Frédéric Lador

Criteria for diagnosis of exercise pulmonary hypertension

The previous definition of exercise pulmonary hypertension (PH) with a mean pulmonary artery pressure (mPAP) >30 mmHg was abandoned because healthy individuals can exceed this threshold at high cardiac output (CO). We hypothesised that incorporating assessment of the pressure–flow relationship using the mPAP/CO ratio, i.e. total pulmonary resistance (TPR), might enhance the accuracy of diagnosing an abnormal exercise haemodynamic response. Exercise haemodynamics were evaluated in 169 consecutive subjects with normal resting mPAP ≤20 mmHg. Subjects were classified into controls without heart or lung disease (n=68) versus patients with pulmonary vascular disease (PVD) (n=49) and left heart disease (LHD) (n=52). TPR and mPAP at maximal exercise produced diagnostic accuracy with area under the receiver operating curve of 0.99 and 0.95, respectively, for discriminating controls versus patients with PVD and LHD. The old criterion of mPAP >30 mmHg had sensitivity of 0.98 but specificity of 0.77. Combining maximal mPAP >30 mmHg and TPR >3 mmHg·min·L−1 retained sensitivity at 0.93 but improved specificity to 1.0. The accuracy of the combined criteria was high across different age groups, sex, body mass index and diagnosis (PVD or LHD). Combining mPAP >30 mmHg and TPR >3 mmHg·min·L−1 is superior to mPAP >30 mmHg alone for defining a pathological haemodynamic response of the pulmonary circulation during exercise. Mean PAP >30 mmHg and total pulmonary resistance >3 WU may be used as new criteria for exercise PH http://ow.ly/LnJbp

Long-Term Data from the Swiss Pulmonary Hypertension Registry

Background: Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. Objective: To provide long-term data of the Swiss PH registry of 1998-2012. Methods: PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. Results: From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. Conclusion: Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications.

PHASE I DYNAMICS OF CARDIAC OUTPUT, SYSTEMIC O2 DELIVERY AND LUNG O2 UPTAKE AT EXERCISE ONSET IN MEN IN ACUTE NORMOBARIC HYPOXIA

We tested the hypothesis that vagal withdrawal plays a role in the rapid (phase I) cardiopulmonary response to exercise. To this aim, in five men (24.6+/-3.4 yr, 82.1+/-13.7 kg, maximal aerobic power 330+/-67 W), we determined beat-by-beat cardiac output (Q), oxygen delivery (QaO2), and breath-by-breath lung oxygen uptake (VO2) at light exercise (50 and 100 W) in normoxia and acute hypoxia (fraction of inspired O2=0.11), because the latter reduces resting vagal activity. We computed Q from stroke volume (Qst, by model flow) and heart rate (fH, electrocardiography), and QaO2 from Q and arterial O2 concentration. Double exponentials were fitted to the data. In hypoxia compared with normoxia, steady-state fH and Q were higher, and Qst and VO2 were unchanged. QaO2 was unchanged at rest and lower at exercise. During transients, amplitude of phase I (A1) for VO2 was unchanged. For fH, Q and QaO2, A1 was lower. Phase I time constant (tau1) for QaO2 and VO2 was unchanged. The same was the case for Q at 100 W and for fH at 50 W. Qst kinetics were unaffected. In conclusion, the results do not fully support the hypothesis that vagal withdrawal determines phase I, because it was not completely suppressed. Although we can attribute the decrease in A1 of fH to a diminished degree of vagal withdrawal in hypoxia, this is not so for Qst. Thus the dual origin of the phase I of Q and QaO2, neural (vagal) and mechanical (venous return increase by muscle pump action), would rather be confirmed.

Editorial: Pediatric Pulmonary Hypertension

Pulmonary hypertension (PH) can present at any age from the neonatal period to adulthood. Pediatric PH is similar to adults but differentiates itself as in a growing child the lungs are still developing (1). It is a hemodynamic condition defined by an increased pulmonary artery mean pressure above or equal to 25 mmHg (1). This can be associated with multiple clinical conditions forming different etiological groups with specific and diverse pathological and pathobiological characteristics (1). When implying an abnormal reduction of small pulmonary arteries section due to endothelial dysfunction, medial proliferation, and adventitial fibrosis, the disease is called pulmonary arterial hypertension (PAH). PAH induces typically a severe and devastating PH that leads to right heart failure and premature death. Until recently, the vast majority of studies published on PH were in the adult population but, as highlighted by the series of manuscript published in this issue of frontiers in pediatrics, awareness about pediatric PH is growing. In this line, a specific subgroup was dedicated to pediatrics at the last world symposium on PH with the publication of an excellent summary (1). Manuscripts not only on clinical research but also on basic science further highlight the interest in pediatric PH. Epidemiologic data, mainly sourced from national and international registries, have recently been published, but the content of these registries varies depending on the center involved and the inclusion criteria (2). Indeed, most of the registries, including centers from developed countries, do not report children with PAH associated with HIV, in contrast to reports coming from developing countries (3). This may be due to the absence of this problem in developed countries in association with aggressive antiretroviral therapies or the absence of screening. L’Huillier et al. report the data from a Swiss cohort of patients with HIV (4). No patient presented with PH, but screening of PH was not systematically performed. This must be kept in mind when analyzing epidemiologic data. In pediatrics, there is a need and a constant search for non-invasive assessments of PH, mainly because right heart catheterization, whenever it is still considered as the gold standard for hemodynamic evaluation and PH diagnosis is associated with potential risk in this particular population. So, the development of non-invasive tools for hemodynamic evaluation is not only desirable but mandatory in pediatrics. To this purpose, echocardiography gives invaluable information during the follow-up. Jone and Ivy did an excellent review of the current knowledge application of this approach in pediatric PH (5) and offer a basis for the remaining work dedicated to validation of most of the discussed parameters. Similarly, Day et al. reported their experience with the use of oxygen and sildenafil for assessment of pulmonary vascular reactivity in children (6). The response to vasoreactivity testing is crucial for orientation of treatment strategy as responders can be treated with calcium channel blockers with an excellent survival rate. This was clearly demonstrated in adults (7) but we still have to work to define a similar approach in children. Here, a major question still remains: what is the definition of a responder? The manuscript of Day et al. brings some more information with regards to vasoreactivity assessments in pediatric PH. Still in the field of non-invasive assessment and potential markers of disease, Latus et al. reported their experience with the analysis of heart rate variability (HRV) showing that this parameter may be altered in pediatric patients with PH (8). HRV may indeed be related to disease severity and serve as an additional marker for PH evaluation. Although there is still no cure for PAH, quality of life and survival have been improved significantly with specific drug therapies (9). Nevertheless, management of pediatric PAH remains challenging and depends mainly on results from adult clinical trials, a few specific pediatric studies and pediatric experts’ recommendations. Any additional report of the use of targeted therapies in children is of interest. Siehr et al. reported their experience with the use of sildenafil and concentrated on its potential side effects (10). One must remember that a question was raised on the use of sildenafil in children as the STARTS study reported an increased risk of death using high doses (11, 12). This led to a warning from the FDA and the approval of the medium dose by the European Medical Authorities. Even, if Siehr et al. reported no new side effects, they mention that the incidence of vascular, gastrointestinal, and neurologic side effects in pediatric patients on sildenafil therapy was 30%. Side effects were more common in patients on combination therapy with an endothelin receptor antagonist and/or a prostacyclin than in patients on sildenafil monotherapy. Prior to the development of new therapeutic pathways, recognition of all pathobiological pathways involved in the development of pulmonary vascular disease are needed. Van loon et al. (13) reported their experience with erythropoietin (EPO) (10). In experimental PAH, EPO treatment restored the number of circulating endothelial progenitor cells (EPCs) to control level, improved pulmonary vascular remodeling, and showed important interplay with heme oxygenase (HO) activity. Inhibition of increased HO activity in PAH rats exacerbated progression of pulmonary vascular remodeling, despite the presence of restored number of circulating EPCs. It may be that both EPO-induced HO and EPCs are promising targets to improve the pulmonary vasculature in PAH. Different specific issues related to pediatric PAH have been reported and highlight the need to continue active research in this field. It is of paramount importance to better understand the pathobiology of the disease, its behavior and discover new treatment pathway in order to finally curing this devastating disease.

Prolonged head down bed rest-induced inactivity impairs tonic autonomic regulation while sparing oscillatory cardiovascular rhythms in healthy humans.

Background Physical inactivity represents a major risk for cardiovascular disorders, such as hypertension, myocardial infarction or sudden death; however, underlying mechanisms are not clearly elucidated. Clinical and epidemiological investigations suggest, beyond molecular changes, the possibility of an induced impairment in autonomic cardiovascular regulation. However, this hypothesis has not been tested directly. Methods Accordingly, we planned a study with noninvasive, minimally intrusive, techniques on healthy volunteers. Participants were maintained for 90 days strictly in bed, 24 h a day, in head-down (−6°) position (HDBR). Physical activity was thus virtually abolished for the entire period of HDBR. We examined efferent muscle sympathetic nerve activity, as a measure of vascular sympathetic control, baroreceptor reflex sensitivity, heart rate variability (assessing cardiovagal regulation), RR and systolic arterial pressure and low-frequency and high-frequency normalized components (as a window on central oscillatory regulation). Measures were obtained at rest and during simple maneuvers (moderate handgrip, lower body negative pressure and active standing) to assess potential changes in autonomic cardiovascular responsiveness to standard stimuli and the related oscillatory profiles. Results HDBR transiently reduced muscle sympathetic nerve activity, RR, heart rate variability and baroreceptor reflex sensitivity late during HDBR or early during the recovery phase. Conversely, oscillatory profiles of RR and systolic arterial pressure variability were maintained throughout. Responsiveness to test stimuli was also largely maintained. Conclusion Prolonged inactivity as induced by HDBR in healthy volunteers reduces both cardiovagal and vascular sympathetic regulation, while largely maintaining peripheral responsiveness to standardized stimuli and sparing the functional structure of central oscillatory cardiovascular regulation.

Resting pulmonary artery pressure of 21-24 mmHg predicts abnormal exercise haemodynamics.

A resting mean pulmonary artery pressure (mPAP) of 21–24 mmHg is above the upper limit of normal but does not reach criteria for the diagnosis of pulmonary hypertension (PH). We sought to determine whether an mPAP of 21–24 mmHg is associated with an increased risk of developing an abnormal pulmonary vascular response during exercise. Consecutive patients (n=290) with resting mPAP <25 mmHg who underwent invasive exercise haemodynamics were analysed. Risk factors for pulmonary vascular disease or left heart disease were present in 63.4% and 43.8% of subjects. An abnormal pulmonary vascular response (or exercise PH) was defined by mPAP >30 mmHg and total pulmonary vascular resistance >3 WU at maximal exercise. Exercise PH occurred in 74 (86.0%) out of 86 versus 96 (47.1%) out of 204 in the mPAP of 21–24 mmHg and mPAP <21 mmHg groups, respectively (OR 6.9, 95% CI: 3.6–13.6; p<0.0001). Patients with mPAP of 21–24 mmHg had lower 6-min walk distance (p=0.002) and higher New York Heart Association functional class status (p=0.03). Decreasing levels of mPAP were associated with a lower prevalence of exercise PH, which occurred in 60.3%, 38.7% and 7.7% of patients with mPAP of 17–20, 13–16 and <13 mmHg, respectively. In an at-risk population, a resting mPAP between 21–24 mmHg is closely associated with exercise PH together with worse functional capacity. Resting mean PAP between 21–24 mmHg predicts abnormal exercise pulmonary haemodynamics and impaired functional capacity http://ow.ly/YfSuG

Cardiovascular determinants of maximal oxygen consumption in upright and supine posture at the end of prolonged bed rest in humans

We tested the hypothesis that, after bed rest, maximal oxygen consumption ( VO₂max ) decreases more upright than supine, because of adequate cardiovascular response supine, but not upright. On 9 subjects, we determined VO₂max and maximal cardiac output (Q ) upright and supine, before and after (reambulation day upright, the following day supine) 35-day bed rest, by classical steady state protocol. Oxygen consumption, heart rate (f(H)) and stroke volume (Q(st)) were measured by a metabolic cart, electrocardiography and Modelflow from pulse pressure profiles, respectively. We computed Q as f(H) times Q(st), and systemic oxygen flow ( QaO₂) as Q. times arterial oxygen concentration, obtained after haemoglobin and arterial oxygen saturation measurements. Before bed rest, all parameters at maximal exercise were similar upright and supine. After bed rest, VO₂max was lower (p<0.05) than before, both upright (-38.6%) and supine (-17.0%), being 30.8% higher supine than upright. Maximal Q(st) decreased upright (-44.3%), but not supine (+3.7%), being 98.9% higher supine than upright. Maximal Q decreased upright (-45.1%), but not supine (+9.0%), being higher supine than upright (+98.4%). Maximal QaO₂ decreased upright (-37.8%), but not supine (+14.8%), being higher (+74.8%) upright than supine. After bed rest, the cardiovascular response (i) did not affect VO₂max supine, (ii) partially explained the VO₂max decrease upright, and (iii) caused the VO₂max differences between postures. We speculate that impaired peripheral oxygen transfer and/or utilisation may explain the VO₂max decrease supine and the fraction of VO₂max decrease upright unexplained by cardiovascular responses.

A practical approach of pulmonary hypertension in the elderly.

Recent reports from pulmonary arterial hypertension (PAH) registries suggest that the mean age at diagnosis is increasing, outlining a growing proportion of elderly male patients. As a consequence, the classical description of the disease is shifting and may no more be described as a rare disease typically affecting young women. Potential explanations of this changing picture may include an aging of populations in western countries, the increase in life expectancy and the growing awareness of PAH and emergence of potential efficient treatments. Diagnostic workup of severe pulmonary hypertension (PH) in the elderly should be performed in such a way as to discriminate between the expected consequences of aging, pulmonary vascular disease, and other frequent causes of secondary PH (left heart failure or lung disease). Careful exploration by right heart catheterization is mandatory, but special attention should be paid to several pitfalls specific to this procedure in this age group. This is a matter of concern as clinical trials that aim to study new specific drug therapy for PAH might be biased by the inclusion of misdiagnosed patients. The aim of this review is to highlight the main difficulties in diagnosing PAH in the elderly and to propose a practical approach to distinguish PAH from the other frequent causes of PH in this population.

Out-of-Proportion Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction

Background: A subset of patients with heart failure with preserved ejection fraction (HFpEF) will have a marked increase in pulmonary artery pressure (PAP). Objective: To evaluate the clinical and hemodynamic characteristics of these patients in comparison to patients with idiopathic pulmonary arterial hypertension (IPAH). Methods: We reviewed the clinical and hemodynamic data of patients with HFpEF with out-of-proportion pulmonary hypertension (HFpEF-PH) and compared it to the corresponding data of age-matched patients with IPAH. Results: Twenty consecutive patients with HFpEF-PH and 20 patients with IPAH were included in the study. The mean age (±SD) was 71.3 ± 7.8 and 70.2 ± 6.7 years, respectively. The majority of the HFpEF-PH patients were postmenopausal females with at least two features of the metabolic syndrome and atrial fibrillation. Although HFpEF-PH patients fulfilled the criteria for out-of-proportion PH, with transpulmonary gradient (TPG) >12 mm Hg, the difference between the diastolic PAP and the pulmonary capillary wedge pressure (PCWP) was significantly lower compared to IPAH (6.3 ± 6.2 vs. 27.5 ± 4.8, p < 0.00001). Conclusions: Our results suggest that a diagnosis of HFpEF-PH should be suspected when severe PH occurs in an elderly postmenopausal female with one or more features of the metabolic syndrome and atrial fibrillation. Interestingly, these patients had significantly lower differences between diastolic PAP and PCWP, suggesting that the increase in TPG is mainly caused by an elevated systolic PAP, possibly as a result of increased pulmonary vascular stiffness, and not pulmonary vascular remodeling.

Diagnostic concordance of different criteria for exercise pulmonary hypertension in subjects with normal resting pulmonary artery pressure

Pulmonary hypertension is defined by a resting mean pulmonary artery pressure (mPAP) ≥25 mmHg [1]. Despite a better understanding of the biology of pulmonary hypertension and new therapeutic advances, pulmonary hypertension remains diagnosed late in its natural history and is largely a non-curable condition [2]. Recently, there has been renewed interest in stress-testing of the pulmonary circulation since the early stages of pulmonary vascular disease (PVD) or left heart disease (LHD) can be associated with normal resting mPAP but an abnormal haemodynamic response that is unmasked by exercise [3–5]. Methodology of pressure–flow assessment needs to be standardized for the diagnosis of exercise pulmonary hypertension http://ow.ly/YMgZw