Novel interventions on the tricuspid valve: how to consider the pulmonary circulation?

PURPOSE OF REVIEW: This review addresses treatment options for moderate to severe tricuspid valve regurgitation and the importance of right ventricular function and the pulmonary circulation. RECENT FINDINGS: Several interventional treatment options for severe tricuspid regurgitation have been developed including transcatheter edge-to-edge repair, annuloplasty and valve replacement. So far, transcatheter edge-to-edge repair is most frequently used with procedural success rates of more than 95% and improvements in functional and quality of life parameters for up to 2 years. Right ventricular function as well as pulmonary artery pressure and resistance levels are important outcome predictors. Mean pulmonary artery pressure more than 30 mmHg, transpulmonary gradient more than 17 mmHg and right ventricular to pulmonary artery coupling ratio less than 0.406 indicate poor outcome. SUMMARY: Despite the remarkable safety of interventional treatment of severe tricuspid regurgitation right ventricular dysfunction and abnormal pulmonary hemodynamics are important determinants of procedural success and clinical outcome.Complete hemodynamic work-up should be an integral part of prerepair assessment although validated data predicting outcome are limited.

Cardiopulmonary exercise testing and efficacy of percutaneous coronary intervention: a substudy of the ORBITA trial.

AIMS: Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) has been associated with myocardial ischaemia. The aim of this analysis was to examine the relationship between CPET parameters, myocardial ischaemia and anginal symptoms in patients with chronic coronary syndrome and to determine the ability of these parameters to predict the placebo-controlled response to percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients with severe single-vessel coronary artery disease (CAD) were randomized 1:1 to PCI or placebo in the ORBITA trial. Subjects underwent pre-randomization treadmill CPET, dobutamine stress echocardiography (DSE) and symptom assessment. These assessments were repeated at the end of a 6-week blinded follow-up period.A total of 195 patients with CPET data were randomized (102 PCI, 93 placebo). Patients in whom an oxygen-pulse plateau was observed during CPET had higher (more ischaemic) DSE score [+0.82 segments; 95% confidence interval (CI): 0.40 to 1.25, P = 0.0068] and lower fractional flow reserve (-0.07; 95% CI: -0.12 to -0.02, P = 0.011) compared with those without. At lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on DSE score [oxygen-pulse plateau presence (Pinteraction = 0.026) and oxygen-pulse gradient (Pinteraction = 0.023)] and Seattle angina physical-limitation score [oxygen-pulse plateau presence (Pinteraction = 0.037)]. Impaired peak VO2, VE/VCO2 slope, peak oxygen-pulse, and oxygen uptake efficacy slope was significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI. CONCLUSION: Although selected CPET parameters relate to severity of angina symptoms and quality of life, only an oxygen-pulse plateau detects the severity of myocardial ischaemia and predicts the placebo-controlled efficacy of PCI in patients with single-vessel CAD.

Dobutamine Stress Echocardiography Ischemia as a Predictor of the Placebo-Controlled Efficacy of Percutaneous Coronary Intervention in Stable Coronary Artery Disease: The Stress Echocardiography-Stratified Analysis of ORBITA.

BACKGROUND: Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina). METHODS: One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling. RESULTS: At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (Pinteraction=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina (Pinteraction=0.116), physical limitation (Pinteraction=0.461), quality of life (Pinteraction=0.689), EuroQOL 5 quality-of-life score (Pinteraction=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (Pinteraction=0.693), and treadmill exercise time (Pinteraction=0.426). CONCLUSIONS: The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease.

BACKGROUND: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. METHODS: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. RESULTS: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR ( Pinteraction=0.318) or iFR ( Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70-1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR ( Pinteraction<0.00001) and decreasing iFR ( Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96-2.80; P=0.072) with no detectable evidence of interaction with FFR ( Pinteraction=0.849) or iFR ( Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30-4.72; P=0.006) but neither FFR ( Pinteraction=0.693) nor iFR ( Pinteraction=0.761) modified this effect. CONCLUSIONS: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial.

BACKGROUND: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. INTERPRETATION: In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. FUNDING: NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Respiratory rate predicts outcome after acute myocardial infarction: a prospective cohort study.

AIMS: Risk stratification after acute myocardial infarction (MI) remains imperfect and new indices are sought that might improve the post-MI risk assessment. In a contemporarily-treated cohort of acute MI patients, we tested whether the respiratory rate provides prognostic information and how this information compares to that of established risk assessment. METHODS AND RESULTS: A total of 941 consecutive patients (mean age 61 years, 19% female) presenting with acute MI were enrolled between May 2000 and March 2005. The last follow-up was performed May 2010. Main outcome measure was total mortality during a follow-up period of 5 years. Patients underwent 10-min resting recordings of the respiratory rate within 2 weeks after MI in addition to the measurement of the left ventricular ejection fraction (LVEF) and standard clinical assessment including the GRACE score. During the follow-up, 72 patients died. The respiratory rate was a significant predictor of death in univariable analysis (hazard ratio 1.19 per 1/min, 95% confidence interval: 1.12-1.27) as was the GRACE score [1.04 (1.03-1.05) per point], LVEF [0.96 (0.94-0.97) per 1%], and the diagnosis of diabetes mellitus [2.78 (1.73-4.47)], all P < 0.0001. On multivariate analysis, the GRACE score (P < 0.0001), respiratory rate (P < 0.0001), LVEF (P = 0.013), and diabetes (P = 0.016) were independent prognostic markers. CONCLUSION: The respiratory rate provides powerful prognostic information which is independent and complementary to that of existing risk assessment. Simple and inexpensive assessment of the respiratory rate should be considered a complementary variable for the assessment of risk after acute MI.

Prognostic Relevance of Cardiopulmonary Exercise Testing for Patients with Chronic Thromboembolic Pulmonary Hypertension.

Background: Following acute pulmonary embolism (PE), a relevant number of patients experience decreased exercise capacity which can be associated with disturbed pulmonary perfusion. Cardiopulmonary exercise testing (CPET) shows several patterns typical for disturbed pulmonary perfusion. Research question: We aimed to examine whether CPET can also provide prognostic information in chronic thromboembolic pulmonary hypertension (CTEPH). Study Design and Methods: We performed a multicenter retrospective chart review in Germany between 2002 and 2020. Patients with CTEPH were included if they had ≥6 months of follow-up and complete CPET and hemodynamic data. Symptom-limited CPET was performed using a cycle ergometer (ramp or Jones protocol). The association of anthropometric data, comorbidities, symptoms, lung function, and echocardiographic, hemodynamic, and CPET parameters with survival was examined. Mortality prediction models were calculated by Cox regression with backward selection. Results: 345 patients (1532 person-years) were included; 138 underwent surgical treatment (pulmonary endarterectomy or balloon pulmonary angioplasty) and 207 received only non-surgical treatment. During follow-up (median 3.5 years), 78 patients died. The death rate per 1000 person-years was 24.9 and 74.2 in the surgical and non-surgical groups, respectively (p < 0.001). In age- and sex-adjusted Cox regression analyses, CPET parameters including peak oxygen uptake (VO2peak, reflecting cardiopulmonary exercise capacity) were prognostic in the non-surgical group but not in the surgical group. In mortality prediction models, age, sex, VO2peak (% predicted), and carbon monoxide transfer coefficient (% predicted) showed significant prognostic relevance in both the overall cohort and the non-surgical group. In the non-surgical group, Kaplan−Meier analysis showed that patients with VO2peak below 53.4% predicted (threshold identified by receiver operating characteristic analysis) had increased mortality (p = 0.007). Interpretation: The additional measurement of cardiopulmonary exercise capacity by CPET allows a more precise prognostic evaluation in patients with CTEPH. CPET might therefore be helpful for risk-adapted treatment of CTEPH.

Effects of dynamic bilevel positive airway pressure support on central sleep apnea in men with heart failure.

BACKGROUND: Treatment with continuous positive airway pressure (CPAP) improves cardiac function in chronic heart failure (CHF) patients with central sleep apnea (CSA)-Cheyne-Stokes respiration (CSR) by stabilizing ventilation, but frequently central apneas and hypopneas persist. Our objective was to test the hypothesis that flow-targeted dynamic bilevel positive airway pressure (BPAP) support (BiPAP autoSV; Respironics; Murrysville, PA) effectively suppresses CSR-CSA in CHF patients. METHODS: We studied 14 CHF patients with CSR-CSA (and residual CSA on positive airway pressure therapy) during 3 consecutive nights: (1) diagnostic polysomnography, (2) CPAP (n=10) or BPAP (n=4) titration, and (3) dynamic flow-targeted dynamic BPAP support with an expiratory positive airway pressure (EPAP) set to suppress obstructive respiratory events, and an inspiratory positive airway pressure (IPAP) dynamically ranging between 0 and 15 cm H2O above the EPAP. RESULTS: CPAP or BPAP significantly reduced the apnea-hypopnea index (AHI) [mean+/-SD, 46+/-4 events/h to 22+/-4 events/h; p=0.001] compared to the first night without treatment. Flow-targeted dynamic BPAP support (mean EPAP, 6.5+/-1.7 cm H2O; maximal IPAP, 21.9+/-2.1 cm H2O) further reduced the AHI to 4+/-1/h of sleep compared to the untreated (p<0.001) and CPAP or BPAP night (p=0.002). After the first night of flow-targeted dynamic BPAP support, patients rated on an analog scale (range, 0 to 10) the treatment as comfortable (6.9+/-0.6), and the sleep quality as improved compared to previous nights (7.4+/-0.6). CONCLUSION: Flow-targeted dynamic BPAP support effectively suppresses CSR-CSA in patients with CHF and is well tolerated.

Abnormal ventilatory response to exercise in adults with congenital heart disease relates to cyanosis and predicts survival.

BACKGROUND: Limited data exist with which to stratify risk in adult congenital heart disease (ACHD). An increased ventilatory response to exercise, expressed as ventilation per unit of carbon dioxide production (V(E)/V(CO2) slope), is an established predictor of impaired survival in acquired heart disease. We sought to establish the distribution, relation to cyanosis, and prognostic value of the V(E)/V(CO2) slope across a wide spectrum of ACHD patients. METHODS AND RESULTS: Five hundred sixty ACHD patients of varying diagnoses and 50 healthy controls underwent cardiopulmonary exercise testing at a single laboratory between 2001 and 2004. Patient age was 33.2 +/- 12.9 years (mean +/- SD). Peak oxygen consumption was 23.5 +/- 9.0 mL.kg(-1).min(-1).V(E)/V(CO2) slope for all patients was 36.3 +/-15.3. The slope was raised in all ACHD groups compared with controls and was 73% higher in cyanotic patients. Cyanosis, with or without pulmonary arterial hypertension, was the strongest predictor of abnormal V(E)/V(CO2) slope. The V(E)/V(CO2) slope was the most powerful univariate predictor of mortality in the noncyanotic group and the only independent predictor of mortality among exercise parameters on multivariate analysis. In cyanotic patients, no parameter was predictive of death. CONCLUSIONS: Ventilatory response to exercise is abnormal across the spectrum of ACHD. Cyanosis is a powerful stimulus for such exaggerated ventilatory patterns irrespective of the presence of pulmonary arterial hypertension. Increased V(E)/V(CO2) slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Changes in exercise capacity, ventilation, and body weight following heart transplantation.

AIMS: Peak oxygen uptake adjusted to body weight (peak VO(2)) and ventilatory efficiency (VE/VCO(2)-slope) are important prognostic parameters in chronic heart failure. Our study prospectively examined changes in these parameters over 24 months following heart transplantation (HTx) and evaluated the potentially confounding effects of weight gain. METHODS AND RESULTS: One hundred patients with chronic heart failure (16 female, mean age at HTx 53.9+/-9.6 years) underwent cardiopulmonary exercise testing before and 3, 6, 12 and/or 24 months after HTx. Twenty-five healthy individuals served as matched normals. VE/VCO(2)-slope during exercise improved significantly at 6 (-23.7%), 12 (-21.3%), and 24 months (-32.3%; all p<0.002 vs. baseline). At 6 months, VE/VCO(2)-slopes were similar to the matched normals (31.8+/-4.3), 46 of 78 patients achieved values within the 95% confidence interval of normal. Peak VO(2) increased significantly after HTx at 6 (+31.8%), 12 (+36.2%), and 24 months (+42.2%; all p<0.005). None of the patients reached values within the 95% CI of normal. Although VE/VCO(2)-slope and peak VO(2) were correlated inversely at every time point (p<0.03), reduction in VE/VCO(2)-slope did not correlate with increase in peak VO(2). Symptoms that limited exercise changed from dyspnoea before HTx to leg fatigue after HTx. CONCLUSION: Following HTX, VE/VCO(2)-slope returns to normal values in the majority of patients; however, despite improvement, peak VO(2) remains abnormal in all patients. Symptoms causing patients to stop exercising change from dyspnoea to leg fatigue.

The anti-CD14 antibody IC14 suppresses ex vivo endotoxin stimulated tumor necrosis factor-alpha in patients with chronic heart failure.

BACKGROUND: Activation of the endotoxin (LPS) receptor, CD14, leads to tumor necrosis factor-alpha (TNF) production. Plasma LPS activity is elevated in patients with severe chronic heart failure (CHF). An anti-CD14 antibody, IC14, blocks TNF production in healthy volunteers. It is not known whether IC14 prevents TNF production in CHF patients. METHODS AND RESULTS: Blood from 20 CHF patients (age 64+/-2.1 years, NYHA class 2.2+/-0.1, LVEF 27+/-3%, mean+/-SEM) was pre-incubated with 0.5, 1.0, 5.0, 10 and 50 microg/mL IC14 for 1 h followed by incubation with 1 or 10 ng/mL LPS for 6 h. Fourteen subjects served as controls (58+/-2.4 years). LPS-stimulated TNF release was 76% and 60% greater at 1 and 10 ng/mL LPS, respectively, in CHF patients versus controls (p=0.07 and p=0.008). IC14 at concentrations of 5.0, 10 and 50 microg/mL substantially reduced TNF production in response to stimulation with LPS (all p<0.05). CD14 receptor density was similar in patients and controls. In controls, but not in CHF patients, there was a positive correlation between CD14 receptor density and TNF production (r=0.61, p=0.03). CONCLUSION: IC14 suppresses LPS-stimulated whole blood TNF production in patients with CHF and in normal subjects and therefore may represent a novel therapeutic strategy for CHF patients with systemic immune activation.

Oxygen Uptake Efficiency Slope and Breathing Reserve, Not Anaerobic Threshold, Discriminate Between Patients With Cardiovascular Disease Over Chronic Obstructive Pulmonary Disease.

OBJECTIVES: The study sought to compare the relative discrimination of various cardiopulmonary exercise testing (CPX) variables between cardiac and respiratory disease. BACKGROUND: CPX testing is used in many cardiorespiratory diseases. However, discrimination of cardiac and respiratory dysfunction can be problematic. Anaerobic threshold (AT) and oxygen-uptake to work-rate relationship (VO2/WR slope) have been proposed as diagnostic of cardiac dysfunction, but multiple variables have not been compared. METHODS: A total of 73 patients with chronic obstructive pulmonary disease (COPD) (n = 25), heart failure with reduced ejection fraction (HFrEF) (n = 40), or combined COPD and HFrEF (n = 8) were recruited and underwent CPX testing on a bicycle ergometer. Following a familiarization test, each patient underwent a personalized second test aiming for maximal exercise after ∼10 min. Measurements from this test were used to calculate area under the receiver-operator characteristic curve (AUC). RESULTS: Peak VO2 was similar between the 2 principal groups (COPD 17.1 ± 4.6 ml/min/kg; HFrEF 16.4 ± 3.6 ml/min/kg). Breathing reserve (AUC: 0.91) and percent predicted oxygen uptake efficiency slope (OUES) (AUC: 0.87) had the greatest ability to discriminate between COPD and HFrEF. VO2/WR slope performed significantly worse (AUC: 0.68). VO2 at the AT did not discriminate (AUC for AT as percent predicted peak VO2: 0.56). OUES and breathing reserve remained strong discriminators when compared with an external cohort of healthy matched controls, and were comparable to B-type natriuretic peptide. CONCLUSIONS: Breathing reserve and OUES discriminate heart failure from COPD. Despite it being considered an important determinant of cardiac dysfunction, the AT could not discriminate these typical clinical populations while the VO2/WR slope showed poor to moderate discriminant ability. (Identifying an Ideal Cardiopulmonary Exercise Test Parameter [PVA]; NCT01162083).

Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing.

BACKGROUND: Primary pulmonary hypertension (PPH) is a life-threatening disease. Prognostic assessment is an important factor in determining medical treatment and lung transplantation. Whether cardiopulmonary exercise testing data predict survival has not been reported previously. METHODS AND RESULTS: We studied 86 patients with PPH (58 female, age 46+/-2 years, median NYHA class III) between 1996 and 2001 who were followed up in a tertiary referral center. Right heart catheterization was performed and serum uric acid levels were measured in all patients. Seventy patients were able to undergo exercise testing. At the start of the study, the average pulmonary artery pressure was 60+/-2 mm Hg, average pulmonary vascular resistance was 1664+/-81 dyne x s x cm(-5), average serum uric acid level was 7.5+/-0.35 mg/dL, and average peak oxygen uptake during exercise (peak VO(2) was 11.2+/-0.5 mL x kg(-1) x min(-1). During follow-up (mean: 567+/-48 days), 28 patients died and 16 underwent lung transplantation (1-year cumulative event-free survival: 68%; 95% CI 58 to 78). The strongest predictors of impaired survival were low peak VO(2) (P<0.0001) and low systolic blood pressure at peak exercise (peak SBP; P<0.0001). In a multivariable analysis, serum uric acid levels (all P<0.005) and diastolic blood pressure at peak exercise independently predicted survival (P<0.05). Patients with peak VO(2) < or =10.4 mL x kg(-1) x min(-1) and peak SBP < or =120 mm Hg (ie, 2 risk factors) had poor survival rates at 12 months (23%), whereas patients with 1 or none of these risk factors had better survival rates (79% and 97%, respectively). CONCLUSIONS: Peak VO(2) and peak SBP are independent and strong predictors of survival in PPH patients. Hemodynamic parameters, although also accurate predictors, provide no independent prognostic information.

Chemical mediators of the muscle ergoreflex in chronic heart failure: a putative role for prostaglandins in reflex ventilatory control.

BACKGROUND: The overactivity of ergoreceptors (intramuscular afferents sensitive to products of skeletal muscle work) may be responsible for the abnormal responses to exercise and symptoms of exercise intolerance in chronic heart failure (CHF); however, little is known of the chemical nature of the stimuli involved. We investigated biochemical factors (H+, VCO2, VO2, HCO3, K+, phosphate, lactate, PGE2, PGF(1alpha), and bradykinin) potentially involved in ergoreceptor activation. METHODS AND RESULTS: Sixteen stable patients with CHF (64.9+/-2.7 years, peak VO2 15.8+/-0.7 mL/kg per min) and 10 age-matched controls were studied. The ergoreceptor test involved two 5-minute handgrip exercises. On one occasion, the subjects recovered normally (control recovery), whereas on the other a posthandgrip regional circulatory occlusion was induced in the exercising arm, isolating the stimulation of the ergoreceptor after exercise. The ergoreflex was quantified as the difference in ventilation between the posthandgrip regional circulatory occlusion and the control recovery periods. During the protocol, the local muscular blood effluent concentrations of metabolic mediators were assessed. Patients had an ergoreflex effect on ventilation greater than controls (4.8+/-1.4 versus 0.4+/-0.1 L/min, P<0.01). During the ergoreflex test in patients, the following metabolites were elevated with respect to resting values in comparison with controls: PGE2 (3.7+/-0.7 versus 1.1+/-0.2 pg/mL), PGF(1alpha) (16.2+/-2.8 versus 7.2+/-1.2 pg/mL), and bradykinin (2.1+/-0.3 versus 1.0+/-0.1 pg/mL), P<0.05 for all comparisons. Only the increases in prostaglandins were predictors of the ergoreflex response (r>0.41, P<0.01). CONCLUSIONS: Although multiple metabolites are concentrated in exercising muscle in CHF, only prostaglandins correlated with ergoreflex activity, suggesting these factors as potential triggers to the exaggerated ergoreflex, which is characteristic of CHF. This may have important implications for novel therapies to improve exercise tolerance.

Global impairment of cardiac autonomic nervous activity late after repair of tetralogy of Fallot.

BACKGROUND: Sustained ventricular tachycardia (VT) and sudden cardiac death (SCD) remain devastating late complications after repair of Tetralogy of Fallot (ToF). Although heart rate variability (HRV) and baroreflex sensitivity (BRS) are recognized as independent markers of autonomic activity and strong predictors of SCD in major cardiovascular disease, little is known about their role in patients with tetralogy. METHODS AND RESULTS: We measured HRV and BRS in 45 ToF patients (27 male, age 35+/-12 years, 26+/-7 years after repair) and 45 matched healthy controls. Subjects underwent 20 minute of resting measurements of heart rate (ECG) and noninvasive beat-to-beat blood pressure recording (Finapres), with 5 minutes of 0.1Hz controlled breathing followed by cardiac MRI. BRS was computed by spectral analysis and the sequence and controlled breathing methods. All HRV time and frequency domain variables were measured. All BRS and HRV variables were significantly reduced in patients compared with controls (P<0.001 in all). HRV tended to increase with years from repair. BRS decreased with previous palliation and increasing patient age. Both HRV and BRS decreased with pulmonary regurgitation, elevated right ventricular end systolic volumes and reduced right and left ventricular ejection fraction. Finally, there was an inverse relation between QRS duration (predictor of sustained VT and SCD) and indices of HRV but no relation with indices of BRS. CONCLUSION: There is global impairment of autonomic nervous system regulation late after repair of tetralogy with marked reduction of BRS and HRV. This seems to relate to previous surgical intervention/s, their timing and current right and left-sided hemodynamics. Reduced HRV also related to markers of sustained VT and SCD, suggesting possible common pathogenic mechanisms. Further studies are required to examine the prognostic significance of impaired BRS and HRV in these patients.

Skeletal muscle reflex in heart failure patients: role of hydrogen.

BACKGROUND: An important role of the increased stimulation of skeletal muscle ergoreceptors (intramuscular afferents sensitive to products of muscle work) in the genesis of symptoms of exertion intolerance in chronic heart failure (CHF) has been proposed. With the use of selective infusions and dietary manipulation methods, we sought to identify the role of H+, K+, lactate, and peripheral hemodynamics on ergoreflex overactivation. METHODS AND RESULTS: Ten stable CHF patients (aged 67.9+/-2.5 years, peak oxygen uptake 16.3+/-1.2 mL x kg(-1) x min(-1)) and 10 age-matched and sex-matched healthy subjects were studied. The ergoreflex contribution to ventilation was assessed by post-handgrip regional circulatory occlusion (PH-RCO) and computed as the difference in ventilation between PH-RCO and a control run without PH-RCO. This test was performed on 6 separate occasions. On each occasion a different chemical was infused (insulin, sodium nitroprusside, sodium bicarbonate, dopamine, or saline) or a 36-hour glucose-free diet was undertaken before the test. During all stages of the protocol, the local muscular blood effluent concentrations of H+, K+, glucose, and lactate were assessed. An ergoreflex effect on the ventilatory response was seen in patients (versus control subjects) during the saline infusions (6.7+/-2.3 L/min versus -0.1+/-0.5 L/min, P<0.01). The only intervention to significantly lower the ergoreflex was sodium bicarbonate (0.4+/-0.3 L/min versus -0.2+/-0.4 L/min in control subjects, P=NS; versus saline P<0.05), which also reduced H(+) concentration during exercise (47.4+/-1.3 versus 50.0+/-1.4 nmol/L on saline, P<0.05). CONCLUSION: A reduction of the H+ concentration by infusion of sodium bicarbonate abolishes the increased ergoreceptor activity in CHF, suggesting a role of H+ in ergoreflex activation, either directly or indirectly.

Global impairment of cardiac autonomic nervous activity late after the Fontan operation.

BACKGROUND: Atrial tachyarrhythmia is a common cause of morbidity and mortality in patients with univentricular physiology undergoing the Fontan operation. We examined cardiac autonomic nervous activity, a predictor of arrhythmia and sudden death in other cardiovascular disease, in patients late after the Fontan operation, employing heart rate variability (HRV) and baroreflex sensitivity. METHODS AND RESULTS: We measured HRV and baroreflex sensitivity in 22 consecutive patients (8 male, age 26+/-9 years) who had undergone the Fontan operation 13+/-6 years previously, and 22 age- and sex-matched healthy controls. Fontan patients had significantly lower HRV (P<0.0001). Baroreflex sensitivity was measured by the alpha-index method (square root of ratio of RR interval spectral power to systolic blood pressure (SBP) spectral power, in the LF and the HF band) and was also significantly depressed in the Fontan group (P<0.0001 for both). Both low frequency (LF) and high frequency (HF) components of HRV were reduced in the Fontan patients (P<0.0001), but there was interindividual variation so that the LF/(LF+HF) ratio may be high, normal, or low, and decreased with increasing right atrial dimensions (r=-0.62, P=0.006). Patients with a history of sustained atrial arrhythmia had a stronger baroreflex than those without (P=0.005). CONCLUSIONS: Autonomic nervous control of the heart is markedly deranged in patients late after the Fontan operation, with reduced HRV and baroreflex sensitivity. A relative suppression of the sympathetic-compared with the parasympathetic-system was observed in patients with marked right atrial dilation within the Fontan group. Furthermore, stronger baroreflexes were seen in Fontan patients in association with a higher incidence of sustained atrial tachyarrhythmia, implying that sinus node dysfunction is unlikely to be the dominant mechanism. Additional studies are clearly required to examine the prognostic importance of impaired BRS and HRV in these patients.

Nocturnal continuous positive airway pressure improves ventilatory efficiency during exercise in patients with chronic heart failure.

OBJECTIVES: Chronic heart failure is closely related to impaired cardiorespiratory reflex control, including decreased ventilatory efficiency during exercise (Ve/Vco(2)-slope) and central sleep apnea (CSA). Continuous positive airway pressure (CPAP) and nocturnal oxygen therapy alleviate CSA. The aim of the present study was to compare the effects of nocturnal CPAP and oxygen therapy on Ve/Vco(2)-slope. DESIGN AND SETTING: Prospective controlled trial at a university hospital. PATIENTS: Twenty-six stable patients with chronic heart failure and CSA. INTERVENTION AND MEASUREMENTS: Ten patients received nocturnal oxygen, and 16 patients were assigned to CPAP treatment. At baseline and after 12 weeks of treatment, symptom-limited cardiopulmonary exercise testing was performed on a cycle ergometer. Expiratory gas was analyzed breath by breath for evaluation of ventilation and ventilatory efficiency in combination with arteriocapillary blood gas analysis during rest and exercise. RESULTS: CPAP treatment significantly reduced the Ve/Vco(2)-slope (31.2 +/- 1.6 vs 26.2 +/- 1.0, p = 0.005) and improved the left ventricular ejection fraction (LVEF) [31.7 +/- 2.6% vs 35.7 +/- 2.7%, p = 0.041]. CPAP treatment significantly reduced the apnea-hypopnea index (AHI) [35.9 +/- 4.0/h vs 12.2 +/- 3.6/h, p = 0.002]. Peak oxygen consumption (Vo(2)) [16.2 +/- 1.1 L/min/kg vs 16.3 +/- 1.2 L/min/kg, p = 0.755] remained similar after CPAP treatment. Oxygen therapy reduced the AHI (28.8 +/- 3.2/h vs 8.7 +/- 4.1/h, p = 0.019), but did not improve exercise capacity (peak Vo(2), 15.4 +/- 1.5 L/min/kg vs 15.6 +/- 1.9 L/min/kg, p = 0.760), LVEF (30.9 +/- 2.4% vs 32.5 +/- 2.3%, p = 0.231), or the Ve/Vco(2)-slope (30.0 +/- 1.5 vs 29.8 +/- 1.5, p = 0.646). CONCLUSION: Nocturnal CPAP and oxygen therapy alleviate CSA to a similar degree. Only CPAP therapy may improve ventilatory efficiency during exercise and may have favorable effects on LVEF. Therefore, our data suggest that CPAP is advantageous compared to oxygen in the treatment of CSA in patients with chronic heart failure.

Exercise hyperventilation in chronic heart failure is not caused by systemic lactic acidosis.

BACKGROUND: Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO(2). AIMS: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO(2) during exercise in heart failure. METHOD AND RESULTS: We studied 18 patients with chronic heart failure. We measured VE/VCO(2) slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO(2) slope nor arterial pCO(2) were related to arterial lactate concentrations at peak exercise (r = -0.16, p = 0.65 and r = -0.15, p = 0.6). During early recovery, patients with a high VE/VCO(2) slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r = 0.57, p < 0.05 and r = 0.84, p < 0.0001) and yet their arterial pCO(2) rose rather than fell (r = 0.79, p < 0.001). The rise in arterial pCO(2) correlated with the increase in arterial hydrogen concentration (r = 0.78, p < 0.001) and with arterial pCO(2) at peak exercise (r = -0.76, p < 0.001). CONCLUSIONS: In heart failure VE/VCO(2) slope and low arterial pCO(2) at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation.

[Assessment of cardiopulmonary function at rest and during exercise in patients with pulmonary hypertension]. / Beurteilung der kardiopulmonalen Funktion und Belastungstests bei Patienten mit pulmonaler Hypertonie.

Pulmonary hypertension is diagnosed by various investigations that are essential for making the diagnosis. Following a careful history and physical examination, an electrocardiogram, a chest X-ray, lung function studies, blood tests and an echocardiogram form the basis of the diagnostic algorithm. Following these studies, a right and sometimes additional left heart catheterization are carried out to establish the diagnosis and to perform acute vasodilator testing. Most of these studies are performed at rest. However, exercise studies are an important part of the functional assessment in this group of patients. Exercise capacity can be estimated by functional class, measured with the 6-min walk test or comprehensively assessed by cardiopulmonary exercise testing with gas exchange analysis. Once the diagnosis and etiology of pulmonary hypertension have been established, several parameters can predict outcome in these patients: functional class, right ventricular function, pulmonary hemodynamics, and certain laboratory parameters (uric acid, brain natriuretic peptide, troponin, endothelin-1). In addition, exercise parameters such as walking distance, peak oxygen uptake or peak systolic blood pressure can reliably predict prognosis in these patients.