Exercise-induced Increase In Heart Rate Research Articles

Influence of Fluid Ingestion on Heart Rate, Cardiac Autonomic Modulation and Blood Pressure in Response to Physical Exercise: A Systematic Review with Meta-Analysis and Meta-Regression.

A systematic review was undertaken to investigate the involvement of hydration in heart rate (HR), HR variability (HRV) and diastolic (DBP) and systolic (SBP) blood pressure in response to exercise. Data synthesis: The EMBASE, MEDLINE, Cochrane Library, CINAHL, LILACS and Web of Science databases were searched. In total, 977 studies were recognized, but only 36 were included after final screening (33 studies in meta-analysis). This study includes randomized controlled trials (RCTs) and non-RCTs with subjects > 18 years old. The hydration group consumed water or isotonic drinks, while the control group did not ingest liquids. For the hydration protocol (before, during and after exercise), the HR values during the exercise were lower compared to the controls (-6.20 bpm, 95%CI: -8.69; -3.71). In the subgroup analysis, "water ingested before and during exercise" showed lower increases in HR during exercise (-6.20, 95%CI: 11.70 to -0.71), as did "water was ingested only during exercise" (-6.12, 95%CI: -9.35 to -2.89). Water intake during exercise only revealed a trend of avoiding greater increases in HR during exercise (-4,60, 95%CI: -9.41 to 0.22), although these values were not significantly different (p = 0.06) from those of the control. "Isotonic intake during exercise" showed lower HRs than the control (-7.23 bpm, 95% CI: -11.68 to -2.79). The HRV values following the exercise were higher in the hydration protocol (SMD = 0.48, 95%CI: 0.30 to 0.67). The values of the SBP were higher than those of the controls (2.25 mmHg, 95%CI: 0.08 to 4.42). Conclusions: Hydration-attenuated exercise-induced increases in HR during exercise, improved autonomic recovery via the acceleration of cardiac vagal modulation in response to exercise and caused a modest increase in SBP values, but did not exert effects on DBP following exercise.

Heart rate response during cardiopulmonary exercise in heart transplant recipients

Abstract Background Denervation at heart transplant (HTx) results in attenuated heart rate (HR) control and limited exercise tolerance. Purpose The aim of this study was to assess longitudinal changes in the HR response to exercise in HTx recipients. We compared the results with those of healthy controls. Methods Seventy-four HTx recipients were enrolled in a cardiopulmonary exercise trial. The HR response to maximal exercise was tested at 11 weeks and at 1- and 3-years follow-up post HTx, and compared with the HR response in 50 age and gender matched controls. The HR was measured at rest, at 25-, 50-, 75-, and 100% of VO2peak, and 30 sec, 1, 2, and 4 min after peak exercise on a treadmill or bicycle ergometer. We also assessed the HR reserve and the chronotropic response index (CRI). Results Elleven weeks after HTx, the HR response to exercise was blunted, but improved significantly during follow-up. The change in HR from rest to peak exercise increased by 53% (41 bpm vs 62 bpm; p<0.001) from inclusion to 12 months follow-up, but levelled off between 12- and 36 months (62 bpm vs 65 bpm; p=0.59) (Figure 1). In comparison, the exercise-induced increase in HR in healthy controls was 117 bpm. In HTx recipients, approximately 40% of the total increase in HR occurred between rest and 25% of VO2peak at inclusion (Figure). In contrast, only 31% of the increase in HR in healthy controls occurred between rest and 25% of VO2peak (p<0.001). The fall in HR during the first 4 minutes after exercise increased over the duration of the study (p<0.001 for all comparisons between inclusion and 12 months, and 12- and 36 months at 30 sec, 1, 2, 3 and 4 min after exercise). During the first minute after the end of exercise, the HR rose 2 bpm at baseline, but fell 10 bpm at 12 months (p for difference <0.001). However, even at 36 months, the decline in HR after exercise remained less rapid than in healthy controls (p<0.001) (Figure). CRI increased between baseline and 12 months, but levelled off between the 12-month visit and 36 months (0.50±0.2 vs 0.79±0.3; p<0.001 and 0.79±0.3 vs 0.81±0.3; p=0.51). The chronotropic response was normalized (>0.85) in 44% of the HTx recipients at 1 year and in 51% at 3 year after HTx. Conclusion The increase and decrease in HR during exercise are considerably muted in de novo HTx recipients. The HR response improves during the first year after surgery, and thereafter levels off. In contrast the decline in HR after exercise seems to increase with time, which may be related to the effect of exercise. This suggests that partial re-innervation takes place. Whether this response continues to improve in the longer term remains to be determined. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health Authority

HIITing The Brain Enhances Cerebrovascular Shear Stress; The Link To Neuroprotection?

High-intensity interval exercise training (HIIT) is considered a more time-efficient alternative to moderate-intensity continuous training (MICT) that can optimize metabolic and cardiovascular health though its impact on the cerebrovasculature is unknown. PURPOSE: Pilot examination to characterise local cerebrovascular shear stress responses during an acute bout of HIIT and MICT. METHODS: Following ethics approval, 2 physically-active males (21-23 yrs) were randomly assigned to HIIT or MICT (semi-recumbent cycling) preceded by a standardized warm-up and separated by sufficient time to allow for full haemodynamic recovery. During HIIT, subjects performed 3 intervals (each consisting of 2 mins at 60W and 2 mins at 100W) and for MICT, isovolume work performed continuously at 80W for 12 mins. Diameter, blood flow and shear rate in the internal carotid artery (ICA) were measured using Doppler ultrasound at rest and averaged over the final 4 min of HIIT and MICT. The end tidal partial pressure of carbon dioxide (PETCO2), heart rate (HR), mean arterial pressure (MAP) and oxygen uptake (VO2) were recorded continuously photoplethysmography and respiratory gas analysis. RESULTS: Exercise-induced increases in HR, MAP and VO2 were comparable between HIIT and MICT and were accompanied by an equivalent, progressive reduction in PETCO2. In contrast, ICA diameter decreased more markedly during HIIT [Δ (exercise minus rest) HIIT: -0.15 mm vs. ΔMICT: -0.01 mm] with increased velocity (ΔHIIT: 7.75 vs. ΔMICT: 3.39 cm.s-1) and corresponding elevation in shear rate (ΔHIIT: 38 vs. ΔMICT: 9 s.-1). CONCLUSIONS: These findings, albeit proof-of-concept, provide preliminary evidence highlighting a fourfold greater elevation in local cerebrovascular shear stress during HIIT compared to an equivalent volume of MICT. This is primarily attributable to local vasoconstriction that cannot be explained by hyperventilation-induced hypocania though likely represents a functional response coupling cerebral O2 delivery to demand. To what extent repeated exposure to the intermittency of HIIT-induced cerebrovascular shear stress confers enhanced neuroprotection in the long-term is currently under investigation. Supported by a Royal Society Research Fellowship (#WM 1000707)

Dynamic QT Interval Changes from Supine to Standing in Healthy Children

BackgroundQT-interval variations in response to exercise-induced increases in heart rate have been reported in children and adults in the diagnosis of long QT syndrome (LQTS). A quick standing challenge has been proposed as an alternative provocative test in adults, with no pediatric data yet available. MethodsA standing test was performed in 100 healthy children (mean age, 9.7 ± 3.1 years) after 10 minutes in a supine position with continuous electrocardiographic recording. QT intervals were measured at baseline, at maximal heart rate, at maximal QT, and at each minute of a 5-minute recovery while standing. Measurements were taken in leads II/V5 and were corrected for heart rate (QTc). ResultsOn standing, the heart rate increased by 29 ± 10 beats per minute (bpm). The QT interval was similar at baseline and on standing (394 ± 34 ms vs 394 ± 34 ms; P = 1.0). However, QTc increased from 426 ± 21 to 509 ± 41 ms (P < 0.001). The 95th percentile for QTc at baseline and maximal heart rate was 457 ms and 563 ms, respectively. At 1 minute of recovery, the QT interval was shorter (375 ± 31 ms) compared with baseline (394 ± 34 ms; P < 0.001) and standing (394 ± 34 ms; P < 0.001). QTc reached baseline values after 1 minute of recovery and remained stable thereafter (423 ± 23 ms at 1 minute; 426 ± 22 ms at 5 minutes; P = 1.0). ConclusionsThis first characterization of QTc changes on standing in children shows substantial alterations, which are greater than those seen in adults. Two-thirds of the children would have been misclassified as having LQTS by adult criteria, indicating the need to create child-specific standards.

Wearing lower-body compression garment with medium pressure impaired exercise-induced performance decrement during prolonged running.

ObjectiveTo investigate the effect of wearing a lower body compression garment (CG) exerting different pressure levels during prolonged running on exercise-induced muscle damage and the inflammatory response.MethodsEight male participants completed three exercise trials in a random order. The exercise consisted of 120 min of uphill running at 60% of VO2max. The exercise trials included 1) wearing a lower-body CG with 30 mmHg pressure [HIGH]; 2) wearing a lower-body CG with 15 mmHg pressure [MED]; and 3) wearing a lower-body garment with < 5 mmHg pressure [CON]. Heart rate (HR), and rate of perceived exertion for respiration and legs were monitored continuously during exercise. Time-course change in jump height was evaluated before and immediately after exercise. Blood samples were collected to determine blood glucose, lactate, serum creatine kinase, myoglobin, free fatty acids, glycerol, cortisol, and plasma interleukin-6 (IL-6) concentrations before exercise, 60 min of the 120 min exercise period, immediately after exercise, and 60 min after exercise.ResultsJump height was significantly higher immediately after the exercise in the MED trial compared with that in the HIGH trial (P = 0.04). Mean HR during the 120 min exercise was significantly lower in the MED trial (162 ± 4 bpm) than that in the CON trial (170 ± 4 bpm, P = 0.01). Plasma IL-6 concentrations increased significantly with exercise in all trials, but the area under the curve during exercise was significantly lower in the MED trial (397 ± 58 pg/ml·120 min) compared with that in the CON trial (670 ± 86 pg/ml·120 min, P = 0.04).ConclusionWearing a lower body CG exerting medium pressure (approximately 15 mmHg) significantly attenuated decrease in jump performance than that with wearing a lower body CG exerting high pressure (approximately 30 mmHg). Furthermore, exercise-induced increases in HR and the inflammatory response were significantly smaller with CG exerted 15mmHg than that with garment exerted < 5 mmHg.

Relationship between exercise-induced heart rate increase and the formation of microbubbles and high-intensity transient signals in mechanical heart valve implanted patients.

IntroductionThe formation and collapse of vapor-filled bubbles near a mechanical heart valve is called cavitation. Microbubbles can be detected in vivo by doppler ultrasonography (USG) as HITS (high intensity transient signals) in cranial circulation. We investigated the relationship between exercise induced heart rate increase and HITS formation in cranial circulation.Material and methodsThirty-nine mechanical heart valve implanted (8 aortic valve replacement (AVR) + mitral valve replacement (MVR), 9 AVR, 22 MVR) patients aged 18-80 years old were included in our study. Microbubbles were counted in the left ventricular cavity via transthoracic echocardiography at rest per cardiac cycle. Afterwards transcranial Doppler USG was performed and HITS were counted in each patient's middle cerebral artery at 5 min duration. Subsequently an exercise test according to the Bruce protocol was performed. After achieving maximal heart rate, microbubbles in the left ventricle and HITS were counted again.ResultsMicrobubbles in the left ventricle and transcranial HITS increased after exercise significantly compared to resting values (15.79 ±10.91 microbubbles/beat vs. 26.51 ±18.00 microbubbles/beat, p < 0.001; 6.13 ±8.07 HITS/5 min vs. 13.15 ±15.87 HITS/5 min, p = 0.001). There was a significant correlation between microbubbles and HITS counts after peak exercise (r = 0.55, p < 0.001).ConclusionsIn our study, we found that the microbubbles were increasing as the heart rate increased and more HITS were propelled to the cerebral circulation. As previously shown, HITS can alter cognitive functions. Therefore heart rate control is essential in mechanical heart valve patients to protect neurocognitive functions.

Orthostatic intolerance and coronary reserve: a matter of a certain gravity

A 74-year-old woman came to our attention complaining of the recent onset of shortness of breath during light physical activity. She reported orthostatic light-headedness, occasional dizziness, and pre-syncope symptoms for a duration of the prior year. The past history included mitral valve prolapse with mild regurgitation, dyslipidemia, and paroxysmal atrial fibrillation. At presentation, the current medications included propafenone, aminosalicylic acid, and simvastatin. A 24-h-ECG demonstrated the presence of polymorphic ventricular premature beats and asymptomatic ST-segment depression. The treadmill exercise test showed limited exercise tolerance, and a significant downward sloping ST-segment depression in leads V4–V6 at the beginning of step 2 of the Bruce protocol. An exercise myocardial perfusion scan was consistent with a reduced coronary reserve of the anterior wall. Upon admission, lying and up-right arterial pressures were 130/80 and 90/50 mmHg, respectively, while a physical examination documented a systolic click and a late systolic murmur. After medications were suspended, a new treadmill exercise test (Fig. 1, left panel) demonstrated orthostatic hypotension [1] with tachycardia upon standing, and a further decline of arterial pressure and heart rate increase during the Bruce stage 1. Exercise was interrupted due to pre-syncope symptoms after 204600 when 88% of the predicted maximal heart rate had been reached, and ST depression (-1.0 mm, V5–V6) observed. Considering the patient’s characteristics, the estimated pre-test probability of a significant coronary stenosis was 20–50% [2, 3]. The positive likelihood ratio of exercise stress test and myocardial perfusion scan for a significant coronary artery disease was about 10[4]. Thus, the patient’s post-test probability of a significant coronary stenosis was in the 70–90% range. A coronary angiography was thus performed, but ruled out a stenosis of the major coronary vessels. In the absence of stenosis, a reduction of coronary reserve may be secondary to functional mechanisms [5], including the originally misdiagnosed orthostatic hypotension. We thus hypothesized a critical decline in coronary blood flow during upright physical activity due to an exercise-induced significant decrease in arterial pressure on a pre-existing orthostatic hypotension background. To test our hypothesis, an exercise bicycle test was performed in the lying posture, a position unlikely to affect arterial pressure. Exercise was interrupted at 703500 because of physical exhaustion (Fig. 1, right panel). Neither a significant reduction in arterial pressure nor ST-segment changes was observed along the exercise-induced heart rate increase. The maximum heart rate systolic pressure product [6], a broad index of cardiovascular function, increased more when exercise was performed in a lying position than during up-right posture, compared to baseline, although the increase in heart rate was lower in the supine than in the standing position (Fig. 1). G. Costantino Medicina Interna II, Ospedale Sacco, Milan, Italy

Serum AChE Activities Predict Exercise Heart Rate Parameters of Asymptomatic Individuals

Background specific heart rate parameters notably associate with variable risks of cardiovascular disease and mortal-ity, however, to date there are no readily available blood tests associated with these parameters. Because of the estab-lished parasympathetic contributions towards cardiac regulation, we challenged the working hypothesis that serum acetylcholinesterase (AChE) activity is involved. Methods A total of 403 Healthy men and women were included in the study and underwent treadmill exercise testing. Prior to exercise testing the subject’s serum AChE activity levels were assessed by measuring rates of acetylthiocholine hydrolysis. Results In male subjects AChE activity was positively cor-related to resting heart rate (r = 0.210, p = 0.001). Complementing this observation, AChE activity was negatively correlated to the exercise-induced heart rate increase (r = –0.181, p = 0.005) and to heart rate recovery at 1, 2 and 5 minutes following cessation of exercise (r = –0.150, p = 0.022; r = –0.157, p = 0.016; r = –0.176, p = 0.008 respec-tively). This indicated that lower than average AChE activities, which presumably reflect increased peripheral ACh levels, might be correlated to favorable heart rate parameters. Similar observations were made in female subjects, ex-cept for lack of correlation to their resting heart rate. Additionally, we observed that we were able to stratify subjects into two groups of significantly different AChE activity (p = 0.001) based on a cut point of heart rate recovery below 20 beats one minute after cessation of exercise. Conclusion In asymptomatic individuals lower than average AChE activity is associated with favorable indices of exercise-inducible heart rate increase as well as heart rate recovery. Future studies will be needed to evaluate the added prognostic significance gained by implementing this marker into routine practice.

Rebuttal from Drs. Richard, Zoll, Mettauer, Piquard, and Geny

Rebuttal from Drs. Richard, Zoll, Mettauer, Piquard, and Geny

Surgical left cardiac sympathetic denervation for long QT syndrome: effects on QT interval and heart rate

The primary aim of the present study was to investigate the short-term effects of surgical left cardiac sympathetic denervation (LCSD) on the QT interval and heart rate in patients with congenital long QT syndrome (LQTS). Left cardiac sympathetic denervation was performed in five LQTS patients who had a history of syncope. The patients' 12-lead and 24-h Holter monitoring ECG was recorded 24 h before and 24 h after LCSD. Treadmill exercise tests were also performed before and 6 days after surgery to assess changes in heart rate and the QT interval after surgery. Left cardiac sympathetic denervation was successful in all patients. The mean value of the corrected QT interval (QTc) in the five patients decreased from 0.59+/-0.05 to 0.48+/-0.04 s (P=0.006) immediately after the procedure and remained short (0.47+/-0.04, P<0.05) after a 21-month follow-up. The mean value of QTc on the 24-h Holter monitoring ECG also decreased in all patients (0.67+/-0.07 vs 0.60+/-0.05 s, P<0.01). The mean, maximum, and minimum heart rate on the 24-h ECG remained unchanged (P>0.05). The maximum heart rate during the exercise tests decreased from 162+/-4 beats/min before surgery to 129+/-10 beats/min (P<0.01). The exercise-induced increase in QTc remained unchanged after the surgery (P>0.05). Although four of the five patients were syncope-free until 21 months postoperatively, the remaining patient had a recurrence of syncope, requiring an increased dose of beta blocker. These findings indicate that LCSD shortens QTc and diminishes the exercise-induced increase in heart rate whereas the resting heart rate and exercise-induced increase in QTc remain unchanged. These results may have implications for the effectiveness and limitations of LCSD.

Anti-anginal and anti-ischemic effects of the selective b-blocker talinolol in patients with stable angina pectoris

To determine the dose dependency of the anti-anginal and antiischemic effects of the selective beta-blocker talinolol administered once-daily in a randomized, double-blind, placebo-controlled multicenter study in patients with stable angina pectoris. Standardized bicycle ergometry at baseline and after 3 and 6 weeks of treatment was used to assess exercise capacity. The primary endpoint was the change in the maximum exercise time (MET) 24 +/- 1 h after the last intake of study medication compared to baseline. Secondary efficacy parameters were time to onset of angina, time to 1 mm ST segment depression, angina attacks, consumption of short-acting nitrates, blood pressure and pulse rate. Patients were randomly allocated to treatment with talinolol (100, 200 or 300 mg once daily) or placebo for a period of 6 weeks. A total of 241 outpatients (204 male and 37 female) aged between 34 and 83 years, were randomized in 31 centers in Germany, Poland and the Czech Republic. At the end of treatment, the primary endpoint (change in MET compared to baseline) showed no significant difference between the talinolol groups and placebo. The means of MET prolongation ranged from 27.4 sec under placebo to a maximum of 47.6 sec in the 200 mg group. However, the time to 1 mm ST segment depression during exercise increased markedly with talinolol, the difference to placebo reaching statistical significance with the 200 mg/d dose (80.1 +/- 32.7 sec, p = 0.0182) and 300 mg/d dose (82.0 +/- 31.6 sec, p = 0.0127). In the case of the other secondary variables, the most pronounced effects were recorded for talinolol doses of 200 and 300 mg/d. Talinolol significantly inhibited the exercise-induced increase in heart rate and blood pressure. The decrease in rate pressure product at 100 W workload was statistically significant with all administered talinolol doses (delta from baseline to final visit 3090, 4351 and 4291 for 100, 200 and 300 mg/d, respectively, p < 0.0001). Despite once-daily dosing, talinolol at doses up to 300 mg/d was very well tolerated. No unexpected adverse drug reactions were observed. The results show that talinolol administered once daily in a dosage of 200 - 300 mg/d is effective and safe in the management of chronic stable angina.

Improving exercise capacity, 6 wk training tends to reduce circulating endothelin after heart transplantation

Short-term survival is no longer the pivotal issue after heart transplantation but, most heart-transplant (Htx) patients still present with increased circulating endothelin-1 (ET) and reduced exercise capacity. ET-1 limits both exercise-induced vasodilation and blood flow redistribution toward acting muscles and might be accessible to training. This study was performed to investigate the effect of training on ET-1 and whether an eventual training-induced improvement in exercise capacity may be related to reduced baseline or exercise circulating ET-1 in Htx patients. Five Htx patients performed a maximal bicycle exercise test and an endurance exercise test before and after a training program of 18 exercises sessions during 6 wk. ET-1 was determined by radioimmunoassay at rest, end endurance exercise and 30 min recovery, before and after training. Training improved significantly Htx's maximal oxygen uptake (+13.1 +/- 4.8%; p < 0.05) and also reduced significantly the endurance exercise-induced heart rate increase. Resting ET-1 was increased in Htx (5.98 +/- 1.88 vs. 1.61 +/- 0.25 pmol/L in controls; p < 0.01) but although ET-1 modulation might participate in training-induced beneficial effects, training failed to modulate either resting or exercise ET-1 plasma level. Training-induced improvement in exercise capacity might not mainly due to decreased ET-1 after heart transplantation. Further supporting the usefulness of training, these preliminary data suggest that improved exercise capacity may not be mainly due to decreased ET-1 in Htx patients. Further, larger scale studies will be needed to investigate whether an impaired nitric oxide pathway stimulation might explain such results and whether a longer training program can reduce local ET-1, arising from working muscles after heart transplantation.

Invited Review: Aging and the cardiovascular system

Aging is associated with complex and diversified changes of cardiovascular structure and function. The heart becomes slightly hypertrophic and hyporesponsive to sympathetic (but not parasympathetic) stimuli, so that the exercise-induced increases in heart rate and myocardial contractility are blunted in older hearts. The aorta and major elastic arteries become elongated and stiffer, with increased pulse wave velocity, evidence of endothelial dysfunction, and biochemical patterns resembling early atherosclerosis. The arterial baroreflex is sizably altered in aging, but different components are differentially affected: there is a definite impairment of arterial baroreceptor control of the heart but much better preserved baroreceptor control of peripheral vascular resistance. Alterations at the afferent, central neural, efferent, and effector organ portions of the reflex arch have been claimed to account for age-related baroreflex changes, but no conclusive evidence is available on this mechanistic aspect. Reflexes arising from cardiopulmonary vagal afferents are also blunted in aged individuals. The cardiovascular and reflex changes brought about by aging may have significant implications for circulatory homeostasis in health and disease.

Beta-adrenoceptor polymorphisms: does altered in vitro function predict in vivo effects?

β 1- and β 2-adrenoceptors (AR) are polymorphic. β 1-AR: There is a Gly389Arg polymorphism of the β 1-AR with the Gly389 exhibiting reduced in vitro responsiveness upon agonist-induced stimulation. To study this in vivo we assessed exercise-induced increase in heart rate and shortening of heart rate-corrected duration of electromechanical systole (QS 2c—a measure of inotropism) in 12 volunteers homozygous for Gly389 and 12 volunteers homozygous for Arg389. In both groups, exercise caused nearly identical increases in heart rate and shortening of QS 2c, indicating that the differential responsiveness observed in vitro is not of major functional importance in vivo. β 2-AR: There are at least three polymorphisms of the β 2-AR: the Arg16Gly and the Gln27Glu polymorphisms differ from the wild-type (WT, Arg16, Gln27) β 2-AR in vitro in their susceptibility to agonist-induced downregulation. We studied in 16 WT-volunteers, 6 volunteers homozygous for Glu27 and 6 volunteers homozygous for Gly16, the effects of 2-week treatment with 3×5 mg/day p.o. terbutaline on terbutaline infusion-induced increases in heart rate and shortening of QS 2c. In all three groups, oral terbutaline treatment reduced terbutaline infusion-induced increases in heart rate and shortening of QS 2c to a similar extent, indicating that the differential susceptibility to agonist-induced downregulation of the Gly16 and Glu27 polymorphism of the β 2-AR observed in vitro is not of major functional importance in vivo. Finally, there is a Thr164Ile polymorphism of the β 2-AR with Ile164 exhibiting reduced in vitro responsiveness upon agonist-induced stimulation. We studied in 12 WT-volunteers and in 6 volunteers heterozygous for the Ile164 polymorphism the effects of terbutaline infusion on heart rate and QS 2c. In the Ile164 volunteers increases in heart rate and shortening of QS 2c induced by the terbutaline infusion were significantly ( p<0.05) lower than in the WT-volunteers, indicating that in healthy volunteers heterozygous for the Ile164 polymorphism of the β 2-AR cardiac β 2-AR responsiveness is reduced. In conclusion, these three examples show that for any given polymorphism, in vivo studies have to be performed in order to test whether data obtained in vitro reflect the in vivo situation.

New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment.

As described in Part I of this 2-part article,1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear understanding of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function. Conceptually, the mechanisms that cause abnormalities in diastolic function that lead to the development of diastolic heart failure can be divided into factors intrinsic to the myocardium itself (myocardial) and factors that are extrinsic to the myocardium (extramyocardial; Table 1). Myocardial factors can be divided into structures and processes within the cardiac muscle cell (cardiomyocyte), within the extracellular matrix (ECM) that surrounds the cardiac muscle cell, and that activate the autocrine or paracrine production of neurohormones. Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure. Myocardial and extramyocardial mechanisms, cellular and extracellular mechanisms, and neurohumoral activation each play a role in the development of diastolic heart failure caused by ischemia, pressure-overload hypertrophy, and restrictive and hypertrophic cardiomyopathy. View this table: Table 1105290. Diastolic Heart Failure: Mechanisms ### Cardiomyocyte Diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves. These include changes in calcium homeostasis caused by (1) abnormalities in the sarcolemmal channels responsible for short- and long-term extrusion of calcium from the cytosol, such as the sodium calcium exchanger and the calcium pump; (2) …

Exercise-Induced Increase in Circulating Adrenomedullin Is Related to Mean Blood Pressure in Heart Transplant Recipients

Adrenomedullin (ADM) is a newly discovered potent vasorelaxing and natriuretic peptide that recently has been shown to be increased after heart transplantation. To investigate the hemodynamic factors modulating its release and the eventual role of ADM in blood pressure regulation after heart transplantation, seven matched heart-transplant recipients (Htx) and seven normal subjects performed a maximal bicycle exercise test while monitoring for heart rate, blood pressure, and circulating ADM. Baseline heart rate and systemic blood pressure were higher in Htx; left ventricular mass index and ADM tended to be higher after heart transplantation and correlated positively in Htx (r = 0.79, P = 0.03). As expected, exercise-induced increase in heart rate was lower in Htx than in controls (60 ± 11 % vs. 121 ± 14 %, respectively) and blood pressure increase was similar in both groups. Maximal exercise increased significantly plasma ADM in both groups (from 25.3 ± 3.1 to 30.7 ± 3.5 pmol/L, P < 0.05 and from 15.2± 1.4 to 29.1 ± 4.4 pmol/L, P = 0.02 in Htx and controls, respectively), the hypotensive peptide level remaining elevated until the 30th min of recovery. A significant inverse relationship was observed between peak mean blood pressure and circulating ADM in Htx (r = −0.86, P < 0.02). Besides showing that circulating ADM is increased after heart transplantation, the present study demonstrates a positive relationship between baseline ADM and left ventricular mass index. Furthermore, maximal exercise-induced increase in ADM is inversely related to mean blood pressure in Htx, suggesting that ADM might participate in blood pressure regulation during exercise after heart transplantation.

Exercise-induced increase in circulating adrenomedullin is related to mean blood pressure in heart transplant recipients.

Adrenomedullin (ADM) is a newly discovered potent vasorelaxing and natriuretic peptide that recently has been shown to be increased after heart transplantation. To investigate the hemodynamic factors modulating its release and the eventual role of ADM in blood pressure regulation after heart transplantation, seven matched heart-transplant recipients (Htx) and seven normal subjects performed a maximal bicycle exercise test while monitoring for heart rate, blood pressure, and circulating ADM. Baseline heart rate and systemic blood pressure were higher in Htx; left ventricular mass index and ADM tended to be higher after heart transplantation and correlated positively in Htx (r = 0.79, P = 0.03). As expected, exercise-induced increase in heart rate was lower in Htx than in controls (60 +/- 11 % vs. 121 +/- 14 %, respectively) and blood pressure increase was similar in both groups. Maximal exercise increased significantly plasma ADM in both groups (from 25.3 +/- 3.1 to 30.7 +/- 3.5 pmol/L, P < 0.05 and from 15.2 +/- 1.4 to 29.1 +/- 4.4 pmol/L, P = 0.02 in Htx and controls, respectively), the hypotensive peptide level remaining elevated until the 30th min of recovery. A significant inverse relationship was observed between peak mean blood pressure and circulating ADM in Htx (r = -0.86, P < 0.02). Besides showing that circulating ADM is increased after heart transplantation, the present study demonstrates a positive relationship between baseline ADM and left ventricular mass index. Furthermore, maximal exercise-induced increase in ADM is inversely related to mean blood pressure in Htx, suggesting that ADM might participate in blood pressure regulation during exercise after heart transplantation.

Cardiovascular and neuroendocrine responses to exercise in hypoxia during impaired neural feedback from muscle.

Reflex mechanisms from contracting skeletal muscle have been shown to be important for cardiovascular, neuroendocrine, and extramuscular fuel-mobilization responses in exercise. Furthermore, because hypoxia results in exaggerated metabolic changes in contracting muscle, the present study evaluated whether enhancement of cardiovascular and neuroendocrine responses by hypoxia during exercise is influenced by neural feedback from contracting muscle. Seven healthy males cycled at 46% maximal O(2) uptake for 20 min both during normoxia and at 11.5% O(2), and both without and with epidural anesthesia (EA; 20 ml 0.25% bupivacain, resulting in cutaneous hypesthesia below T10-T12 and 25% reduction in maximal leg strength). Exercise to exhaustion was also performed at 7.8% O(2). The exercise-induced increases in heart rate; cardiac output; leg blood flow; plasma concentrations of growth hormone, adrenocorticotropin, cortisol, and catecholamines; renin activity; glucose production and disappearance; norepinephrine spillover [2, 190 +/- 341 ng/min (exercise at 11.5% O(2)) vs. 988 +/- 95 ng/min (exercise during normoxia)]; lactate release from and glucose uptake in the leg; and the decreases in plasma insulin and free fatty acids were exaggerated in hypoxia (P < 0.05). In muscle, concentrations of lactate, creatine, and inosine 5'-monophosphate were higher, and those of phosphocreatine were lower after exercise in hypoxia compared with normoxia. The exercise-induced increase in mean arterial blood pressure was not affected by hypoxia, but it was reduced by EA [108 +/- 4 mmHg (control) vs. 97 +/- 4 mmHg (EA); P < 0.05], and the reduction was more pronounced during severe hypoxia compared with normoxia. Apart from this, time to exhaustion at extreme hypoxia, circulatory responses, concentrations of neuroendocrine hormones, and extramuscular substrate mobilization were not diminished by EA. In conclusion, in essence the hypoxia-induced enhancement of systemic adaptation to exercise is not mediated by neural feedback from working muscle in humans.

Plasma brain natriuretic peptide during ergometric exercise in hypertensive patients with left ventricular hypertrophy

Cardiac ventricle is shown to be an important source of circulating brain natriuretic peptide (BNP) in hypertensive rats with left ventricular hypertrophy (LVH). This study examined the effect of short-term exercise with a bicycle ergometer on plasma BNP concentrations in 21 essential hypertension patients with LVH established by echocardiography. The results were compared with those from 24 age-matched hypertensive without LVH. Blood pressure, heart rate, plasma renin activity (PRA), and plasma norepinephrine level increased during exercise, but the mean increases of these parameters were not different in the two groups. Resting BNP levels were slightly but significantly higher in the LVH group than in the non-LVH group. This peptide increased during exercise in the two groups, but the exercise-induced increase (percent increase) in plasma BNP was significantly greater in the LVH group than in the non-LVH group (207% ± 50% v 141% ± 36%, P < .05). The exercise-induced increase in BNP was significantly correlated with the left ventricular (LV) mass index ( N = 45, r = .60, P < .01). By contrast, the exercise-induced increase in BNP was not correlated with the exercise-induced increase in heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, PRA, or noradrenaline level. These results suggest that short-term exercise induces an accelerated increase of plasma BNP in hypertensive subjects with LVH. The LV mass appeared to be related to the observed increase of plasma BNP concentration, at least in our hypertensive patients with LVH.

A comparison of the β1–selectivity of conventional metoprolol and metoprolol CR during exercise in healthy volunteers

This paper reports on a randomized double-blind crossover study to compare the effects of daily treatment with 100 mg conventional metoprolol (M100), 50 or 100 mg slow-release metoprolol CR (CR50, CR100) and placebo on the response to treadmill walking exercise in 12 healthy volunteers. Twenty minutes of exercise was undertaken at 1.5 h post-dose (Ex1) and again at 4 h (Ex2). During Ex1 all metoprolol preparations caused a reduction in the exercise-induced increase in heart rate when compared to placebo (P < 0.001). The exercise-induced increase in plasma glycerol, an indicator of lipolysis, was diminished by all metoprolol preparations but to a greater extent by M100 (P < 0.05). Rises in plasma ammonia were used to assess the net degradation of energy-rich adenine nucleotides by skeletal muscle during exercise. When compared to placebo, a significant elevation in plasma ammonia was seen only during exercise with M100 (P < 0.05). The perceived exertion at the end of exercise was also greatest on conventional metoprolol. The differences between the effects of conventional and CR formulations of metoprolol were less when exercise was repeated 4 h post dosing. We conclude that metoprolol CR may offer advantages over the conventional preparation, in subjects regularly engaging in exercise, by reducing the metabolic stress imposed upon skeletal muscle.