Roland Wensel

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 · s · cm−5, average serum uric acid level was 7.5±0.35 mg/dL, and average peak oxygen uptake during exercise (peak &OV0312;o2) was 11.2±0.5 mL · kg−1 · 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 &OV0312;o2 (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 &OV0312;o2 ≤10.4 mL · kg−1 · min−1 and peak SBP ≤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 &OV0312;o2 and peak SBP are independent and strong predictors of survival in PPH patients. Hemodynamic parameters, although also accurate predictors, provide no independent prognostic information.

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 (&OV0312;e/&OV0312;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 &OV0312;e/&OV0312;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. &OV0312;e/&OV0312;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 &OV0312;e/&OV0312;co2 slope. The &OV0312;e/&OV0312;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 &OV0312;e/&OV0312;co2 slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Impaired ventilatory efficiency in chronic heart failure: Possible role of pulmonary vasoconstriction

BACKGROUND Patients with chronic heart failure show impairment of ventilatory efficiency, defined as the relation between ventilation and carbon dioxide output. It is caused by ventilation of excess physiologic dead space. We hypothesized a role of active vasoconstriction in the increase of physiologic dead space, presumed to lead to alveolar hypoperfusion. METHODS AND RESULTS In 57 patients with chronic heart failure (New York Heart Association classification II through IV, ejection fraction 25.6%+/-10.4%) and 7 control subjects, gas exchange at rest and on exercise was compared with hemodynamic measurements and, in a subgroup of 15 patients, with endothelin-1, epinephrine, and norepinephrine levels in the pulmonary and systemic circulation. Ventilatory efficiency at rest (VE/VCO2 ratio) correlated with ventilatory efficiency on exercise (VE vs VCO2 slope). Impairment of ventilatory efficiency correlated strongly negative with exercise tolerance (maximal oxygen uptake: r = -0.67) and cardiac output (r = -0.66) and positive with pulmonary hypertension (mean pulmonary artery pressure: r = 0.69, pulmonary vascular resistance: r = 0.60). None of the vasoconstrictors correlated with reduction of ventilatory efficiency in the subgroup studied. CONCLUSIONS Impairment of ventilatory efficiency in chronic heart failure is correlated with resting pulmonary artery pressures and associated with the impairment of exercise capacity. An imbalance of pulmonary vascular tone probably leads to both pulmonary hypertension and alveolar hypoperfusion.

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.

Muscle metaboreflex-induced increases in stroke volume.

PURPOSE Accumulation of by-products of metabolism within skeletal muscle may stimulate sensory nerves, thus evoking a pressor response named muscle metaboreflex. The aim of this study was to evaluate changes in central hemodynamics occurring during the metaboreflex activation. METHODS In seven healthy subjects, the metaboreflex was studied by postexercise regional circulatory occlusion at the start of the recovery from a mild rhythmic forearm exercise. Central hemodynamics was evaluated by means of impedance cardiography. RESULTS The main findings of this study were that, with respect to rest, the metaboreflex: 1) raised mean blood pressure (+13%; P < 0.01); 2) enhanced myocardial contractility (-12% in preejection period/left ventricular ejection time ratio; P < 0.01); 3) prolonged diastolic time (+11%; P < 0.01); 4) increased stroke volume (+ 10%; P < 0.05); and 5) increased cardiac output (+6%; P < 0.05). These responses were present neither during recovery without circulatory occlusion nor during circulatory occlusion without prior exercise. Moreover, the metaboreflex did not affect systemic vascular resistance and induced bradycardia with respect to recovery without circulatory occlusion. CONCLUSION These results suggest that the blood pressure response during metaboreflex activation after mild rhythmic exercise is strongly dependent on the capacity to increase cardiac output rather than due to increased vascular resistance.

Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension

Pulmonary arterial hypertension (PAH) results in chronic right heart failure, which is associated with an increase in sympathetic tone. This may adversely affect cardiac autonomic control. We investigated the changes in cardiac autonomic nervous activity in relation to disease severity in patients with PAH. In 48 patients with PAH (median World Health Organization class III, pulmonary artery pressure 52±14 mmHg, pulmonary vascular resistance 1,202±718 dyn·s·cm−5, cardiac index 2.0±0.8 L·min−1·m−2) and 41 controls, cardiac autonomic nervous activity was evaluated by measurement of heart rate variability (HRV) and baroreflex sensitivity. All patients underwent cardiopulmonary exercise testing (peak oxygen uptake 13.2±5.1 mL·kg−1·min−1, minute ventilation/carbon dioxide production slope 47±16). In patients with PAH, spectral power of HRV was reduced in the high-frequency (239±64 versus 563±167 ms2), low-frequency (245±58 versus 599±219 ms2) and very low-frequency bands (510±149 versus 1106±598 ms2; all p<0.05). Baroreflex sensitivity was also blunted (5.8±0.6 versus 13.9±1.2 ms·mmHg−1; p<0.01). The reduction in high-frequency (r = 0.3, p = 0.04) and low-frequency (r = 0.33, p = 0.02) spectral power and baroreflex sensitivity (r = 0.46, p<0.01) was related to the reduction in peak oxygen uptake. Patients with PAH have a marked alteration in cardiac autonomic control that is related to exercise capacity and may, therefore, serve as an additional marker of disease severity.

Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.

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

BackgroundAtrial 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 ResultsWe 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 &agr;-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). ConclusionsAutonomic 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.

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, PGF1α, 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...

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 · kg−1 · 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.