Impaired cardiopulmonary response to exercise in moderate hypertension.

OBJECTIVE: To identify the limiting factors of exercise performance in subjects with hypertension associated with left ventricular hypertrophy. The secondary objective was to establish relationship between peripheral function and exercise capacity. DESIGN: Cardiopulmonary exercise testing was conducted using two protocols: a graded exercise test to maximal effort established maximal exercise capacity, followed by a step-incremental test combining gas-exchange measures and radionuclide angiography. The exercise responses were compared within and between groups. SETTING: All hypertensive subjects were selected from the Toronto Tri-Hospital Hypertension Clinic. Normal subjects were recruited from the surrounding community. PATIENTS: Twelve patients with established hypertension and left ventricular hypertrophy (determined by echocardiography) were studied as a referred/volunteer sample. All had no evidence of coincident diseases and were unmedicated at time of testing. A volunteer sample of normal, healthy subjects acted as a control. INTERVENTIONS: Graded exercise to maximum and step-incremental (submaximal and steady-state) exercise was used to quantify cardiopulmonary function during exercise stress. MAIN OUTCOME MEASURES: These included (for exercise performance) maximal oxygen intake (VO2max), the ventilatory anaerobic threshold, total peripheral resistance and blood lactate. Cardiac function measures included ejection fraction and ventricular volumes. RESULTS: Cardiac function data obtained during exercise in hypertensive subjects included an increase in the pressure to volume ratio, but a blunted ejection fraction response at peak exercise (P less than 0.05). Although end-diastolic volume increased during exercise (P less than 0.05), values were lower during both levels of exercise compared with normal subjects. Mean +/- SD end-systolic volume increased from 39 +/- 22 at rest to 42 +/- 23 mL during peak exercise. Hypertensive subjects had a lower VO2 max (mean 27.4 +/- 4.8 mL/kg/min) compared with normals (40.0 +/- 8.5 mL/kg/min) and a lower ventilatory anaerobic threshold (14.4 +/- 2.9 versus 27.6 +/- 5.8 mL/kg/min, P less than 0.005). Furthermore, hypertensive patients had a significantly elevated total peripheral resistance at rest (2.5 +/- 1.0 versus 1.8 +/- 0.4 peripheral resistance units) and at peak exercise (1.6 +/- 0.7 versus 0.8 +/- 0.2, P less than 0.01) compared with normal subjects (P less than 0.05). A correlation coefficient of 0.92 was found between total peripheral resistance and VO2 max in hypertensive subjects (P less than 0.01). CONCLUSIONS: These data suggest that peripheral factors, specifically a failure to reduce significantly total peripheral resistance, limits exercise performance despite a maintenance of left ventricular function during exercise in patients with moderate hypertension. The use of cardiopulmonary exercise testing can help in identifying the underlying cause of exercise intolerance in this population and limited left ventricular reserve at peak exercise, and may offer a sensitive measure of therapeutic end-points.     

Augmented ventilatory response to exercise in pulmonary hypertension

The ventilatory response to submaximal exercise, defined as the slope of minute ventilation over carbon dioxide production (VE/VCO2), was determined in 12 normal subjects, ten patients with pulmonary hypertension before and after heart-lung transplantation, and eight patients following heart transplantation. Patients with pulmonary hypertension show an augmented ventilatory response compared to normal subjects (pulmonary hypertension [mean, 57.7 +/- 6.8 (SE) ml/ml VCO2; normal subjects, 22.3 +/- 1.4 ml/ml VCO2; p less than 0.001]). Following heart-lung transplantation, VE/VCO2 slope fell to 24.7 +/- 1.6 ml/ml VCO2, a value which is not significantly different than the value in normal subjects. Patients after heart transplantation show a mean slope value of 25.3 +/- 1.3 ml/ml VCO2, which is not significantly different than the normal value or the value found after heart-lung transplantation. The augmented ventilatory response to exercise did not correlate with the usual chemical modulators of ventilation (arterial pH, arterial carbon dioxide tension, or arterial oxygen tension). These results suggest the following: the existence of a neural system in patients with pulmonary hypertension which results in an augmentation of ventilatory drive in response to exercise; the augmented ventilatory response reflects excessive neural activity of pulmonary afferents during exercise; narrow regulation of the ventilatory response to exercise in normal subjects which is preserved in the denervated lung, indicating that pulmonary afferents are not critical to ventilatory control during exercise in the normal subject; and the possible use of measurements of the ventilatory response to exercise as a noninvasive screening test for pulmonary hypertension.     

Pathophysiology of exercise intolerance in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic disease with poor prognosis and important exercise limitation despite the proliferation of treatment options in the last decade. Chronically increased right ventricular (RV) afterload results in right heart failure and without treatment, rapid clinical deterioration is common. Exercise intolerance is the cardinal feature of the disease impacting upon quality of life and clinical outcome. The pathophysiological mechanisms that lead to reduced exercise capacity in this population are complex with ventriculoarterial uncoupling likely to be the predominant feature. The relative contributions of additional factors that contribute to exercise limitation beyond ventriculoarterial uncoupling have not been characterized. This review addresses these factors with a focus on recent developments and uncertainties. RV maladaptation and the intricate interplay between the heart, abnormal pulmonary vascular bed and peripheral factors such as dysfunction of the respiratory and peripheral muscles are discussed in detail.     

Prevalence of exercise pulmonary arterial hypertension in scleroderma

Pulmonary arterial hypertension (PAH) is a complication of scleroderma (systemic sclerosis, SSc); as soon as PAH develops, the patient's prognosis deteriorates rapidly. Early detection of PAH ensures timely treatment. We investigated the prevalence of exercise-induced PAH in a cohort of patients with SSc, and examined the relation between exercise-induced PAH and clinical characteristics and biochemical markers. METHODS: Patients with SSc and normal resting systolic pulmonary arterial pressure (sPAP) were studied. Eligible patients were asked to perform cycloergometer exercise until exhaustion, and exercise sPAP was measured. All patients had their pulmonary function tested and underwent echocardiography at rest. Brain natriuretic peptide (BNP) was also determined. RESULTS: Forty-one patients with SSc were studied. Mean sPAP at rest was 29.7 mm Hg, rising to a mean of 41.4 mm Hg on exercise. Eleven of 41 patients (26.8%) had sPAP post-exercise > 50 mm Hg and 8/41 (19.5%) > 55 mm Hg. A significant correlation was found between exercise sPAP and DLCO (p = 0.008) and between sPAP and BNP levels (p = 0.04). Pre-existing severe Raynaud's phenomenon was more prevalent (50% vs 20%), DLCO levels lower (78.9 vs 92.7 % predicted), and BNP levels higher (72.6 vs 42.1 pmol/ml) in patients with exercise sPAP > 55 mm Hg. CONCLUSION: The prevalence of exercise-induced PAH in patients with scleroderma is high. Patients with lower DLCO and higher levels of BNP are at higher risk of developing higher sPAP. Studies with longterm followup are required to evaluate the risk of developing resting PAH in these patients.     

Physiological response to the six-minute walk test in pulmonary arterial hypertension.

The 6-min walk test (6MWT) is commonly used to evaluate exercise capacity in patients with pulmonary arterial hypertension (PAH). However, little is known about the corresponding metabolic stress as measured by cardiopulmonary exercise testing. The present study, therefore, measured ventilatory variables and heart rate during the 6MWT and symptom-limited incremental maximal exercise testing in 20 patients with PAH. The distance walked in 6 min was 450+/-22 m (mean+/-se). During the 6MWT, ventilation, O2 consumption, CO2 production and heart rate increased during the first 3-4 min, and then remained stable. As compared with the maximum values measured during the cardiopulmonary exercise test, O2 consumption tended to be higher (14.2+/-0.6 versus 12.9+/-0.7 mL.kg-1.min-1), while maximum ventilation (46+/-3 versus 57+/-4 L.min-1), respiratory quotient (0.90+/-0.02 versus 1.15+/-0.02) and heart rate (119+/-4 versus 135+/-4 beats.min-1) remained lower. In conclusion, patients with pulmonary arterial hypertension exercise at higher aerobic capacity and lower metabolic stress during the 6MWT than during a cardiopulmonary exercise test.     

Impaired transforming growth factor-beta signaling in idiopathic pulmonary arterial hypertension

Mutations in transforming growth factor-beta family receptor-II, bone morphogenetic protein receptor-2, and activin-like kinase-1 have been associated with pulmonary hypertension. In the present study, we determined that pulmonary arteries in normal lungs and in lungs of patients with emphysema and idiopathic pulmonary arterial hypertension comparably expressed transforming growth factor-beta receptors I and II, Smad(1, 5, 8), Smad2, Smad3, Smad4, phosphorylated Smad(1, 5, 8), and phosphorylated Smad2 (the latter two both indicative of active in vivo signaling) in endothelial cells, as assessed by immunohistochemistry and quantitative morphometry. Medial or intimal smooth muscle cells had weak or absent expression of these molecules. In clear contrast to endothelial cell expression in pulmonary arteries and in endothelial cells lining incipient vessels within plexiform lesions of hypertensive lungs, endothelial cells present in the core of the lesions lacked expression of all examined members of the signaling molecules. These findings were made irrespective of the mutation status of bone morphogenetic protein receptor-2 in hypertensive patients. Our findings suggest that pulmonary artery endothelial cells in both normal and severely hypertensive lungs have active transforming growth factor-beta family signaling, and that loss of signaling might contribute to the abnormal growth of endothelial cells in plexiform lesions in idiopathic pulmonary arterial hypertension.     

Impaired microcirculation in mild-to-moderate essential arterial hypertension.

OBJECTIVE: The aim of this study was to correlate capillary morphology and erythrocyte velocity to blood pressure in mild-to-moderate essential arterial hypertension. DESIGN: Ambulatory blood pressure measurement may provide more precise information about a patient's mean blood pressure than office measurements. METHODS: Fifteen patients with recently diagnosed, previously untreated mild-to-moderate essential hypertension underwent 24-h ambulatory blood pressure recording and a capillaroscopic examination of finger microcirculation. Erythrocyte velocity was determined by the flying spot technique. RESULTS: Both mean 24-h ambulatory systolic blood pressure (SBP) and mean 24-h ambulatory diastolic blood pressure (DBP) were significantly inversely correlated with capillary erythrocyte velocity. However, the correlation between erythrocyte velocity and office SBP and office DBP was less significant. Capillary length was related to 24-h ambulatory DBP but not to office DBP. Capillary number was not related to any blood pressure parameter. CONCLUSIONS: These results indicate that, in patients with mild-to-moderate essential hypertension, erythrocyte velocity is significantly lower than for matched controls. It is also inversely related to mean 24-h ambulatory SBP and 24-h ambulatory DBP.     

Characteristics of response to isometric exercise in women with stable arterial hypertension

In 50 females with Stage II persistent hypertension, tetrapolar thoracic rheography was employed to measure cardiac index (CI), stroke index (SI), specific peripheral resistance (SPR), blood pressure (BP), heart rate (HR) before and during isometric exercise when antihypertensive drugs were withdrawn. The patients with a family history of hypertension were found to have impaired homeostatic mechanisms preventing an excess elevation in BP during isometric exercise. The females of reproductive age showed a greater increase in BP, HR, SI, CI and a lower decrease in SPR in response to the exercise than did menopausal females. Left ventricular hypertrophy contributes to a positive inotropic action shown by sympathetic cardiac stimulation during isometric exercise, as evidenced by a lower reduction or elevation in SI. The detected responses to isometric exercise may serve as criteria for differential approach to the choice of adequate antihypertensive therapy.     

Inflammation in pulmonary arterial hypertension.

Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension (PH), including monocrotaline-induced PH in rats and pulmonary arterial hypertension of various origins in humans, such as connective tissue diseases (scleroderma, systemic lupus erythematosus, mixed connective disease), human immunodeficiency virus infection, or plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal (M) protein and skin changes (POEMS) syndrome. Interestingly, some patients with severe pulmonary arterial hypertension associated with systemic lupus erythematosus have experienced significant improvements with immunosuppressive therapy, emphasising the relevance of inflammation in a subset of patients presenting with PH. Patients with primary PH (PPH) also have some immunological disturbances, suggesting a possible role for inflammation in the pathophysiology of this disease. A subset of PPH patients have been shown to have circulating autoantibodies, including antinuclear antibodies, as well as elevated circulating levels of the pro-infammatory cytokines, interleukins -1 and -6. Lung histology has also revealed inflammatory infiltrates in the range of plexiform lesions in patients displaying severe PPH, as well as an increased expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and fractalkine. Further analysis of the role of inflammatory mechanisms is necessary to understand whether this component of the disease is relevant to its pathophysiology.     

Excessive ventilatory response during exercise in patients with non-hypoxic pulmonary hypertension.

The slope of the regression line between carbon dioxide output (VCO2) and minute ventilation (VE) (SLOPE) is useful for evaluating ventilation-perfusion inequality during exercise. A cardiopulmonary exercise test was carried out in 8 pulmonary hypertension (PH) patients without hypoxemia (group PH), 38 male patients with old myocardial infarction (group OMI), and 20 healthy men (group Ctrl). The average SLOPE for each group was 36.3+/-3.3, 28.7+/-0.9 and 25.6+/-0.5, respectively. There were significant differences among them. Group OMI was divided into 3 groups: OMI class 0: peak oxygen consumption (VO2) > or =21 ml x kg(-1) min(-1); OMI class I: 14 ml x kg(-1) x min(-1) < or =peak VO2<21 ml x kg(-1) min(-1); OMI class II: peak VO2< 14ml x kg(-1) x min(-1). There were no significant differences in peak VO2 between the groups PH and OMI class I, but the SLOPE in the group PH was greater than the SLOPE in OMI class I (p=0.0019). Compared with OMI class II, group PH had a greater peak VO2 (p=0.0215), although their SLOPE was equivalent to that of OMI class II. These results suggest that PH patients have severe ventilation-perfusion inequality despite good exercise capacity. When performing a cardiopulmonary exercise test on PH patients, it is necessary to observe not only VO2 or VCO2, but also VCO2/VE, in order to prevent aggravation of the ventilation-perfusion inequality, which leads to exercise-induced hypoxemia.     

Reproducibility of cardiopulmonary exercise measurements in patients with pulmonary arterial hypertension

BACKGROUND AND OBJECTIVES: As part of a recent study, cardiopulmonary exercise tests (CPETs) were used to evaluate and follow up patients with pulmonary arterial hypertension (PAH). These patients were more impaired than those in other published series evaluating CPET reproducibility. We used these patient tests to assess patient performance variability and evaluate reading variability. To achieve this end, six independent evaluators graded key CPET measurements in patients with PAH who underwent duplicate CPETs within 3 days of each other.Setting and patients: Over a 15-month period at two tertiary-care teaching hospitals, 42 patients with PAH underwent repeated, paired CPETs using cycle ergometry. INTERVENTIONS AND MEASUREMENTS: Each patient underwent one to six pairs of cycle ergometry tests to maximal tolerance. Each pair of tests was separated by 3 months, with each test in the pair separated by 1 to 3 days. Specific guidelines were given to the independent evaluators for the key measurements assessed from each CPET study: peak O(2) uptake (Vo(2)), peak heart rate, peak O(2) pulse, anaerobic threshold (AT), and end-tidal Po(2), end-tidal Pco(2), and the ventilatory equivalent for CO(2) at the AT (Ve/Vco(2)@AT). RESULTS: There were no fatalities or complications occurring among the 242 tests performed on 42 patients. The mean peak Vo(2) was 722 mL/min or 41% of predicted; 34 patients were Weber class C or D. Using the specific guidelines to measure the variability of measurements made by the six independent evaluators, the coefficients of variation were < 2.2% for peak Vo(2), peak heart rate, peak O(2) pulse, end-tidal values at the AT, and Ve/Vco(2)@AT, while for the AT, it was 8.5%. There were no significant differences in these measurements between the first and second tests of any pair or between the earlier and later sets of pairs. CONCLUSIONS: Using specific guidelines, key CPET measurements can be safely, reliably, and reproducibly assessed even in patients with severe exercise intolerance.     

Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension

In a clinical trial of 178 patients with pulmonary arterial hypertension, treatment improved the 6-minute walk (6MW) distance but not the peak VO2. To clarify this discrepancy, we examined the exercise data from all study sites. Patients received either the endothelin receptor antagonist sitaxsentan or placebo and underwent serial 6MW and cardiopulmonary exercise testing (CPET). In 518 pairs of body weight-adjusted and unadjusted 6MW and CPET data, the correlation between 6MW and peak VO2 was 0.48. In the 4 sites with the highest overall correlation at baseline (r = 0.62 compared with 0.46 for the other 19 sites, p = 0.04), the correlations at baseline (0.66) and at week 12 (0.65) were similar (p = 0.90). However, the correlation increased significantly from baseline (0.34) to week 12 (0.54, p = 0.0005) for the other 19 sites. The correlations between weight-adjusted 6MW distance and peak VO2 for all centers (0.76) were significantly higher than the unadjusted correlations (0.48, p < 0.0001). Improvement in the correlations over time between the 6MW and CPET data at less-experienced sites was most consistent with improved technical skill with increasing experience. Weight adjustment of the 6MW improved its correlation with peak VO2. In conclusion, in future multicenter trials, CPET expertise should be validated at all sites before subject enrollment.     

Assessing response to therapy in idiopathic pulmonary arterial hypertension: a consensus survey of Canadian pulmonary hypertension physicians

BACKGROUND:

Many treatment options are now available for patients with idiopathic pulmonary arterial hypertension (IPAH). Data regarding the optimal combination of therapies are lacking, as is consensus on how to assess response to therapy and when to change therapeutic regimens.

OBJECTIVES:

To gather the opinions of Canadian pulmonary hypertension (PH) experts regarding standard practice in the care of IPAH patients after therapy is initiated.

METHODS:

Canadian PH physicians were surveyed using short questionnaires to assess their opinions and practices in the care of IPAH patients. A Delphi forecasting approach was used to gain consensus among Canadian physicians on the most important clinical parameters to consider when assessing patients after the initiation of therapy.

RESULTS:

Twenty-six of 37 Canadian PH experts who were invited to participate completed the study. All endorsed the use of combination therapy for IPAH patients despite the lack of universal provincial coverage for this approach. By consensus, WHO functional class, 6 min walk distance and hospitalization for right heart failure were the most important clinical parameters. The most highly rated physical examination parameters were jugular venous pressure, peripheral edema, the presence of ascites and body weight.

CONCLUSIONS:

The overall approach to care of IPAH patients is similar across PH centres in Canada. A limited number of clinical and physical examination parameters were considered to be most important to reassess patients after therapy is initiated. These parameters, along with definition of threshold values, will facilitate the development of standard practice guidelines for IPAH patients in Canada.     

Impaired systemic arterial compliance in borderline hypertension

Arterial compliance was evaluated by pulse wave velocity, pulse pressure/stroke volume, and by an exponential analysis of the diastolic blood pressure decay curve in three groups of normotensive, borderline hypertensive, and established essential hypertensive patients. Two of the above three indices reflected significantly impaired arterial compliance in borderline hypertension, and all three indices were distinctly abnormal in patients with established hypertension. A close correlation among the three indices was observed in the entire study population. Multiple regression analysis indicated that age (p < 0.005), systolic (p < 0.005) and diastolic (p < 0.025) pressure were independent determinants of pulse wave velocity; other factors such as total peripheral resistance, pulse pressure, and stroke volume were not. We conclude that arterial compliance becomes impaired early in hypertensive cardiovascular disease at the time when arterial pressure may be only slightly elevated. Thus structural alteration of the arterial wall can be demonstrated in borderline hypertension. Age, systolic and, to a lesser degree, diastolic pressures are the best determinants of arterial compliance in large vessels and are therefore important risk factors for evolving systemic arterial disease in essential hypertension.