Treadmill Exercise Tolerance Test Research Articles

Abstract P3196: Voluntary Exercise Training Does Not Prevent High Phosphate Diet-induced Mitochondrial Dysfunction

Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in processed foods consumed as part of a Western diet. Mice fed high-Pi diet (HP) for 12 weeks display decreased maximal exercise capacity but no change in cardiac function. Expression of fatty acid metabolism genes are decreased and expression of glucose metabolism genes are increased in skeletal muscle after HP diet. Consequently, mitochondrial function is significantly impaired in skeletal muscle from mice fed HP diet. In the current study we test the hypothesis that voluntary exercise training prevents the negative metabolic consequences of HP diet. We housed mice in voluntary wheel running cages and fed them a normal-Pi (NP) or HP diet. HP diet did not alter body weight or composition, and NP- and HP-fed mice voluntarily ran the same distance in wheel cages throughout the study. Using incline treadmill exercise tolerance tests we observed no differences in medium-intensity exercise capacity between NP- and HP-fed mice subjected to voluntary wheel running, contrary to findings in sedentary mice. Despite preserved exercise capacity, muscle mitochondrial function in mice fed HP diet was significantly decreased after 5 weeks, which continued to decline after 12 weeks of HP diet and voluntary exercise. To investigate mechanisms of HP-induced mitochondrial dysfunction we measured expression of key metabolic genes and found that fatty acid metabolism genes were significantly decreased in muscle from mice fed HP diet and subjected to voluntary exercise. These data suggest that voluntary exercise training does not prevent the negative metabolic consequences of consuming a high-phosphate diet. Thus, dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.

Direct thrombin inhibitors as alternatives to heparin to preserve lung growth and function in a murine model of compensatory lung growth

Infants with congenital diaphragmatic hernia (CDH) may require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We investigated the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. In vitro assays of lung endothelial cell proliferation and apoptosis were performed. C57BL/6 J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin and outcomes were assessed on postoperative day 8. Heparin administration inhibited endothelial cell proliferation in vitro and significantly decreased lung volume in vivo, while bivalirudin and argatroban preserved lung growth. These findings correlated with changes in alveolarization on morphometric analysis. Treadmill exercise tolerance testing demonstrated impaired exercise performance in heparinized mice; bivalirudin/argatroban did not affect exercise tolerance. On lung protein analysis, heparin decreased angiogenic signaling which was not impacted by bivalirudin or argatroban. Together, this data supports the use of DTIs as alternatives to heparin for systemic anticoagulation in CDH patients on bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted.

Lipopolysaccharide-induced murine lung injury results in long-term pulmonary changes and downregulation of angiogenic pathways

Acute respiratory distress syndrome is the most severe form of acute lung injury (ALI) and is associated with significant mortality. Lipopolysaccharide (LPS)-induced injury is a valuable murine model of ALI but there is a paucity of data on lung regeneration and the role of angiogenic signaling involving vascular endothelial growth factor (VEGF). Eight-week-old male C57BL/6J mice were randomized to receive intratracheal instillation of either LPS or isovolumetric phosphate buffered saline as a vehicle control. Mice were observed at a single follow-up time-point that was either short-term (24 h or 4 days) or long-term (7 days or 4 weeks). On pulmonary function testing, LPS-treated mice had increased compliance at 4 weeks post-instillation, which correlated with decreased vascularization and with time-dependent, progressive decrease in alveolarization. Treadmill exercise tolerance testing demonstrated impaired performance at 24 h, 4 days and 4 weeks following LPS exposure. On lung protein analysis, LPS instillation decreased VEGF expression at up to 4 weeks, and decreased activation of its key receptor, VEGFR2 at 7 days and 4 weeks post-instillation. Together, these data provide insight on long-term pulmonary functional outcomes 4 weeks after ALI and identify angiogenic proteins as possible therapeutic targets following lung injury.

Abstract 13471: HFpEF in Spontaneously Obese Mice Due to Genomic Rearrangement in Non-Coding Region of Chromosome 1

Background: Obesity is the most common comorbidity and risk factor for heart failure (HF) in patients with preserved ejection fraction (HFpEF), a subclass containing more than 50% of HF cases. However, effective treatment of HFpEF remains scarce due to the incomplete understanding of the mechanisms. Methods: A mouse line (C57/B6J) of Floxed-stop Overexpression of IF1 (FEI) was generated and maintained for Cre-mediated conditional IF1 overexpression. We observed that severe obesity became a fixed phenotype in inbred FEI mice after inbreeding for 5-6 generations. Targeted-Locus-Amplification (TLA) analyses revealed that FEI inbreeding triggered a genomic rearrangement in a non-coding region of chromosome 1. A heterozygous line with genotype and phenotype fixation was obtained via outbreeding with wild type mice. In the present study, we focus on assessing the cardiac phenotype of FEI mice using echocardiography, histology, and exercise tolerance tests. Results: The early onset of obesity was consistent in the heterozygotes of obese FEI mice with increased peripheral fats and circulating tissue lipids, as well as reduced systemic metabolic rates. FEI mice also exhibited increased food intake, fasting blood glucose, insulin, and leptin with impaired glucose/insulin tolerance. Echocardiography revealed that the FEI mice developed concentric left ventricular hypertrophy with preserved ejection fraction. However, E/A ratio results from Doppler flow measurement at mitral valve suggest diastolic dysfunction in the FEI mice. Heart weight to tibial length ratio was significantly increased in FEI compared with WT mice. H&E and Trichrome blue staining on heart sections exhibited increased cardiomyocyte hypertrophy and cardiac fibrosis. Treadmill exercise tolerance test revealed a significantly decreased exercise tolerance in FEI mice. Conclusions: We conclude that the cardiac phenotypes in the obese FEI mice closely recapitulate obese patients who suffer from HFpEF. Thus, further studies on these mice should yield novel and translational insight into the molecular and metabolic mechanisms underlying the HFpEF development, leading to improved treatments.

Altered spatio-specific CaMKII activation in autophagy deficient mice

Abstract Background Autophagy is linked to preventing the development of cardiac hypertrophy and failure. While aberrant activation of Ca2+/calmodulin-dependent kinase II (CaMKII) promotes myocardial remodeling, the role of autophagy in maintaining cardiac Ca2+ homeostasis and regulating CaMKII signaling is unknown. Objective To test whether loss of autophagy promotes subcellular alterations in CaMKII activation in early myocardial remodelling, and whether compromised in vivo cardiac function parallels those changes. Methods Young (10–15 weeks) cardiomyocyte-specific autophagy protein 5-deficient mice (Atg5−/−) mice and their littermate controls (Atg5+/+) underwent comprehensive in vivo phenotyping using echocardiography, exercise tolerance and hemodynamic stress testing. In vitro assessment included gravimetry, qPCR of hypertrophy marker genes and cellular and nuclear dimensions of isolated ventricular myocytes. CaMKII activation was studied by immunocytochemistry in cardiomyocytes upon exposure to basal (1Hz) or high (4Hz) pacing frequency. Autophosphorylated CaMKII (pT286) signal was evaluated in different subcellular spaces (i.e. cytoplasm, nucleoplasm and nuclear envelope). Results Before symptomatic cardiac dysfunction occurred, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation (dp/dt max: 9475±126 vs 7364±496 mmHg/s, N=4–5; p=0.041), despite similar maximum heart rate. Consequently, effort intolerance (distance run: 251±22 vs 152±13 m, N=8; p=0.03) and maximal oxygen consumption (2093±66 vs 1763±131 ml/h/kg, N=8; p=0.04) were reduced during treadmill exercise tolerance testing. Increased heart-to-body weight ratio (8.1±0.5 vs 10.2±0.8 N=9; p=0.017) was associated with elevated mRNA expression of hypertrophy marker NppB (278% of Atg5+/+, N=5; p=0.016) in Atg5−/− mice, which showed enlarged cardiomyocytes and nuclei, as width-to-length ratio. Because Atg5−/− cardiomyocytes exhibit elevated nuclear Ca2+ levels at high pacing frequency, we now measured subcellular CaMKII activation under the same experimental conditions. Interestingly, at 1Hz, p-CaMKII was increased specifically at the nuclear envelope (154% of Atg5+/+, N=5 mice, 153–159 cells; p=0.029), but not in the cytoplasm or nucleoplasm. Increasing pacing frequency to 4Hz did not alter p-CaMKII levels in Atg5+/+ cells. However, p-CaMKII was increased by ∼30% and ∼20% in the cytoplasm and nucleoplasm of Atg5−/− cells respectively (N=5 mice, 153–155 cells). Conclusion Loss of ATG5-dependent autophagy causes cardiac hypertrophy and impaired cardiac reserve upon acute stress, which involves CaMKII activation, likely through the imbalance of nuclear Ca2+ load. Although, selective increase in p-CaMKII at the nuclear envelope in Atg5−/− mice may temporarily protect from nuclear Ca2+ overload, excessive CaMKII activation in the cytoplasm and the nucleoplasm upon increased workload, likely drives hypertrophic signalling toward heart failure in autophagy-defective mice. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund (FWF)

Investigation of the mechanisms of VEGF-mediated compensatory lung growth: the role of the VEGF heparin-binding domain

Morbidity and mortality for neonates with congenital diaphragmatic hernia-associated pulmonary hypoplasia remains high. These patients may be deficient in vascular endothelial growth factor (VEGF). Our lab previously established that exogenous VEGF164 accelerates compensatory lung growth (CLG) after left pneumonectomy in a murine model. We aimed to further investigate VEGF-mediated CLG by examining the role of the heparin-binding domain (HBD). Eight-week-old, male, C57BL/6J mice underwent left pneumonectomy, followed by post-operative and daily intraperitoneal injections of equimolar VEGF164 or VEGF120, which lacks the HBD. Isovolumetric saline was used as a control. VEGF164 significantly increased lung volume, total lung capacity, and alveolarization, while VEGF120 did not. Treadmill exercise tolerance testing (TETT) demonstrated improved functional outcomes post-pneumonectomy with VEGF164 treatment. In lung protein analysis, VEGF treatment modulated downstream angiogenic signaling. Activation of epithelial growth factor receptor and pulmonary cell proliferation was also upregulated. Human microvascular lung endothelial cells (HMVEC-L) treated with VEGF demonstrated decreased potency of VEGFR2 activation with VEGF121 treatment compared to VEGF165 treatment. Taken together, these data indicate that the VEGF HBD contributes to angiogenic and proliferative signaling, is required for accelerated compensatory lung growth, and improves functional outcomes in a murine CLG model.

Exercise tolerance and quality of life in patients with known or suspected coronary artery disease.

Coronary artery disease (CAD) is known to impact on patients' physical and mental health. The relationship between performance on treadmill exercise tolerance test (ETT) and health-related quality of life (HRQL)has never been specifically investigated in the setting of CAD. Consecutive patients undergoing an ETT with the Bruce protocol during a diagnostic workup for CAD (n = 1,631, age 55 ± 12years) were evaluated. Exercise-related indices were recorded. Detailed information on cardiovascular risk factors and past medical history were obtained. HRQLwas assessed with the use of the validated 36-Item Short Form Survey (SF-36) questionnaire. Increasing age and the presence of cardiovascular risk factors and comorbidities correlated with lower scores on the physical and mental health component of SF-36(all P < 0.05). Subjects with arrhythmias during exercise and slow recovery of systolic blood pressure had lower scores on the physical health indices or the Social Role Functioning component (P < 0.05). Achieved target heart rate and good exercise tolerance were independently associated with better scores of the physical and mental health domains of SF-36 and overall HRQLscores (β = 0.05 for target HR and PCS-36, β = 1.86 and β = 1.66 per increasing stage of exercise tolerance and PCS-36 and MCS-36, respectively, P < 0.001 for all associations). Ischemic ECG changes were associated with worse scores on Physical Functioning (β = - 3.2, P = 0.02) and Bodily Pain (β = - 4.55, P = 0.026). ETT parameters are associated with HRQL indices in patients evaluated for possible CAD. Physical conditioning may increase patient well-being and could serve as a complementary target in conjunction with cardiovascular drug therapy.

Personalized determination of target training heart rates for all ages, including patients with heart disease

BackgroundLack of physical exercise was recently accepted as a clinical diagnosis (ICD‐10‐CM Z72.3). The prescription of exercise requires a personalized training plan. Currently the Karvonen formula is used to calculate a target training heart rate (HR) by subtracting the age from 220. Because of individual differences in aerobic exercise capacities, resting parasympathetic tone, cardiac disease state, co‐morbidities, and medications (especially beta blocker), we suggest applying treadmill exercise tolerance testing to determine a personalized training HR zone, including patients with heart disease.Methods and study protocolIn 1999, the Austrian ambulatory cardiac rehabilitation was established and currently includes 12 centers. The cardiac rehabilitation program consists of three phases; phase I begins during the hospital stay, while phase II (6 weeks, 4 times/week) and phase III (up to 13 months, 2 times/week) are conducted in ambulatory cardiac rehabilitation centers under physician supervision. Additional home‐based training is recommended every day of the week. Male and female subjects participating in phase II and phase III rehabilitation underwent initial screening, and subjects with aortic stenosis, low systolic output (EF% &lt; 15), and dyspnea at rest (NYHA Class IV) were excluded. Bicycle ergometer exercise protocols used were 10W/10W/min (~90% of subjects) or 20W/20W/min (~10% of subjects) and HR was monitored continuously to generate a continuous HR curve to show a clear HR deflection point.ResultsWe retrospectively analyzed 9042 ECG treadmill test results (male = 7053, female = 1989) conducted at the Center for Ambulatory Rehabilitation Graz between 1‐1‐1999 and 10‐31‐2019. No significant difference in maximal training capacities was found between male and female subjects. Under physician supervision treadmill exercise tolerance testing was safe and well tolerated by maximally challenged male and female subjects of all ages, and no cardiac or cerebral events occurred during or after treadmill testing. The HR deflection point was assessed for each subject. The personalized training HR zone was compiled of 80–95% of the HR deflection point (not 220‐age), and training initiated during phase II and continued during phase III. Subjects were encouraged to achieve optimal training HR for 30 minutes daily and advised to perform muscle strengthening exercises twice per week.ConclusionOur study shows that optimal training heart rates can be determined by treadmill exercise testing, when patients are maximally challenged. Once “true” exhaustion is tested (which is often not achieved) a personalized target training HR zone can be calculated utilizing the individual HR deflection point. This approach will offer two advantages: 1) evaluation of underlying cardiovascular disease (cardiac ischemia), and 2) determination of an individualized and recommended target training heart rates for the “medical prescription of exercise”.

Cardiac Exercise Stress Testing: A Safe Tool to Design an Individualized Physical Exercise Training Plan for Older Adults

IntroductionIn the United States about 10% of premature mortality is associated with insufficient physical activity. New 2018 Physical Activity Guidelines (PAG) were announced recently but it is unclear how these guidelines will be implemented in the general population. Recommending an individualized training plan in elderly patients is challenging. Cardiac stress tests are primarily used to evaluate potential underlying cardiovascular disease but can also be used to assess cardiorespiratory fitness (CRT). We hypothesized that treadmill cardiac exercise stress testing in older adults will be safe and useful to initiate an exercise training plan.MethodsWe retrospectively investigated ECG treadmill test results conducted at the Center for Ambulatory Rehabilitation Graz (ZARG), Austria. The Austrian cardiac rehabilitation program consists of three phases; phase I begins during the hospital stay, and phase II (6 weeks, 4 times/week) as well as phase III (up to 13 months, 2 times/week) are conducted in ambulatory cardiac rehabilitation centers and a home‐based training recommended every day of the week. Patients participating in phase II and phase III rehabilitation underwent initial screening and subjects with aortic stenosis, low systolic output (EF% &lt; 45), and dyspnea at rest (NYHA Class IV) were excluded. Male and female patients age 65y–75y (n= 3006) and 75y–90y (n= 2493) were included. The ECG stress test training protocol was conducted, heart rate (HR) monitored continuously, and the HR threshold (HRT) calculated from the whole HR curve over time. We further documented body weight, height, body mass index, resting HR, maximal HR, resting/baseline as well as maximal systolic and diastolic blood pressure, calculated VO2Max, 50Watt HR, 100‐Watt HR, max Watt, and Watt/kg.ResultsBaseline bicycle ergometer exercise was performed until perceived exertion. Protocols used were 10W/10W increments per min (~90% of patients) or 20W/20W/1min (~10% of patients). Treadmill exercise tolerance testing was well tolerated by male and female patients of all ages (total n=5499). No differences between “maximal training capacity (Max Watt)” were found in male and female patients. Further, no difference in exercise capacity was found between the 65–75‐year (n= 3006) and 75–90‐year (n= 2493) age groups due to a wide range of individual exercise capacity amongst all participants. A personal training plan was compiled based on 70% of maximal performance. Patients were encouraged to achieve optimal training heart rates for 30 minutes daily and advised to perform muscle strengthening twice per week.ConclusionTreadmill exercise stress testing in older adults is safe and of great value to implement a home‐based personalized endurance exercise program. Since a direct link between CRT and early mortality has been shown, our data suggest that cardiac exercise stress testing should be routinely performed, not only to document and monitor cardiovascular disease, but also to prescribe a detailed, safe, individual, and home‐based exercise plan to achieve the new 2018 PAG.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiorespiratory fitness in survivors of cervical, endometrial, and ovarian cancers: The Cooper Center Longitudinal Study

BackgroundCardiorespiratory fitness (CRF), a strong predictor of mortality, is impaired among cancer patients. There is limited data, however, regarding CRF levels in women diagnosed with gynecologic cancers. MethodsWe compared CRF among ovarian, endometrial, and cervical cancer cases (n=89) to age-matched controls (n=89) in the Cooper Center Longitudinal Study (CCLS). CRF was evaluated by a maximal treadmill exercise tolerance test using a modified-Balke protocol. Conditional logistic regression was used to test for case–control differences in cardiorespiratory fitness, after controlling for age and body mass index, and adhering to the matched pairs design. ResultsThe mean ages of cancer cases and controls were 50.9years and 51.1years, respectively (p=0.81). Peak METs (1 MET=3.5mLkg−1min−1) were 9.2±2.0 in cancer cases compared to 10.0±2.2 in controls (p=0.03). When stratifying by type of cancer, peak METs were 8.9±2.2, 8.4±1.9, 9.5±2.0 for patients with ovarian, endometrial, and cervical cancer, respectively. A gynecological cancer diagnosis was associated with greater odds of having 1-MET lower CRF compared to controls (OR 1.31, 95% CI: 1.05–1.64, p=0.018), after controlling for age and BMI. ConclusionGynecologic cancer survivors were more likely to have a 1-MET lower CRF than controls. Given a 1-MET change in CRF is associated with a significant, we advocate for more robust research regarding CRF in gynecologic cancer patients.

Impact of utilizing a women-based formula for determining adequacy of the chronotropic response during exercise treadmill testing.

A women-based formula for calculation of age-predicted maximum heart rate [age-predicted maximum heart rate=206-(0.88×age)] was established in asymptomatic volunteer women undergoing treadmill exercise tolerance testing (ETT). We sought to perform a comparison of the performance of this women-based formula for prediction of peak heart rate to the traditional formula [220-age] and our own database-generated prediction formula in a large database of women undergoing ETT. We performed a retrospective analysis of all consecutive women who underwent symptom-limited Bruce protocol ETT at the Mayo Clinic from 1994 to 2010. Women with known cardiovascular disease or those using beta blockers, calcium channel blockers, or digitalis were excluded. Separate analyses were performed according to symptomatic status. The study included 11,029 women (89.4% Caucasian) with a mean age 52±12 years; 3,632 (33%) were referred specifically for evaluation of symptoms. Age-predicted maximum heart rate calculated by the traditional formula was achieved by 49.7% of women versus 69.9% by the women-based formula with most of the underestimation observed in older women. Average absolute deviation between achieved and predicted peak heart rate (HR) was 10.85±9.18 bpm for traditional versus 11.98±9.00 for women-based formulas (dependent t=-16.64, p<0.0001). The linear regression line calculated from our population [HR=201-(0.67×age)] was closer to the women-based formula, both in terms of intercept and slope than the traditional formula. Peak HR was shown to be slightly affected (-2.5 bpm) by symptom status at referral, whereas smoking and diabetes more significantly reduced achieved peak HR. The women-based formula underestimated peak HR, especially in older women, but was observed to be closer in both intercept and slope to the regression line determined from our study in this large population of female patients. These sex-unique observations should be taken into account when determining adequacy and targets for ETT in women.

Feasibility Study of Treadmill Exercise Tolerance Test as a Surrogate for the Measurement of VO2max

Feasibility Study of Treadmill Exercise Tolerance Test as a Surrogate for the Measurement of VO2max

128 MORE DISCHARGES, LESS FOLLOW-UP AND SIMILAR RATES OF CORONARY ANGIOGRAPHY: INITIAL ‘REAL-WORLD’ EXPERIENCE OF NICE GUIDANCE ON ASSESSMENT OF CHEST PAIN OF RECENT ONSET IN THE RAPID ACCESS CHEST PAIN CLINIC

IntroductionIn March 2010 NICE clinical guideline number 95 described a new protocol-driven pathway for the investigation of chest pain of recent onset. This emphasised the importance of establishing pre-test probability...

Poster 80: Evaluating Submaximal Exercise Tolerance Testing Designed to be Appropriate for Mobility-Limited Older Adults

Objective: To evaluate the validity of a submaximal exercise tolerance testing (ETT) protocol designed for use among older adults with limitations in mobility. Design: A cross-sectional analysis. Setting: An outpatient rehabilitation center. Participants: 67 mobility-limited, community-dwelling adults, ages 65 and older with mobility limitations as manifested by the Short Physical Performance Battery (SPPB). Interventions: Not applicable. Main Outcome Measures: Exercise duration was quantified via treadmill ETT.

The treadmill exercise-tolerance test is useful for the prediction and prevention of ischemic coronary events in elderly diabetics

Background Approximately 80% of cases of ischemic heart disease (IHD) occur in patients with nonstenotic coronary arteries, and few studies have systematically assessed exercise testing (TMT) as a predictor of risk in the elderly. Methods TMT was carried out using a protocol for the independent and active elderly ( n=176). After 4.1±0.5 years follow-up, logistic regression analysis was performed for each coronary risk factor such as diabetes mellitus (DM) and hypercholesterolemia (HC). According to the results, patients were divided into Gp HC, hypercholesterolemic patients; Gp DM, diabetics; Gp HC+DM, hypercholesterolemic diabetics; and Gp C, nonhyperlipidemic and nondiabetics. Sensitivity and specificity of TMT for IHD (significant stenosis or acute coronary syndrome) were analyzed. Results Odds ratios for each risk factors are as follows: DM, 4.167; HC, 4.485; and DM+HC, 8.652. Notably, TMT was 17.59. Age was a significant risk, but hypertension was not. Positive ischemic signs in TMT were observed in 52.7%, 28.6%, 33.3%, and 16.3% in the Gp HC+DM, HC, DM, and C groups, respectively. Only three participants complained of chest pain during the TMT. Significant stenosis was observed in 75.0%, 71.4%, 69.2%, and 60.0% of coronary angiography (CAG)-receiving patients of Gp HC, DM, HC+DM, and C. During the observation term, acute coronary syndromes occurred in 4.7%, 3.3%, 5.5%, and 0% of patients in the Gp HC, DM, HC+DM, and C groups, respectively. The sensitivity of TMT for IHD was higher than 66.7% and specificity was higher than 94.1% in each group. Conclusion An exercise tolerance test in the elderly, especially for diabetics and hypercholesterolemic patients, is useful for the diagnosis of IHD.

Comparison of controlled-onset, extended-release verapamil with amlodipine and amlodipine plus atenolol on exercise performance and ambulatory ischemia in patients with chronic stable angina pectoris

This multicenter, randomized, double-blind, parallel group, placebo lead-in, placebo-controlled study compared the antianginal and anti-ischemic effects of once-daily bedtime dosing of controlled-onset extended-release (COER-24) verapamil to a once-daily morning dosing of amlodipine ± atenolol in patients with chronic stable angina. A total of 551 patients with exercise-induced myocardial ischemia and evidence of coronary artery disease were randomized to a 4-week, forced-dose titration treatment period with (1) COER-24 verapamil 240 mg titrated to 480 mg at bedtime (n = 173), (2) amlodipine 5 mg titrated to 10 mg/day (n = 149), (3) amlodipine 5 mg (titrated to 10 mg) plus atenolol 50 mg/day in the a.m. (n = 154), or (4) placebo (n = 75). Treadmill exercise tolerance testing (standard Bruce protocol), and 48-hour ambulatory electrocardiographic (Holter) monitoring were performed at the end of placebo lead-in and double-blind treatment. Each active treatment significantly improved symptom-limited exercise duration and time to moderate angina (p ≤0.01 vs placebo). For patients with baseline ischemia, amlodipine resulted in a statistically significant increase in total duration of ischemic episodes compared with placebo, whereas COER-24 verapamil and amlodipine plus atenolol resulted in statistically significant decreases compared with placebo and amlodipine. Heart rate at onset of ischemic episodes and ST product were also significantly increased with amlodipine (p <0.05) compared with either COER-24 or amlodipine plus atenolol. COER-24 and amlodipine alone or in combination with atenolol improved exercise capacity in patients with angina pectoris. COER-24 verapamil monotherapy or amlodipine plus atenolol combination therapy were more effective than amlodipine monotherapy in decreasing ambulatory myocardial ischemia, especially during the hours of 6 a.m. to 12 noon.

Adding the new calcium antagonist mibefradil to patients receiving long-term β-blocker therapy results in improved antianginal and antiischemic efficacy

Objective The objective of this study was to evaluate the efficacy, tolerability, and safety of mibefradil, a new selective T-type calcium channel blocker, in patients with chronic stable angina pectoris receiving concomitant β-blocker therapy. Design This was a multicenter, double-blind, placebo-controlled study. Methods Ninety-five patients receiving a stable dose of β-blockers, which was not changed for the purpose of the study, were administered either 50 mg mibefradil once daily for 2 weeks, then 100 mg once daily for 2 weeks, or matching placebo. Efficacy was evaluated by treadmill exercise tolerance testing 24 hours after dose and by diary registration of anginal episodes and nitroglycerin consumption. Results Two weeks of treatment with 50 mg mibefradil resulted in a significant increase in symptom-limited exercise duration and a significant delay in the onset of persistent 1 mm ST-segment depression (placebo-corrected treatment effect: 23.2 and 51.7 seconds, respectively). Treatment with the 100 mg dose for 2 additional weeks resulted in a larger improvement in treadmill exercise tolerance testing duration and onset of ischemia (placebo-corrected treatment effect: 52.7 and 75.8 seconds, respectively). In addition, a significant decrease in weekly anginal episodes was observed with the 100 mg dose of mibefradil compared with the effect in the placebo group (-53% vs -12%, p = 0.037). Conclusions The combined treatment of mibefradil and β-blockers was well tolerated, and the overall incidence of adverse events was no different from that with β-blockers alone. The results indicate that adding mibefradil to chronic β-blocker treatment is associated with significant improvement in efficacy, which is not achieved at the expense of tolerability. (Am Heart J 1998;135:272-80.)

Perioperative Sympatholysis

Perioperative Sympatholysis

Dose‐Ranging Study of a New, Once‐Daily Diltiazem Formulation for Patients with Stable Angina

A double-blind safety and efficacy dose-ranging study was conducted with a new, once-daily, extended-release (XR) diltiazem hydrochloride formulation (Dilacor XR, Rhône-Poulenc Rorer, Collegeville, PA) in 189 patients with chronic stable angina pectoris. After a 2-week placebo lead-in phase, the patients were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: placebo, XR diltiazem 120 mg, 240 mg, or 480 mg. Extended-release diltiazem, at 240-mg and 480-mg once-daily doses, significantly improved (P < .05) total exercise time during treadmill exercise tolerance testing after 2 weeks of treatment when assessed 24 hours after the previous dose. These increasing doses of XR diltiazem were associated with incremental improvements in exercise tolerance. Outpatient function, as assessed by frequency of anginal attacks, nitroglycerin use, and ambulatory electrocardiogram (Holter, Scole Engineering Culver City, CA) monitoring of ischemic events, was also improved by XR diltiazem. This extended-release diltiazem formulation can be clinically titrated within the 120- to 480-mg dosing range, permitting effective once-daily administration for treating chronic stable angina.

各種β遮断薬の狭心症に対する効果の比較検討 トレッドミル運動負荷試験を用いて

各種β遮断薬の狭心症に対する効果の比較検討 トレッドミル運動負荷試験を用いて