pulmonary artery catheterization to define Starling and LV pressure-volume curves; secondary functional outcomes included Doppler echocardiography, magnetic resonance imaging assessment of cardiac morphology, arterial stiffness (total aortic compliance and arterial elastance), and maximal exercise testing. Nine of 12 sedentary seniors (70.6±3 years; 6 male, 3 female) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline, during decreased cardiac filling with lower-body negative pressure, and increased filling with saline infusion. LV compliance was assessed by the slope of the pressure-volume curve. Before training, Vo(2)max, LV mass, LV end-diastolic volume, and stroke volume were significantly smaller and the LV was less compliant in sedentary seniors than Masters athletes. One year of exercise training had little effect on cardiac compliance. However, it reduced arterial elastance and improved Vo(2)max by 19% (22.8±3.4 versus 27.2±4.3 mL/kg/mL; P<0.001). LV mass increased (10%, 64.5±7.9 versus 71.2±12.3 g/m(2); P=0.037) with no change in the mass-volume ratio. CONCLUSIONS: Although 1 year of vigorous exercise training did not appear to favorably reverse cardiac stiffening in sedentary seniors, it nonetheless induced physiological LV remodeling and imparted favorable effects on arterial function and aerobic exercise capacity.

Characterization of static and dynamic left ventricular diastolic function in patients with heart failure with a preserved ejection fraction.

BACKGROUND: Congestive heart failure in the setting of a preserved left ventricular (LV) ejection fraction is increasing in prevalence among the senior population. The underlying pathophysiologic abnormalities in ventricular function and structure remain unclear for this disorder. We hypothesized that patients with heart failure with preserved ejection fraction (HFPEF) would have marked abnormalities in LV diastolic function with increased static diastolic stiffness and slowed myocardial relaxation compared with age-matched healthy controls. METHODS AND RESULTS: Eleven highly screened patients (4 men, 7 women) aged 73±7 years with HFPEF were recruited to participate in this study. Thirteen sedentary healthy controls (7 men, 6 women) aged 70±4 years also were recruited. All subjects underwent pulmonary artery catheterization with measurement of cardiac output, end-diastolic volumes, and pulmonary capillary wedge pressures at baseline; cardiac unloading (lower-body negative pressure or upright tilt); and cardiac loading (rapid saline infusion). The data were used to define the Frank-Starling and LV end-diastolic pressure-volume relationships. Doppler echocardiographic data (tissue Doppler velocities, isovolumic relaxation time, propagation velocity of early mitral inflow , E/A-wave ratio) were obtained at each level of cardiac preload. Compared with healthy controls, patients with HFPEF had similar LV contractile function and static LV compliance but reduced LV chamber distensibility with elevated filling pressures and slower myocardial relaxation as assessed by tissue Doppler imaging. CONCLUSIONS: In this small, highly screened patient population with hemodynamically confirmed HFPEF, increased end-diastolic static ventricular stiffness relative to age-matched controls was not a universal finding. Nevertheless, patients with HFPEF, even when well compensated, had elevated filling pressures, reduced distensibility, and increased diastolic wall stress compared with controls. In contrast, LV relaxation as assessed by tissue Doppler variables appeared consistently impaired in patients with HFPEF.

Oxygen uptake response to stroke rate manipulation in freestyle swimming.

UNLABELLED: During gait, humans choose a combination of step length and step rate that minimizes V˙O2. However, little work has been reported on the existence of such optimization in swimming. PURPOSE: The purpose of this study was to examine the manipulation of stroke rate on V˙O2 in submaximal, constant speed freestyle swimming. METHODS: Preferred stroke rate for swimming freestyle at 1.0 m·s(-1) in a flume was determined for 10 competitive swimmers (mean ± SD: age = 33.3 ± 13.6 yr, height = 175.3 ± 8.6 cm, weight = 74.9 ± 12.2 kg). Participants then completed flume swims at 1.0 m·s(-1) with stroke rates equal to -20%, -10%, 0%, +10%, and +20% of their preferred stroke rate in a randomized order during which V˙O2 was continuously monitored. Each trial continued for 1 min after steady-state V˙O2 was verified (∼4-5 min). During the final minute of each trial, V˙O2 was measured using the Douglas bag technique, HR was recorded, and kick rate (KR) was computed using the time needed to complete 30 kicks. RPE was reported immediately after each trial. RESULTS: V˙O2 increased 11%-16% (P < 0.05) when stroke rate was reduced but was nominally affected when stroke rate was increased. Likewise, HR increased 4%-6% (P < 0.05), and RPE increased 15%-30% (P < 0.05) when stroke rate was reduced but not affected when stroke rate was increased. CONCLUSIONS: These data suggest that these swimmers preferred to swim freestyle at the lowest stroke rate (or the longest stroke length) that did not require an increase in V˙O2.

The effects of aging and physical activity on Doppler measures of diastolic function.

Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70+/-4 years) and 12 fit Masters athlete (68+/-3 years) seniors were recruited. Twelve young healthy (32+/-9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), -15 and -30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p<0.001), TDI Emean (p<0.001), and propagation velocity of mitral inflow (p<0.001) and an increase in IVRT (p=0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p=0.212), IVRT (p=0.546), or propagation velocity of mitral inflow (p=1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors at baseline (p=0.012) and during maximal lower body negative pressure (p=0.036), but not during saline solution infusion (p=0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.

The safety of intra-abdominal surgery in patients with cirrhosis: model for end-stage liver disease score is superior to Child-Turcotte-Pugh classification in predicting outcome.

HYPOTHESIS: We hypothesized that the model for end-stage liver disease (MELD) score may be a better and less subjective method than the Child-Turcotte-Pugh score for stratifying patients with cirrhosis before abdominal surgery. DESIGN: Retrospective medical record review. SETTING: Tertiary care institution. PATIENTS: Fifty-three adult patients with histologically proven cirrhosis undergoing abdominal surgery at Saint Louis University Hospital, St Louis, Mo, between 1991 and 2001. Those undergoing hepatic surgery (such as resection or transplantation) or closed abdominal surgery (such as hernia repair) were excluded. MAIN OUTCOME MEASURE: A poor outcome after surgery was defined as death or liver transplantation within 90 days of the operative procedure or a hospital stay of longer than 21 days. Demographic, clinical, and laboratory features predictive of poor outcome were assessed by multivariate analysis. RESULTS: A total of 13 patients (25%) had poor outcomes including 9 deaths (17%). Model for end-stage liver disease score and plasma hemoglobin levels lower than 10 g/dL were found to be independent predictors of poor outcomes. A MELD score of 14 or greater was a better clinical predictor of poor outcome than Child-Turcotte-Pugh class C. CONCLUSIONS: A MELD score of 14 or greater should be considered as a replacement for Child-Turcotte-Pugh class C as a predictor of being very high risk for abdominal surgery. Patients with cirrhosis with hemoglobin levels lower than 10 g/dL should receive corrective blood transfusions before abdominal surgery.

Effect of aging and physical activity on left ventricular compliance.

BACKGROUND: Left ventricular compliance appears to decrease with aging, which may contribute to the high incidence of heart failure in the elderly. However, whether this change is an inevitable consequence of senescence or rather secondary to reduced physical activity is unknown. METHODS AND RESULTS: Twelve healthy sedentary seniors (69.8+/-3 years old; 6 women, 6 men) and 12 Masters athletes (67.8+/-3 years old; 6 women, 6 men) underwent pulmonary artery catheterization to define Starling and left ventricular pressure-volume curves. Data were compared with those obtained in 14 young but sedentary control subjects (28.9+/-5 years old; 7 women, 7 men). Pulmonary capillary wedge pressures and left ventricular end-diastolic volumes by use of echocardiography were measured at baseline, during decreased cardiac filling by use of lower-body negative pressure (-15 and -30 mm Hg), and after saline infusion (15 and 30 mL/kg). Stroke volume for any given filling pressure was greater in Masters athletes compared with the age-matched sedentary subjects, whereas contractility, as assessed by preload recruitable stroke work, was similar. There was substantially decreased left ventricular compliance in healthy but sedentary seniors compared with the young control subjects, which resulted in higher cardiac pressures for a given filling volume and higher myocardial wall stress for a given strain. The pressure-volume curve for the Masters athletes was indistinguishable from that of the young, sedentary control subjects. CONCLUSIONS: A sedentary lifestyle during healthy aging is associated with decreased left ventricular compliance, leading to diminished diastolic performance. Prolonged, sustained endurance training preserves ventricular compliance with aging and may help to prevent heart failure in the elderly.