Circulatory improvement after hydralazine or isosorbide dinitrate administration in patients with heart failure: Effect on metabolic responses to submaximal exercise

Hydralazine and isosorbide dinitrate can increase the cardiac output during submaximal exercise in patients with heart failure but whether this increase improves oxygen delivery to underperfused exercising muscle is uncertain. To investigate this question, we measured three systemic markers of skeletal muscle oxygen availability—exercise V?O₂, mixed venous lactate concentration and oxygen debt—during submaximal exercise in 15 patients with heart failure both before and after hydralazine (nine patients) or isosorbide dinitrate (eight patients) administration. Hydralazine increased the cardiac output during exercise from 4.9 ± 1.2 liter/min to 6.5 ± 1.8 liter/min (p < 0.01) but had no effect on exercise V?O₂ (control, 531 ± 135 ml/min; hydralazine, 489 ± 102 ml/min), peak lactate concentration (control, 18.3 ± 4.2 mg/dl; hydralazine, 17.9 ± 3.6 mg/dl) or oxygen debt (control, 474 ± 213 ml; hydralazine, 465 ± 170 ml) (all p > 0.10). Isosorbide dinitrate increased the cardiac output during exercise from 4.6 ± 0.9 liter/min to 5.3 ± 0.8 liter/min (p < 0.01) but also did not change exercise V?O₂ (control, 488 ± 62 ml/min; isosorbide, 473 ± 44 ml/min), peak lactate concentration (control, 19.2 ± 6.0 mg/dl; isosorbide, 21.4 ± 8.2 mg/dl) or oxygen debt (control, 522 ± 154 ml; isosorbide, 445 ± 147 ml) (all p > 0.10). We conclude that short-term administration of hydralazine or nitrates to patients with heart failure can substantially improve circulatory function during exercise but that this improvement probably does not enhance skeletal muscle nutritional flow.     

Accuracy of cardiac output,oxygen uptake and arteriovenous oxygen difference at rest,during exercise and after vasodilator therapy in patients with severe,chronic heart failure

Measurement of cardiac output, arteriovenous oxygen difference and oxygen uptake in patients with heart failure may be subject to technical and biologic inaccuracies. We measured these 3 variables in 16 patients with chronic heart failure at rest and during exercise. When cardiac output was measured by thermodilution and compared with values calculated by the Pick principle, there was a significant correlation at rest (r = 0.91, p < 0.001) and at exercise (r = 0.93, p < 0.001). When the arteriovenous oxygen difference was measured by spectrophotometry of arterial and mixed venous samples and compared with values calculated by the Pick principle, there was a significant correlation at rest (r = 0.80, p < 0.01) and at exercise (r = 0.76, p < 0.01). When oxygen uptake was measured from expired gas analysis and compared with values calculated by the Pick principle, there was a significant correlation at rest (r = 0.84, p < 0.01) and at exercise (r = 0.94, p < 0.001). In addition, 10 patients received vasodilator treatment which increased cardiac output and decreased the arteriovenous oxygen difference at rest and exercise. There was no significant difference between measured and calculated values for the 3 variables under those additional conditions. It is concluded that despite technical and biologic difficulties, cardiac output, arteriovenous oxygen difference and oxygen uptake, when calculated from Pick's principle, yield results equivalent to direct measurement.     

Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: Role of cardiac pump dysfunction as determined by the effect of dobutamine

The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently reduced, partly because of inadequate skeletal muscle nutritive flow. To investigate whether this altered muscle nutritive flow is a result of inability of the heart to increase cardiac output normally during exercise, the effect of dobutamine on systemic and leg blood flow and metabolism during maximal exercise was examined in 11 patients with CHF. At maximal exercise before dobutamine, all patients were limited by fatigue and had reduced maximal systemic oxygen uptake (11.9 ± 1.1 ml/min/kg) (± standard error of the mean), markedly elevated leg oxygen extraction (85 ± 2%) and elevated femoral venous lactate (53 ± 5 mg/dl), consistent with impaired nutritive flow to working muscle. Dobutamine increased the peak cardiac output from (6.5 ± 0.9 to 7.4 ± 0.7 liters/min, p < 0.01) and peak leg flow (from 1.7 ± 0.3 to 2.1 ± 0.3 liters/min, p < 0.05) during exercise. In contrast, no change occurred in maximal exercise duration (5.5 ± 0.8 vs 5.8 ± 0.8 min), peak systemic VO₂ (829 ± 97 vs 869 ± 77 ml/min), peak arterial lactate (34 ± 2 vs 35 ± 4 mg/dl) or peak leg lactate output (248 ± 39 vs 275 ± 53 mg/min), whereas peak leg oxygen extraction decreased (85 ± 2 to 80 ± 2%, p < 0.01), suggesting no improvement in muscle nutritive flow. These data suggest that nutritive flow to working skeletal muscle is impaired in patients with CHF and that this impairment is not due simply to an inability of the heart to increase the cardiac output normally during exercise.     

Identification of Three Exercise-induced Mortality Risk Factors in Patients with COPD

The survival rate of chronic obstructive pulmonary disease (COPD) patients with severely reduced exercise capacity is extremely low. We recently identified three life-threatening pathophysiological conditions during cardiopulmonary exercise testing (CPET): (1) exercise-induced hypoxemia, (2) sympathetic overactivity, and (3) progressive respiratory acidosis at low-intensity exercise. The present prospective observation study aimed to determine whether these parameters constitute risk factors of mortality in moderate-to-very severe COPD. Ninety-six COPD patients were followed-up, monthly, for >3 years. Subsequently, spirometry and CPET were performed to examine parameters of exercise-induced hypoxemia ([PaO₂ slope, mmHg/L · min^?1] = Decrease in PaO₂/ΔV˙ O₂ (Difference in ΔV˙ O₂ between at rest and at peak exercise)), progression of acidosis ([ΔpH/ΔV˙ O₂,/L · min^?1] = Decrease in pH/ΔV˙ O₂), and sympathetic overactivity ([Δnorepinephrine (NE)/ΔV˙ O₂, ng/mL/L · min^?1] = Increase in NE/ΔV˙ O₂). Univariate analysis revealed a significant association between the three conditions with increased mortality. Kaplan–Meier analysis showed that the quartile combining the steepest PaO₂ slope (≤–55 mmHg/ΔV˙ O₂ [L/min]), steepest decrease in arterial blood pH (≤ –1.72/ΔV˙ O₂ [L/min]), and most rapid increase in plasma NE level (≥ 5.2 ng/VO₂ [L/min]) during incremental exercise was associated with higher all-cause mortality. These conditions showed cumulative effects on COPD patients’ survival. Multivariate analyses revealed that these three life-threatening factors are also independent predictors of mortality based on age, heart rate and PaO₂ at rest, body mass index, and forced expiratory volume in 1 s. Thus, these new exercise-induced mortality risk factors may lead to more efficient pulmonary rehabilitation programs for COPD patients based on patient-specific exercise-induced pathophysiological profiles.     

Effects of vasodilators on pulmonary hemodynamics and gas exchange in left ventricular failure

Nitroprusside (NP) has been shown to improve left ventricular function in patients with congestive heart failure, but despite an increased cardiac output and decreased pulmonary capillary pressure, arterial oxygen tension (P_aO₂) may fall. In order to determine the mechanism of this hypoxemia, and to determine if similar effects occur with non-parenteral vasodilators, hemodynamic, respiratory, and blood gas responses to NP, hydralazine (H), and hydralazine combined with isiosorbide dinitrate (H+N) were studied in 10 patients with left ventricular failure. At the dosages used, all three drug regimens increased cardiac output equivalently, but pulmonary vascular responses differed. NP and H+N decreased mean pulmonary artery pressure, pulmonary wedge pressure, and pulmonary arteriolar resistance, while H did not. NP decreased P_aO₂ by 10.4 mm. Hg (p < .01) and H+N decreased it by 5.3 mm. Hg (p < .06) while H did not alter P_aO₂. Arteriolar-alveolar oxygen gradient increased with NP (150 ± 39 per cent, p < .01) and with H+N (73 ± 23 per cent, p < .01) but not H alone (51 ± 16 per cent). Similarly, per cent change in venous admixture increased on NP (28.7 ± 3.3 to 38.5 ± 3.1 per cent, p < .01) and H+N (28.1 ± 3.3 to 36.8 ± 3.5 per cent, p < .01) but not H alone (28.1 ± 3.3 to 31.5 ± 4.1 per cent). There was no increase in arterial carbon dioxide tension or change in pulmonary function studies with any of the drugs. Due to the increase in cardiac output, oxygen delivery index (cardiac output times arterial oxygen content) increased with each regimen despite the changes in P_aO₂. Changes in arteriolar-alveolar oxygen gradient correlate with the changes in pulmonary arteriolar resistance. Thus vasodilators which have prominent pulmonary vascular effects can decrease P_aO₂ in patients with congestive heart failure, and this effect is most likely due to increasing ventilation-perfusion inequities.     

Lactate threshold is not an onset of insufficient oxygen supply to the working muscle in patients with chronic heart failure

It has been argued that the lactate threshold (LT) serves as an index to reflect circulatory insufficiency in transporting oxygen during submaximal exercise in patients with chronic heart failure (CHF). We examined whether or not the LT was related to an insufficient oxygen supply in patients with CHF. Sixty-nine patients were divided by NYHA classification. All underwent invasive cardiopulmonary exercise testing. The rate of increase in oxygen delivery (O₂D) versus VO₂ (ΔO₂D/ ΔVO₂) was significantly lowered when work rate exceeded LT, that is, 1.32 ± 0.35 to 1.05 ± 0.37 (p < 0.01), 1.22 ± 0.40 to 0.98 ± 0.40 (p < 0.05), and 1.04 ± 0.26 to 0.78 ± 0.39 (p < 0.05) in NYHA classes I, II, and III, respectively. However, the rate of increase in leg O₂D versus leg VO₂ (ΔLO₂D/ΔLVO₂) did not change, that is, 1.25 ± 0.20 to 1.29 ± 0.20 (NS), 1.27 ± 0.23 to 1.21 ± 0.28 (NS), and 1.19 ± 0.24 to 1.15 ± 0.17 (NS) in classes I, II, and III, respectively. Leg venous PO₂ was significantly different among three groups, that is, 23.7 ± 3.4 mmHg, 23.2 ± 2.8 mmHg, and 20.1 ± 2.3 mmHg (p < 0.001), respectively. Thus, the oxygen supply to the working muscle did not become insufficient when work rate exceeded LT, and the LT occurred at different levels of leg PO₂. It was concluded that the LT was not a result of anaerobiosis in patients with CHF.     

Sympathetic Activation is Associated with Exercise Limitation in COPD

Exercise intolerance, skeletal muscle dysfunction, and reduced daily activity are central in COPD patients and closely related to quality of life and prognosis. Studies assessing muscle exercise have revealed an increase in sympathetic outflow as a link to muscle hypoperfusion and exercise limitation. Our primary hypothesis was that muscle sympathetic nerve activity (MSNA) correlates with exercise limitation in COPD.

MSNA was evaluated at rest and during dynamic or static handgrip exercise. Additionally, we assessed heart rate, blood pressure, CO2 tension, oxygen saturation (SpO2), and breathing frequency. Ergospirometry was performed to evaluate exercise capacity.

We assessed MSNA of 14 COPD patients and 8 controls. In patients, MSNA was negatively correlated with peak oxygen uptake (VO₂% pred) (r = ?0.597; p = 0.040). During dynamic or static handgrip exercise, patients exhibited a significant increase in MSNA, which was not observed in the control group. The increase in MSNA during dynamic handgrip was highly negatively correlated with peak exercise capacity in Watts (w) and peak oxygen uptake (VO2/kg) (r = ?0.853; p = 0.002 and r = ?0.881; p = 0.002, respectively).

Our study reveals an association between increased MSNA and limited exercise capacity in patients with COPD. Furthermore, we found an increased sympathetic response to moderate physical exercise (handgrip), which may contribute to exercise intolerance in COPD.     

What can we learn from exercise testing beyond the detection of myocardial ischemia?

Noninvasive cardiopulmonary exercise (CPX) testing has proven useful in the assessment of heart and lung disease, including cardiac and ventilatory reserves. CPX includes the monitoring of respiratory gas exchange, O₂ uptake and CO₂ production, together with minute ventilation and its components—tidal volume and respiratory rate—together with surveillance of electrocardiography and blood pressure during supervised, incremental exercise. Exercise responses in anaerobic threshold and/or maximal O₂ uptake are used to grade functional capacity objectively and to predict cardiac reserve (exercise cardiac output), which grades the severity of chronic cardiac or circulatory failure. CPX also serves to distinguish primary cardiac from ventilatory-based exertional dyspnea.     

Oxygen uptake efficiency slope, a new submaximal parameter in evaluating exercise capacity in chronic heart failure patients

Background

The oxygen uptake efficiency slope (OUES) is a new submaximal parameter which objectively predicts the maximal exercise capacity in children and healthy subjects. However, the usefulness of OUES in adult patients with and without advanced heart failure remains undetermined. The present study investigates the stability and the usefulness of OUES in adult cardiac patients with and without heart failure.

Methods

Forty-five patients with advanced heart failure (group A) and 35 patients with ischemic heart disease but normal left ventricular ejection fraction (group B) performed a maximal exercise test. PeakVO₂ and percentage of predicted peakVO₂ were markers of maximal exercise capacity, whereas OUES, ventilatory anaerobic threshold (VAT), and slope VE/VCO₂ were calculated as parameters of submaximal exercise.

Results

Group A patients had lower peakVO₂ (P < .001), lower percentage of predicted peakVO₂ (P = .001), lower VAT (P < .05), steeper slope VE/VCO₂ (P < .001), and lower OUES (P < .02). Within group A, significant differences were found for VAT, slope VE/VCO₂, and OUES (all P < .01) between patients with peakVO₂ above and below 14 mL O₂/kg/min. Of all the submaximal parameters, VAT correlated best with peakVO₂ (r =.814, P < .01) followed by OUES/kg (r = .781, P < .01), and slope VE/VCO₂ (r = −.492, P < .001). However, VAT could not be determined in 18 (23%) patients.

Conclusions

OUES remains stable over the entire exercise duration and is significantly correlated with peakVO₂ in adult cardiac patients with and without impaired LVEF. Therefore, OUES could be helpful to assess exercise performance in advanced heart failure patients unable to perform a maximal exercise test. Further studies are needed to confirm our hypothesis.     

Effects of isosorbide dinitrate and hydralazine on regional metabolic responses to arm exercise in patients with heart failure

The reduced exercise capacity of patients with heart failure is thought to be due in part to impaired skeletal muscle oxygen delivery. To determine if hydralazine and isosorbide dinitrate improve skeletal muscle oxygen delivery in such patients, the effects of these agents on regional metabolic responses to forearm exercise were examined in 16 patients with heart failure. Arm oxygen extraction and brachial venous lactate concentration were measured at rest and during 3 minutes of rhythmic handgrip and then remeasured after administration of oral hydralazine (nine patients) or sublingual isosorbide dinitrate (nine patients). Hydralazine increased mean (± standard deviation) cardiac output at rest from 3.5 ± 0.5 to 4.9 ±1.0 liters/min (p < 0.01) and decreased arm oxygen extraction from 39 ± 8 to 33 ± 10 percent (probability [p] < 0.01), suggesting improved resting limb oxygen delivery. However, hydralazine did not reduce arm oxygen extraction during exercise (control 63 ± 4, hydralazine 60 ± 12 percent; p = notsignificant[NS]) or venous lactate during exercise (control 16.6 ± 7.8, hydralazine 17.1 ± 4.8 mg/100 ml; p = NS). Isosorbide dinitrate increased the cardiac output from 3.6 ± 0.7 to 4.5 ± 0.7 liters/min (p < 0.01) but had no effect on arm oxygen extraction at rest (control 40 ± 11, isosorbide dinitrate 38 ± 11 percent; p = NS) and during exercise (control 66 ± 5, isosorbide dinitrate 64 ± 8 percent; p = NS) or on venous lactate during exercise (control 17.9 ± 6.4, isosorbide dinitrate 17.1 ± 3.9 mg/100 ml; p = NS). These data suggest that hydralazine and isosorbide dinitrate do not improve skeletal muscle oxygen delivery during exercise in patients with heart failure.     

Diastolic exercise stress testing in heart failure with preserved ejection fraction: The DEST-HF study

Aims

Pulmonary capillary wedge pressure (PAWP) ≥25 mmHg during bicycle ergometry is recommended to uncover occult heart failure with preserved ejection fraction. We hypothesized that PAWP increase would differ in available diastolic stress tests and that the margin of PAWP ≥25 mmHg would only be reliably achieved through ergometry.

Methods and results

We conducted a prospective, single-arm study in patients with an intermediate risk for heart failure with preserved ejection fraction according to the ESC HFA-PEFF score. A total of 19 patients underwent four stress test modalities in randomized order: leg raise, fluid challenge, handgrip, and bicycle ergometry. The primary outcome was the difference (Δ) between resting and exercise PAWP in each modality. Secondary outcomes were differences (Δ) in mean pulmonary artery pressure (mPAP), cardiac output (CO), as well as the ratios between mPAP and PAWP to CO. Compared to resting values, passive leg raise (Δ7.7 ± 8.0 mmHg, p = 0.030), fluid challenge (Δ9.2 ± 6.4 mmHg, p = 0.003), dynamic handgrip (Δ9.6 ± 7.5 mmHg, p = 0.002), and bicycle ergometry (Δ22.3 ± 5.0 mmHg, p < 0.001) uncovered increased PAWP during exercise. Amongst these, bicycle ergometry also demonstrated the highest ΔmPAP (27.2 ± 7.1 mmHg, p < 0.001), ΔCO (3.3 ± 2.6 L/min, p < 0.001), ΔmPAP/CO ratio (2.3 ± 2.0 mmHg/L/min, p < 0.001), and ΔPAWP/CO ratio (2.2 ± 1.4 mmHg/L/min, p < 0.001) compared to other modalities. PAWP ≥25 mmHg was only reliably achieved in bicycle ergometry (31.1 ± 3.9 mmHg). In all other modalities only 10.5% of patients achieved PAWP ≥25 mmHg (handgrip 18.4 ± 6.6 mmHg, fluid 18.1 ± 5.6 mmHg, leg raise 16.5 ± 7.0 mmHg).

Conclusions

We demonstrate that bicycle ergometry exhibits a distinct haemodynamic response with higher increase of PAWP compared to other modalities. This finding needs to be considered for valid detection of exercise PAWP ≥25 mmHg when non-bicycle tests remain inconclusive.     

Cardiac Autonomic Function and Cardiovascular Response to Exercise in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is associated with impaired exercise tolerance, but it has not been established to what extent cardiac autonomic function impacts on exercise capacity. Objective: To evaluate whether there is an association between airflow limitation and cardiac autonomic function and whether cardiac autonomic function plays a role in exercise intolerance and daily physical activity (PA) in patients with COPD. Methods: Univariate and multivariate analyses were performed to evaluate the association between both 6-minute walking test (6MWT) and PA (steps per day) and pulmonary function, cardiac autonomic function (HR at rest, HRR and heart rate variability, HRV) in patients with COPD. Results: In 154 COPD patients (87 females, mean [SD]: age 62.5 [10.7] years, FEV₁%predicted (43.0 [19.2]%), mean HR at rest was elevated (86.4 [16.4] beats/min) and HRV was reduced (33.69 [28.96] ms) compared to published control data. There was a significant correlation between FEV₁ and HR at rest (r = -0.32, p < 0.001), between HR at rest and 6MWD (r = -0.26, p = 0.001) and between HR at rest and PA (r = -0.29, p = 0.010). No correlation was found between HRV and 6MWD (r = 0.089, p = 0.262) and PA (r = 0.075, p = 0.322). In multivariate analysis both HR and FEV₁ were independent predictors of exercise capacity in patients with COPD. Conclusions: In patients with COPD the degree of airflow limitation is associated with HR at rest. The degree of airflow limitation and cardiac autonomic function, as quantified by HR at rest, are independently associated with exercise capacity in patients with COPD.     

Multiparameter assessment of exercise capacity in patients with arterial hypertension

Introduction: Arterial hypertension (AH) can lead to the development of heart failure.

Aim: Evaluating the relationship between parameters of exercise capacity assessed via a six-minute walk test (6MWT) and cardiopulmonary exercise test (CPET), with a hemodynamic assessment via impedance cardiography (ICG), in patients with AH.

Methods: Exercise capacity was assessed in 98 hypertensive patients (54.5 ± 8.2 years) by means of oxygen uptake (VO₂) get from CPET, 6MWT distance (6MWTd) and hemodynamic parameters measured by ICG: heart rate (HR), stroke volume (SV), cardiac output (CO). Correlations between these parameters at rest, at anaerobic threshold (AT) and at peak of exercise as well as their changes (Δpeak-rest, Δpeak-AT, ΔAT-rest) were evaulated.

Results: A large proportion of patients exhibited reduced exercise capacity, with 45.9% not reaching 80% of predicted peak VO₂ and 43.9% not reaching predicted 6MWTd. Clinically relevant correlations were noted between the absolute peak values and AT values of VO₂ vs HR and VO₂ vs CO. Furthermore ΔVO₂(peak–AT) correlated with ΔHR(peak–AT), ΔCO(peak–AT) and ΔSV(peak–AT); ΔVO₂(peak–rest) with ΔHR(peak–rest) and ΔCO(peak–rest); ΔVO₂(AT–rest) with ΔHR(AT–rest) and ΔCO(AT–rest). Stronger correlations between changes in the evaluated parameters were demonstrated in the subgroup of subjects with peak VO₂ < 80% of the predicted value; particularly ΔVO₂(peak–AT) correlated with ΔSV(peak–AT) and ΔCO(peak–AT).

Conclusions: The hemodynamic parameters show significant correlations with more measures of cardiovascular capacity of proven clinical utility. Impedance cardiography is a reliable method for assessing the cardiovascular response to exercise.     

The Impact of Homogeneous Versus Heterogeneous Emphysema on Dynamic Hyperinflation in Patients With Severe COPD Assessed for Lung Volume Reduction

Dynamic hyperinflation (DH) is a pathophysiologic hallmark of Chronic Obstructive Pulmonary Disease (COPD). The aim of this study was to investigate the impact of emphysema distribution on DH during a maximal cardiopulmonary exercise test (CPET) in patients with severe COPD.

This was a retrospective analysis of prospectively collected data among severe COPD patients who underwent thoracic high-resolution computed tomography, full lung function measurements and maximal CPET with inspiratory manouvers as assessment for a lung volume reduction procedure. ΔIC was calculated by subtracting the end-exercise inspiratory capacity (eIC) from resting IC (rIC) and expressed as a percentage of rIC (ΔIC %). Emphysema quantification was conducted at 3 predefined levels using the syngo PULMO-CT (Siemens AG); a difference >25% between best and worse slice was defined as heterogeneous emphysema.

Fifty patients with heterogeneous (62.7% male; 60.9 ± 7.5 years old; FEV₁% = 32.4 ± 11.4) and 14 with homogeneous emphysema (61.5% male; 62.5 ± 5.9 years old; FEV₁% = 28.1 ± 10.3) fulfilled the enrolment criteria. The groups were matched for all baseline variables. ΔIC% was significantly higher in homogeneous emphysema (39.8% ± 9.8% vs.31.2% ± 13%, p = 0.031), while no other CPET parameter differed between the groups. Upper lobe predominance of emphysema correlated positively with peak oxygen pulse, peak oxygen uptake and peak respiratory rate, and negatively with ΔIC%. Homogeneous emphysema is associated with more DH during maximum exercise in COPD patients.     

Aerobic Exercise Training Improves Right- and Left Ventricular Systolic Function in Patients with COPD

Abstract

Objective: The aim of this study was to investigate the effects of moderate continuous training (MCT) and high intensity aerobic interval training (AIT) on systolic ventricular function and aerobic capacity in COPD patients. Methods: Seventeen patients with COPD (64 ± 8 years, 12 men) with FEV₁ of 52.8 ± 11% of predicted, were randomly assigned to isocaloric programs of MCT at 70% of max heart rate (HR) for 47 minutes) or AIT (～90% of max HR for 4×4 minutes) three times per week for 10 weeks. Baseline cardiac function was compared with 17 age- and sex-matched healthy individuals. Peak oxygen uptake (VO_2-peak) and left (LV) and right ventricular (RV) function examined by echocardiography, were measured at baseline and after 10 weeks of training. Results: At baseline, the COPD patients had reduced systolic function compared to healthy controls (p < 0.05). After the training, AIT and MCT increased VO_2-peak by 8% and 9% and work economy by 7% and 10%, respectively (all p < 0.05). LV and RV systolic function both improved (p < 0.05), with no difference between the groups after the two modes of exercise training. Stroke volume increased by 17% and 20%, LV systolic tissue Doppler velocity (S’) by 18% and 17% and RV S’ by 15% after AIT and MCT, respectively (p < 0.05). Conclusion: Systolic cardiac function is reduced in COPD. Both AIT and MCT improved systolic cardiac function. In contrast to other patient groups studied, higher exercise intensity does not seem to have additional effects on cardiac function or aerobic capacity in COPD patients.     

Abnormal Dynamic Cardiorespiratory Responses to Exercise in Pediatric Patients After Fontan Procedure

Objectives. Novel protocols were used to focus on dynamic cardiorespiratory function during submaximal exercise and on the recovery from 1-min pulses of exercise in children who had undergone Fontan corrections for single-ventricle lesions.Background. Particularly in children, maximal oxygen uptake (V̇o₂max), which is commonly used to assess the functional capability of patients after the Fontan procedure, is highly effort dependent and not physiologic and leads to uncomfortable metabolic and cardiorespiratory stress. Alternative approaches include the measurement of dynamic responses during progressive exercise and recovery after short bursts of exercise. These strategies yield mechanistic insight into cardiorespiratory impairment and can be used to gauge limitations in daily life activity.Methods. Sixteen patients (mean [±SD] age 12.2 ± 2.4 years; 9 boys) and 10 age-matched control subjects (mean age 12.2 ± 2.4 years; 6 boys) performed two separate cycle ergometer tests in which gas exchange was measured on a breath by breath basis: 1) Progressive exercise was used to determine the dynamic relation among V̇o₂, carbon dioxide production (V̇co₂), ventilation (V̇e), heart rate (HR) and work rate (WR). 2) A 1-min constant WR test was used to determine the recovery time for gas exchange and HR.Results. Peak V̇o₂and anaerobic threshold were reduced in patients who underwent the Fontan procedure compared with control subjects by 57% and 52%, respectively (p < 0.001). Dynamic relations during progressive exercise—ΔV̇o₂/ΔHR and ΔV̇o₂/ΔWR—were decreased (p < 0.001) and ΔV̇e/ΔV̇co₂was increased (p < 0.005) in the Fontan group patients. Recovery times for HR and V̇o₂were prolonged in the Fontan group patients by 154% and 69%, respectively (p < 0.01).Conclusions. The results demonstrate that submaximal gas exchange responses to progressive exercise and recovery times after brief high intensity exercise are abnormal in patients after the Fontan procedure. These observations complement the findings of reduced V̇o₂max observed here and by others. We speculate that the mechanisms for these responses are related to 1) a pervasive reduction in stroke volume for both low and high intensity exercise, 2) an abnormal linkage of ventilation to tissue carbon dioxide production, and 3) increased dependence on anaerobic metabolism in skeletal muscles. The prolonged recovery of HR and V̇o₂provides a possible mechanism for reduced physical activity.     

Implications of Doppler Echocardiography-guided Heart Rate Modulation Using Ivabradine

Objective Heart rate modulation therapy using ivabradine reduces both morbidity and mortality in patients with systolic heart failure. However, the target heart rate for this patient population remains to be elucidated. Methods In this prospective observational study, we included patients with heart failure and a reduced ejection fraction who received 5.0 mg/day of ivabradine for three days. At baseline and three days later, the overlap length between E-wave and A-wave using trans-mitral Doppler echocardiography, as well as the cardiac output using AESCLONE mini, were simultaneously measured. The associations between Δ overlap length and Δ cardiac output were then investigated. Results Eight patients [77 (53, 87) years old, 2 men] were included. The heart rate decreased from 81 (69, 104) bpm down to 64 (57, 79) bpm (p=0.012). The overlap length increased in four patients and decreased in the other four patients. During the time period of ivabradine therapy, patients who had a greater decrease in overlap length had a greater increase in cardiac output (r=0.84, p=0.009). Conclusion Decreases in the overlap length between E-wave and A-wave by Doppler echocardiography were associated with an increase in the cardiac output while on ivabradine therapy. The implications of Doppler echocardiography-guided heart rate modulation therapy targeting a minimal overlap length therefore require further evaluation in larger, prospective studies.     

R-wave amplitude changes during exercise in adolescents with left ventricular pressure and volume overload

To determine the diagnostic value of exerciseinduced R-wave changes in adolescents with congenital heart disease, the responses of 50 adolescents without significant heart disease were compared with those of 72 patients with either a left ventricular (LV) pressure or volume overload lesion. Among the pressure overload group, 24 patients had valvular aortic stenosis (AS) and 27 had coarctation of the aorta. The volume overload group included 12 patients with mitral regurgitation (MR) and 9 with aortic regurgitation (AR). Severity of the cardiac lesion was assessed using cardiac catheterization in patients with AS, physical examination in patients with coarctation of the aorta and clinical or angiographiec criteria, or both, in patients with valvular regurgitation. The R wave was measured in 10 consecutive QRS complexes in leads II, aVF and V₅ at rest, maximal exercise and 1-minute recovery. At maximal exercise, control subjects had a mean decrease in amplitude (ΔR) of ?3.6 mm (p < 0.0001). Compared with the control group, the AS group had a similar decrease of ?3.5 mm, but the coarctation group had a ΔR of ?1.4 (p < 0.005) and the volume overload group a ΔR of ?1.1 mm (p < 0.003). Patients with AS and ischemic ST-segment changes during exercise (n = 12) had greater decreases in R-wave amplitude than did those with no ST changes (n = 12) (p < 0.04). In patients with AS and an LV end-diastolic pressure ? 12 mm Hg (n = 7), the decrease in ΔR was also greater than that in patients with LV end-diastolic pressure ≤ 12 mm Hg (n = 14) (p < 0.006). Among patients with volume overload, more severe valvular regurgitation was associated with a smaller ΔR (p < 0.03). In patients with AS an increased ΔR reflects ischemia or diminished LV compliance, or both, whereas in patients with volume overload a decrease in ΔR is an indicator of the severity of regurgitation.     

Respiratory muscle weakness and inefficient ventilation in heart failure due to light-chain amyloidosis

Background. Cardiac involvement in light-chain amyloidosis (AL) frequently results in heart failure with dyspnoea. In heart failure due to ischemic or idiopathic etiology, respiratory muscle dysfunction and ventilatory inefficiency contribute to symptoms and are independent prognostic predictors. However, in patients with AL, respiratory muscle function has not been elucidated.

Methods. In 46 consecutive male patients with AL, lung function, maximal inspiratory (Pi_max) and expiratory (Pe_max) mouth occlusion pressures, cardiopulmonary exercise testing, echocardiography, and cardiac biomarkers were prospectively studied.

Results. Pi_max and Pe_max were reduced, P_0.1 did not differ between controls and AL. Pi_max and Pe_max were reduced in AL with congestive heart failure compared with asymptomatic patients (median (range) 5.4 (2.3–12.4) kPa vs 10.4 (6.5–14.0) kPa; p < 0.05). Respiratory muscle weakness occurred in systolic and diastolic LV dysfunction. Pi_max was associated with peak exercise oxygen uptake, respiratory inefficiency, wall thickness, and N-terminal pro-brain natriuretic peptide.

Conclusions. Respiratory muscle dysfunction and ventilatory inefficiency correlates well with intraventricular septum thickness and peak oxygen uptake and are present even in patients with diastolic dysfunction. Respiratory muscle dysfunction might contribute to dyspnea and exercise limitation and appears to represent a marker of cardiac impairment even in diastolic heart failure. Further studies of Pi_max as a potential non-invasive prognostic marker are needed.     

Risk of New-Onset Atrial Fibrillation in Elderly Patients with the Overlap Syndrome: A Retrospective Cohort Study

Background Co-existence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) is referred to as overlap syndrome. Overlap patients have greater degree of hypoxia and pulmonary hypertension than patients with OSA or COPD alone. Studies showed that elderly patients with OSA alone do not have increased risk of atrial fibrillation (AF) but it is not known if overlap patients have higher risk of AF. Objective To determine whether elderly patients with overlap syndrome have an increased risk of AF. Methods In this single center, community-based retrospective cohort analysis, data were collected on 2,873 patients > 65 years of age without AF, presenting in the year 2006. Patients were divided into OSA group (n = 60), COPD group (n = 416), overlap syndrome group (n = 28) and group with no OSA or COPD (n = 2369). The primary endpoint was incidence of new-onset AF over the following two years. Logistic regression was performed to adjust for heart failure (HF), coronary artery disease, hypertension (HTN), cerebrovascular disease, cardiac valve disorders, diabetes mellitus, hyperlipidemia, chronic kidney disease (CKD) and obesity. Results The incidence of AF was 10% in COPD group, 6% in OSA group and 21% in overlap syndrome group (P < 0.05). After adjusting for age, sex, HF, CKD, and HTN, patients with overlap syndrome demonstrated a significant association with new-onset AF (OR = 3.66, P = 0.007). HF, CKD and HTN were also significantly associated with new-onset AF (P < 0.05). Conclusion Among elderly patients, the presence of overlap syndrome is associated with a marked increase in risk of new-onset AF as compared to the presence of OSA or COPD alone.