Chronotropic Reserve Research Articles

Size, Shape, and Stamina

Although several studies have examined the cardiac functional determinants of exercise capacity, few have investigated the effects of structural remodeling. The current study evaluated the association between cardiac geometry and exercise capacity. Subjects with ejection fraction > or = 50% and no valvular disease, myocardial ischemia, or arrhythmias were identified from a large prospective exercise echocardiography database. Left ventricular mass index and relative wall thickness were used to classify geometry into normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. All of the subjects underwent symptom-limited treadmill exercise according to standard Bruce protocol. Maximal exercise tolerance was measured in metabolic equivalents. Of 366 (60+/-14 years; 57% male) subjects, 166 (45%) had normal geometry, 106 (29%) had concentric remodeling, 40 (11%) had eccentric hypertrophy, and 54 (15%) had concentric hypertrophy. Geometry was related to exercise capacity: in descending order, the maximum achieved metabolic equivalents were 9.9+/-2.8 in normal, 8.9+/-2.6 in concentric remodeling, 8.6+/-3.1 in eccentric hypertrophy, and 8.0+/-2.7 in concentric hypertrophy (all P<0.02 versus normal). Left ventricular mass index and relative wall thickness were negatively correlated with exercise tolerance in metabolic equivalents (r=-0.14; P=0.009 and r=-0.21; P<0.001, respectively). Augmentation of heart rate and ejection fraction with exercise were blunted in concentric hypertrophy compared with normal, even after adjusting for medications. In conclusion, the pattern of ventricular remodeling is related to exercise capacity among low-risk adults. Subjects with concentric hypertrophy display the greatest limitation, and this is related to reduced systolic and chronotropic reserve. Reverse remodeling strategies may prevent or treat functional decline in patients with structural heart disease.

Heart Rate Recovery and Oxygen Kinetics After Exercise in Obstructive Sleep Apnea Syndrome

Patients who suffer from obstructive sleep apnea (OSA) have a decreased exercise capacity and abnormal autonomic nervous function. However, the kinetics of early oxygen (O2) and heart rate recovery (HRR) have not been described. We evaluated 21 men with moderate to severe OSA (mean age: 48 +/- 11 yrs, mean apnea-hypopnea index [AHI]: 55 +/- 13) and without known heart disease and 10 healthy men matched for age and body mass index (BMI; controls). Men with OSA underwent overnight polysomnography, and both groups underwent symptom-limited incremental cardiopulmonary exercise testing (CPET). We recorded the CPET parameters including peak O2 uptake (VO2p), kinetics of early O2 recovery by the first degree slope of VO2 during the first minute (VO2/t slope), the time required for a 50% decline of VO2p during recovery (T(1/2)), and early heart rate recovery (HRR = HR at maximal exercise - HR at 1 min of recovery), as well as the chronotropic reserve to exercise ([CR] = [peak HR - resting HR/220 - age - resting HR] x 100). Patients with OSA had a lower VO2p (28.7 +/- 4.0 vs 34.7 +/- 6.2 mL/kg/min), VO2/t slope (1.04 +/- 0.3 vs 1.4 +/- 0.17 mL/kg/min2), and T(1/2) (74 +/- 10 vs 56 +/- 6 sec) compared to controls (all P < 0.001). In addition, both HRR and CR were lower in the OSA group (22.0 +/- 7.0 vs 31.0 +/- 6.0 bpm, P:0.003, and 79.0% +/- 15% vs 99.0% +/- 13.0%, P:0.01, respectively). Patients with OSA demonstrate reduced exercise capacity, delayed oxygen kinetics, and reduced HRR. These data point to abnormal oxygen delivery and/or oxidative function of the peripheral muscles and impaired autonomic nervous activity in OSA patients.

Relation of ventricular-vascular coupling to exercise capacity in ischemic cardiomyopathy: a cardiac multi-modality imaging study

The purpose of this study was to examine the relationship between noninvasive measurements of ventricular-vascular coupling (VVC) with exercise tolerance, and compared the value of VVC versus other traditional determinants of exercise capacity in this population. 43 patients with ischemic CMP (age 59 +/- 9 years, mean EF 24 +/- 8%) underwent cardiopulmonary exercise testing, echocardiography and cardiac magnetic resonance (CMR). VVC was defined non-invasively by the ratio of ventricular systolic elastance (Ees) to the arterial elastance (Ea), where Ees = end-systolic pressure/end-systolic volume index and Ea = end-systolic pressure/stroke volume index. VVC significantly correlated with baseline heart rate (HR), peak exercise systolic blood pressure, maximum oxygen consumption (MVO(2)) and peak O(2) pulse (MVO(2)/HR). A higher VVC was associated with higher LVEF and RVEF but showed inverse relation to mitral E wave velocity. Univariate predictors of MVO(2) are baseline HR, chronotropic reserve, VVC and aortic distensibility; whilst mitral E wave velocity, LVEF, VVC, Ees significantly correlated with peak O(2) pulse. By stepwise multivariate analysis, VVC remained the only independent predictor of peak O(2) pulse. Ventricular-vascular coupling at rest may be a clinically important parameter in predicting exercise capacity in patients with advanced heart failure, and may become an additional target for therapeutic interventions.

Reduced cardiac functional reserve and quality of life in adults with GH deficiency

Patients with severe GH deficiency (GHD) suffer with a reduced quality of life in addition to diverse changes in cardiac size and performance. So far, the cardiac reserve ability to maintain the circulation during peak exercise has not been measured. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls and that this could explain, in part, their reduced quality of life. Eighteen patients with severe GHD and an assessment of GHD in adults (AGHDA) score > or =11 (mean 20.0, range 12-25) were studied and compared with 18 age-, sex- and body mass index-matched healthy controls. Peak cardiac power and cardiorespiratory fitness were investigated using noninvasive haemodynamic measurements during maximal cardiopulmonary exercise testing. Compared with matched controls, the cardiac power of GHD patients during exercise to volitional exhaustion was significantly reduced by 15% (mean +/- SD 4.4 +/- 1.0 W vs. 5.2 +/- 1.0 W, P = 0.02). Patients with GHD also had lower cardiac chronotropic reserve (peak heart rate 154 +/- 21/min vs. 174 +/- 11/min, P = 0.001) and a lower cardiac pressure-generating capacity (systolic blood pressure 160 +/- 25 mmHg vs. 200 +/- 15 mmHg, P < 0.0001). We found no correlation between any measure of peak cardiac power or function and the AGHDA score. Using this robust noninvasive method of assessing functional cardiac pumping capacity, we have for the first time shown that, while patients with severe GHD have a significantly impaired cardiac functional reserve associated with chronotropic incompetence and impaired pressure-generating capacity, this does not correlate with their reduced quality of life assessed using the current standard AGHDA score.

Cardiac Functional Reserve is Diminished in Growth Hormone‐Deficient Adults

Various studies have shown that patients with severe growth hormone deficiency (GHD) have diverse changes in left ventricular (LV) size or performance but so far there is no direct indication of cardiac reserve ability to maintain the circulation during peak exercise. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls. Eighteen patients with severe GHD were studied and compared with 18 age-, sex-, and body mass index (BMI)-matched healthy controls. Peak cardiac power and cardiorespiratory fitness were investigated using noninvasive hemodynamic measurements during maximal cardiopulmonary exercise testing. Compared with matched controls, the cardiac power of GHD patients during exercise to volitional exhaustion was significantly reduced by 15% (mean +/- SD: 4.4 +/- 1.0 watts (W) vs. 5.2 +/- 1.0 W, P= 0.02), despite attaining similar aerobic exercise peaks (VO(2max), GHD: 2390 +/- 822 mL/min vs. controls: 2461 +/- 872 mL/min, P= 0.80) and similar peak respiratory exchange ratios. The lower peak cardiac power could not be accounted for by peripheral alterations because both groups reached similar peak exercise systemic vascular resistances. Patients with GHD also had lower cardiac chronotropic reserve (peak heart rate: 154 +/- 21 bpm vs. 174 +/- 11 bpm, P= 0.001) and a lower cardiac pressure-generating capacity (systolic blood pressure [SBP] 160 +/- 25 mmHg vs. 200 +/- 15 mmHg, P < 0.0001). Using this robust noninvasive method of assessing functional cardiac pumping capacity we have for the first time shown that patients with severe GHD have a significantly impaired cardiac functional reserve associated with chronotropic incompetence and impaired pressure-generating capacity.

Consecutive administration of atropine and isoproterenol for the evaluation of asymptomatic sinus bradycardia

Sinus node function is commonly evaluated by the atropine test. The isoproterenol test is less used. The aim of this study was to evaluate chronotropic reserve in patients with asymptomatic sinus bradycardia using the combined administration of atropine and isoproterenol. A total of 100 patients were studied, 18-70 years old, with permanent, asymptomatic, sinus bradycardia and no detectable cardiac disease. The standard administration protocols for atropine and isoproterenol were used and successive heart rate recorded. Patients were stratified into three groups: Group A (control), showing normal response to atropine and isoproterenol; Group B, demonstrating abnormal response to atropine; Group C, with abnormal response to atropine and isoproterenol. No statistically significant difference was observed between Groups A and B (P = 0.11), whereas Group C differed statistically from both Groups A (P < 0.000001) and B (P = 0.000003) to a significant extent. By the end of the 3-year follow-up period, 47% of the Group C patients had undergone permanent pacemaker implantation (DDDR)--Kaplan-Maier survival curves predict only 35% survival without pacing--whereas none did so in Groups A and B. In patients with deficient chronotropic response to atropine administration, isoproterenol tests could differentiate those with inadequate chronotropic reserves, possibly requiring preventive pacemaker implantations.

Human cardiovascular responses to passive heat stress

Humans, like other tropical animals, can tolerate high levels of heat stress (albeit for short periods of time) provided that (1) they avoid contact with extremely hot surfaces, (2) they can produce and evaporate sufficient sweat, and (3) the cardiovascular system that supports homeostasis under such conditions is not compromised. Indeed, during episodic severe heat waves that result in increased death rates especially among the elderly, cardiovascular disease is the primary or contributing cause of death in > 80% of examined cases (Smenza et al. 1996). Crandall et al. (2008) point out in this issue of The Journal of Physiology that ‘whole-body heating has the potential to cause significant cardiovascular stress that … may be second only to [that] associated with exercise’. Because of the high compliance of the cutaneous circulation and the lack of muscle pump function during severe and prolonged passive heating, the strain on the left ventricle – which provides all of the energy to essentially double cardiac output under such conditions – may be even greater than that seen during exercise. The response of the cardiovascular system to passive heat stress is an elegant example of homeostatic regulation and integration, worthy of being taught in every physiology class. In the classic experimental model of passive whole-body heating, skin temperature is elevated and clamped using water-perfused suits and core temperature rises as heat is transferred internally by convection and conduction. Cutaneous blood flow increases remarkably from basal values of 200 ml min−1 to upwards of 8 l min−1, yet arterial pressure is well maintained by a doubling of cardiac output (due to an increase in heart rate and maintenance of, or a slight elevation in, stroke volume despite falling central venous pressure) coupled with a redistribution of flow from renal and splanchnic vascular beds (Rowell et al. 1969). Elderly subjects, even those with no apparent cardiac dysfunction, respond to passive heating with an attenuated rise in skin blood flow coupled with both a lower cardiac output response and a diminished ability to redistribute flow from splanchnic and renal circulations, relying on a greater portion of their chronotropic reserve to compensate for a reduced inotropic response (Minson et al. 1998). A compromised left ventricle, e.g. due to heart disease or advanced ageing, may not be capable of meeting these demands in light of the requisite increase in cardiac work (i.e. the area of the flow–volume loop). While flow characteristics of the integrated cardiovascular response to heating are well understood, some controversy has existed about capacitance characteristics of the response. Muller (1905) first hypothesized a reduction in central blood volume (CBV) during passive heating, yet Rowell et al. (1969) noted a slight increase in CBV which he later described as a ‘pre-ventricular sump’ phenomenon. Crandall et al. (2008) approached this question using γ camera imaging of 99mTc-labelled autologous red blood cells. Their results demonstrated that thoracic blood volume, an index of CBV, was indeed decreased during supine passive heating. Further, blood volume was reduced in splanchnic circulations. These two findings support the hypothesized shift of blood volume from the central circulation to the skin to sustain heat dissipation. A second important finding from Crandall and colleagues (2008) is the 13% increase in left ventricular ejection fraction (EF) that occurs in concert with the elevation in heart rate in young heated subjects. The fact that stroke volume does not fall (and may increase slightly) despite falling central venous pressure presents a strong argument for increased cardiac contractility. While the authors concede that EF is an imperfect index of contractility, the link between the two is particularly robust under conditions of supine heating. In combination with the data of Rowell and Minson, the preponderance of cardiovascular morbidity and mortality (e.g. Smenza et al. 1996) during heat waves – the most closely related natural occurrence of sustained passive heating – is predictable. It is important to note that the subjects in this meritorious investigation were young, healthy and medication free. Given the preponderance of heat-related problems in the elderly and the otherwise cardiovascularly compromised, it remains uncertain whether their attenuated flow responses (Minson et al. 1998) are balanced by disparate volume characteristics. However, the present contribution of Crandall et al. lends additional support to the hypothesis that a large number of heat-related deaths among the elderly during heat waves may be attributable to increased strain on an already compromised left ventricle.

Native cardiac reserve predicts survival in acute post infarction heart failure in mice

Cardiac reserve can be used to predict survival and outcome in patients with heart failure. The aim of this study was to investigate if native cardiac reserve could predict survival after myocardial infarction (MI) in mice.MethodWe investigated 27 healthy C57Bl6 mice (♂10–12 weeks old) with echocardiography using a high-frequency 15-MHz linear transducer. Investigations were performed both at rest and after pharmacological stress induced by dobutamine (1 μg/g body weight i.p.). The day after the echocardiography examination, a large MI was induced by ligation of the left anterior descending (LAD) coronary artery for evaluation of mortality rate.ResultsTwo weeks after induction of MI, 7 mice were alive (26%). Evaluation of the difference between the surviving and deceased animals showed that the survivors had a better native ability to increase systolic performance (ΔLVESd -1.86 vs -1.28mm p = 0.02) upon dobutamine challenge, resulting in a better cardiac reserve (ΔFS 37 vs 25% p = 0.02 and ΔCO 0.27 vs -0.10 ml/min p = 0.02) and a better chronotropic reserve (ΔR-R interval -68 vs -19 ms p < 0.01). A positive relationship was found between ability to survive and both cardiac (p < 0.05) and chronotropic reserve (p < 0.05) when the mice were divided into three groups: survivors, surviving < 7 days, and surviving < 1 day.ConclusionWe conclude that before MI induction the surviving animals had a better cardiac function compared with the deceased. This indicates that native cardiac and chronotropic reserve may be an important determinant and predictor of survival in the setting of large MI and post-infarction heart failure.

Cardiac Reserve in the Transplanted Heart: Effect of a Graft Polymorphism in the β 1-adrenoceptor

Polymorphism of the beta1-adrenoceptor (beta1-AR) affects outcome and beta-blocker efficacy in patients with heart failure. We studied the influence of the beta1-AR Ser49Gly polymorphism on cardiac reserve in transplanted hearts. Beta1-AR polymorphism was determined by allelic discrimination analysis. Patients were divided into two groups: either homozygous for Ser49 (n = 15) or with Gly49 in one or both alleles (Gly49; n = 5). Patients underwent a maximal bicycle exercise test and echocardiographic evaluation at rest and during low-dose dobutamine stress. Patients with Gly49 grafts had better physical endurance (144 +/- 26 vs 112 +/- 31 W, p = 0.03), a trend toward better chronotropic reserve (deltaHR 64 +/- 13 vs 47 +/- 16 bpm, p = 0.056) during exercise, and lower resting heart rate (82 +/- 7 vs 90 +/- 7 bpm, p = 0.04) than those homozygous for Ser49. There were no significant differences in left ventricular ejection fraction (LVEF), with the exception of a decrease in cardiac reserve in patients with the Gly49 variants at the lowest dose of dobutamine (deltaLVEF -4.4 +/- 1.5 vs 2.2 +/- 5.8%, p = 0.04). Doppler myocardial tissue velocities of early relaxation were increased in patients with the Gly49 variants compared with patients homozygous for Ser49, both at rest (14.5 +/- 3.2 vs 10.4 +/- 2.0 cm/s, p = 0.03) and during the lowest dose of dobutamine (15.0 +/- 3.7 vs 10.9 +/- 2.5 cm/s, p = 0.04). Heart transplant patients with the beta1-AR Gly49 variants had a lower heart rate, and better stress endurance and diastolic function compared with patients homozygous for Ser49. They also showed a trend toward better chronotropic reserve. These results provide a possible explanation for differences in cardiac reserve among patients with heart transplants.

Cycle-ergometry stress testing and use of chronotropic reserve adjustment of ST depression for identification of significant coronary artery disease in clincal practice

Diagnostic reliability of indexations of peak exercise ST segment depression (ΔST) for heart rate reserve (HRi) or chronotropic reserve (CR) to identify significant coronary artery disease (CAD) by cycle-ergometer exercise testing has not been evaluated previously. Exercise testing by upright cycle-ergometer (25 W/3 min) were performed in consecutive patients in primary prevention with history of exercise-related chest discomfort and cardiovascular risk factors, or with overt peripheral artery disease, with or type-2 diabetes associated with two or more additional cardiovascular risk factors. Coronary angiography was performed after the test to assess significant CAD. Three different criteria for definition of inducible myocardial ischemia were tested versus significant CAD: peak ΔST ≥ 100 μV, ST/HRi > 1.69 μV/bpm or ST/CR > 1.76 μV/%. Diagnostic accuracy vs. CAD of ΔST ≥ 100 μV, of ST/HRi > 1.69 μV/bpm, and of ST/CR > 1.76 μV/% were 78%, 72%, and 89% respectively; sensitivity and specificity of the three criteria were 91% and 50%, 84% and 43%, 88% and 93%, respectively. Abnormal ST/CR predicted CAD independent of risk factors, pre-test probability, and more strongly than ΔST. Combination of ST/HRi and ST/CR criteria did not improve CAD prediction. In conclusions, in clinical setting in patients in primary prevention but with moderate-to-high pre-test probability of CAD, exercise testing by cycle-ergometry and use of ST/CR > 1.76 μV/% showed elevated sensitivity and specificity, and the best accuracy for diagnosis of significant CAD.

Risk Stratification by Treadmill Exercise Echocardiography in Patients with Excellent Exercise Capacity

The incremental value of exercise echocardiography (EE) has been demonstrated to be maximal in patients with moderate pretest probability for coronary artery disease, but there is a lack of data in patients with low pretest probability or patients with good functional capacity. To investigate whether such incremental value is maintained in patients with excellent exercise capacity, we studied 1,433 patients who had excellent exercise capacity (>or=8 METs for women, >or=10 METs for men). During a follow-up of 2.3 +/- 1.5 years, 42 hard events occurred (cardiac death or nonfatal myocardial infarction). Variables independently associated to hard events were male gender (P = 0.04), % of the age-predicted maximum heart rate (P = 0.02), chronotropic reserve (P = 0.002), and abnormal EE (P = 0.03; incremental P value of EE = 0.03). EE has incremental value over clinical variables, resting echocardiography, and exercise testing variables in patients with excellent exercise capacity. EE may be preferable to ECG exercise testing even in patients expected to have good exercise capacity.

Impaired Chronotropic and Vasodilator Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection Fraction

Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role. Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180+/-71 versus 455+/-184 seconds; peak oxygen consumption 9.0+/-3.4 versus 14.4+/-3.4 mL x kg(-1) x min(-1); both P<0.001). At matched low-level workload, HFpEF subjects displayed approximately 40% less of an increase in heart rate and cardiac output and less systemic vasodilation (all P<0.05) despite a similar rise in end-diastolic volume, stroke volume, and contractility. Heart rate recovery after exercise was also significantly delayed in HFpEF patients. Exercise capacity correlated with the change in cardiac output, heart rate, and vascular resistance but not end-diastolic volume or stroke volume. Lung blood volume and plasma norepinephrine levels rose similarly with exercise in both groups. HFpEF patients have reduced chronotropic, vasodilator, and cardiac output reserve during exercise compared with matched subjects with hypertensive cardiac hypertrophy. These limitations cannot be ascribed to diastolic abnormalities per se and may provide novel therapeutic targets for interventions to improve exercise capacity in this disorder.

Heart failure-associated alterations in troponin I phosphorylation impair ventricular relaxation-afterload and force-frequency responses and systolic function

Recent studies have found that selective stimulation of troponin (Tn)I protein kinase A (PKA) phosphorylation enhances heart rate-dependent inotropy and blunts relaxation delay coupled to increased afterload. However, in failing hearts, TnI phosphorylation by PKA declines while protein kinase C (PKC) activity is enhanced, potentially augmenting TnI PKC phosphorylation. Accordingly, we hypothesized that these site-specific changes deleteriously affect both rate-responsive cardiac function and afterload dependence of relaxation, both prominent phenotypic features of the failing heart. A transgenic (TG) mouse model was generated in which PKA-TnI sites were mutated to mimic partial dephosphorylation (Ser22 to Ala; Ser23 to Asp) and dominant PKC sites were mutated to mimic constitutive phosphorylation (Ser42 and Ser44 to Asp). The two highest-expressing lines were further characterized. TG mice had reduced fractional shortening of 34.7 +/- 1.4% vs. 41.3 +/- 2.0% (P = 0.018) and slight chamber dilation on echocardiography. In vivo cardiac pressure-volume studies revealed near doubling of isovolumic relaxation prolongation with increasing afterload in TG animals (P < 0.001), and this remained elevated despite isoproterenol infusion (PKA stimulation). Increasing heart rate from 400 to 700 beats/min elevated contractility 13% in TG hearts, nearly half the response observed in nontransgenic animals (P = 0.005). This blunted frequency response was normalized by isoproterenol infusion. Abnormal TnI phosphorylation observed in cardiac failure may explain exacerbated relaxation delay in response to increased afterload and contribute to blunted chronotropic reserve.

Effects of exercise rehabilitation program on heart rate recovery in patients with chronic heart failure

Heart rate recovery (HRR1) immediately after exercise reflects parasympathetic activity, which is markedly attenuated in chronic heart failure (CHF) patients. The aim of our study was to examine both continuous and interval exercise training effects on HRR1 in these patients. The population study consisted of 29 stable CHF patients that participated at a rehabilitation program of 36 sessions, three times per week. Of the 29 patients, 24 completed the program. Patients were randomly assigned to interval {n=10 [100% peak work rate (WRp) for 30 s, alternating with rest for 30 s]} and to continuous training [n=14 (50%WRp)]. All patients performed a symptom-limited cardiopulmonary exercise test on a cycle ergometer before and after the completion of the program. Measurements included peak oxygen uptake (VO2p), anaerobic threshold (AT), WRp, first degree slope of VO2 during the first minute of recovery (VO2/t-slope), chronotropic response [% chronotropic reserve (CR)=(peak HR - resting HR)x100/(220 - age - resting HR)], HRR1 (HR difference from peak exercise to one minute after). After the completion of the rehabilitation program there was a significant increase of WRp, VO2p, AT and VO2/t-slope (by 30%, P=0.01; 6%, P=0.01; 10%, P=0.02; and 27%, P=0.03 respectively for continuous training and by 21%, P<0.05; 8%, P=0.01; 6%, P=NS; and 48%, P=0.02 respectively for interval training). However, only patients exercised under the continuous training regime had a significant increase in HRR1 (15.0+/-9.0 to 24.0+/-12 bpm; P=0.02) and CR (57+/-19 to 72+/-21%, P=0.02), in contrast with those assigned to interval training (HRR1: 21+/-11 to 21+/-8 bpm; P=NS and CR: 57+/-18 to 59+/-21%, P=NS). Both continuous and interval exercise training program improves exercise capacity in CHF patients. However, continuous rather than interval exercise training improves early HRR1, a marker of parasympathetic activity, suggesting a greater contribution to the autonomic nervous system.

Early heart rate recovery after exercise predicts mortality in patients with chronic heart failure

Background Patients with chronic heart failure (CHF) have multiple abnormalities of autonomic regulation that have been associated to their high mortality rate. Heart rate recovery immediately after exercise is an index of parasympathetic activity, but its prognostic role in CHF patients has not been determined yet. Methods Ninety-two stable CHF patients (83M/9F, mean age: 51 ± 12 years) performed an incremental symptom-limited cardiopulmonary exercise testing. Measurements included peak O 2 uptake (VO 2p), ventilatory response to exercise (V E/VCO 2 slope), the first-degree slope of VO 2 for the 1st minute of recovery (VO 2/t-slope), heart rate recovery [(HRR 1, bpm): HR difference from peak to 1 min after exercise] and chronotropic response to exercise [%chronotropic reserve (CR, %) = (peak HR − resting HR/220 − age − resting HR) × 100]. Left ventricular ejection fraction (LVEF, %) was also measured by radionuclide ventriculography. Results Fatal events occurred in 24 patients (26%) during 21 ± 6 months of follow-up. HRR 1 was lower in non-survivors (11.4 ± 6.4 vs. 20.4 ± 8.1; p < 0.001). All cause-mortality rate was 65% in patients with HRR 1 ≤ 12 bpm versus 11% in patients with HRR 1 > 12 bpm (log-rank: 32.6; p < 0.001). By multivariate survival analysis, HRR 1 resulted as an independent predictor of mortality ( χ 2 = 19.2; odds ratio: 0.87; p < 0.001) after adjustment for LVEF, VO 2p, V E/VCO 2 slope, CR and VO 2/t-slope. In a subgroup of patients with intermediate exercise capacity (VO 2p: 10–18, ml/kg/min), HRR 1 was a strong predictor of mortality ( χ 2: 14.3; odds ratio: 0.8; p < 0.001). Conclusions Early heart rate recovery is an independent prognostic risk indicator in CHF patients and could be used in CHF risk stratification.

Rhythmic Ca2+ Oscillations Drive Sinoatrial Nodal Cell Pacemaker Function to Make the Heart Tick

Excitation-induced Ca(2+) cycling into and out of the cytosol via the sarcoplasmic reticulum (SR) Ca(2+) pump, ryanodine receptor (RyR) and Na(+)-Ca(2+) exchanger (NCX) proteins, and modulation of this Ca(2+)cycling by beta-adrenergic receptor (beta-AR) stimulation, governs the strength of ventricular myocyte contraction and the cardiac contractile reserve. Recent evidence indicates that heart rate modulation and chronotropic reserve via beta-ARs also involve intracellular Ca(2+) cycling by these very same molecules. Specifically, sinoatrial nodal pacemaker cells (SANC), even in the absence of surface membrane depolarization, generate localized rhythmic, submembrane Ca(2+) oscillations via SR Ca(2+) pumping-RyR Ca(2+) release. During spontaneous SANC beating, these rhythmic, spontaneous Ca(2+) oscillations are interrupted by the occurrence of an action potential (AP), which activates L-type Ca(2+) channels to trigger SR Ca(2+) release, unloading the SR Ca(2+) content and inactivating RyRs. During the later part of the subsequent diastolic depolarization (DD), when Ca(2+) pumped back into the SR sufficiently replenishes the SR Ca(2+) content, and Ca(2+)-dependent RyR inactivation wanes, the spontaneous release of Ca(2+) via RyRs again begins to occur. The local increase in submembrane [Ca(2+)] generates an inward current via NCX, enhancing the DD slope, modulating the occurrence of the next AP, and thus the beating rate. Beta-AR stimulation increases the submembrane Ca(2+) oscillation amplitude and reduces the period (the time from the prior AP triggered SR Ca(2+) release to the onset of the local Ca(2+) release during the subsequent DD). This increased amplitude and phase shift causes the NCX current to occur at earlier times following a prior beat, promoting the earlier arrival of the next beat and thus an increase in the spontaneous firing rate. Ca(2+) cycling via the SR Ca(2+) pump, RyR and NCX, and its modulation by beta-AR stimulation is, therefore, a general mechanism of cardiac chronotropy and inotropy.

Chronotropic reserve beyond anerobic threshold (CRAT) predicts survival in advanced heart failure

Background: Measurement of peak aerobic capacity is an important predictor of prognosis in heart failure and helps to assess need for transplantation. We tested the hypothesis that chronotropic reserve at anaerobic threshold (CRAT), a new measure of cardiac endurance might serve to provide an independent prognostic measure of heart failure severity.

Attenuated cardiovascular reserve during prolonged submaximal cycle exercise in healthy older subjects

ObjectivesThe goal of this study was to determine the effect of age on the hemodynamic response to prolonged submaximal aerobic exercise in healthy volunteers. BackgroundReductions in peak work rate, heart rate (HR), and left ventricular (LV) emptying but higher blood pressure (BP) and systemic vascular resistance occur in healthy older versus younger humans during short bursts of graded maximal aerobic exercise. However, the effect of aging on the cardiovascular response to prolonged exercise at submaximal work rates typical of daily aerobic activities remains unknown. MethodsWe evaluated cardiovascular performance throughout prolonged submaximal upright cycle ergometry in 40 carefully screened healthy untrained volunteers, 8 men and 12 women <50 years old, mean = 37 ± 8 years (younger), and 10 men and 10 women ≥50 years old, mean = 66 ± 9 years (older), during upright cycle exercise at 70% of peak cycle oxygen consumption (VO2) to exhaustion or a maximum of 120 min. Cardiac volumes were acquired by gated blood pool scans with 99mTc at rest and every 10 min throughout exercise. ResultsDuration of exercise was similar in younger ([81 ± 28 min] versus older [71± 29 min] subjects, p = NS). At 10 min of exercise in the steady state, older subjects demonstrated lower VO2 (1.1 ± 0.2 l/min vs. 1.3 ± 0.3 l/min) and lower HR (118 ± 17 vs. 135 ± 11 beats/min, p < 0.001) but larger end-diastolic (80 ± 11 ml/m2 vs. 73 ± 8 ml/m2, p = 0.03) and end-systolic volume index (ESVI) 20 ± 6 ml/m2 vs. 17 ± 4 ml/m2, p < 0.05) than younger ones. Between 10 min and exercise termination, with VO2 held constant in both groups, increases in HR (14.0 ± 12.4 beats/min vs. 5.9 ± 11.5 beats/min, p = 0.04), cardiac index (1.6 ± 1.0 l/min/m2 vs. 0.8 ± 1.1 l/min/m2, p = 0.03), and LV ejection fraction (7.1 ± 4.0% vs. 2.9 ± 4.4%, p = 0.003) were greater in younger than older subjects, respectively, as was the reduction in ESVI (−5.1 ± 3.0 ml/m2 vs. −1.8 ± 3.3 ml/m2, p = 0.002), despite similar declines in systolic BP (−12.3 ± 6.3 mm Hg vs. −12.1 ± 15.0 mm Hg, p = NS). ConclusionsThus, age-associated deficits in chronotropic and LV systolic reserve performance occur during prolonged submaximal upright cycle ergometry, analogous to those observed during graded maximal exercise.

Cardiovascular hemodynamics and exercise tolerance in thyroid disease.

The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiovascular performance are detected with small variations in thyroid hormone serum concentrations. Most patients with thyroid disease experience cardiovascular manifestations, and the most serious complications of thyroid dysfunction occur as a result of cardiac involvement. The increased metabolic state and oxygen consumption that occur in hyperthyroid patients require an increased supply of oxygen and removal of metabolic products from the periphery. This is accomplished by increasing the cardiac output to meet the needs of the periphery. Circulation time is decreased in hyperthyroid patients, and a lowered arterial resistance and increased venous resistance promote the return of blood to the heart. Thyroid hormones may significantly decrease the strength of respiratory and skeletal muscles and affect regulatory mechanisms of adaptation to incremental effort. In hyperthyroidism, cardiovascular exercise testing and analysis of respiratory gas exchange demonstrate low efficiency of cardiopulmonary function as well as impaired chronotropic, contractile, and vasodilatatory reserves, which are reversible when euthyroidism is restored. During exercise, the increment (delta) of minute ventilation (respiratory rate x tidal volume), and oxygen pulse (oxygen uptake per heart beat) are significantly lower in dysthyroidism versus euthyroidism. Especially in older patients with thyroid dysfunction, markedly reduced workload, delta ejection fraction, and delta heart rate, both at the anaerobic threshold as well as at maximal exercise, are observed. In thyrotoxicosis, mitochondria oxidative dysfunction during exercise mostly causes intracellular acidosis, whereas in hypothyroidism, inadequate cardiovascular support appears to be one of the principal factors involved. These abnormalities partly explain why subjects with dysthyroidism are intolerant to exertion. Thus, in thyroid disease, both cardiac structures and function may remain normal at rest, however impaired cardiovascular and respiratory adaptation to effort becomes unmasked during exercise.

Impact of the etiology of congestive heart failure on chronotropic reserve after exercise training

Impact of the etiology of congestive heart failure on chronotropic reserve after exercise training