Non-invasive methods for estimating mPAP in COPD using cardiovascular magnetic resonance imaging.

PURPOSE: Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. METHODS: Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. RESULTS: Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHC-mPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). CONCLUSION: CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. KEY POINTS: • Pulmonary hypertension is a marker of poor outcome in COPD. • MRI can predict invasively measured mean pulmonary artery pressure. • Cardiac MRI allows for estimation of survival in COPD. • Cardiac MRI may be useful for follow up or future trials. • MRI is potentially useful to assess pulmonary hypertension in patients with COPD.

Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners.

Systemic sclerosis (SSc) is a rare disabling autoimmune disease with a similar mortality to many cancers. Two randomized controlled trials of autologous hematopoietic stem cell transplantation (AHSCT) for SSc have shown significant improvement in organ function, quality of life and long-term survival compared to standard therapy. However, transplant-related mortality (TRM) ranged from 3-10% in patients undergoing HSCT. In SSc, the main cause of non-transplant and TRM is cardiac related. We therefore updated the previously published guidelines for cardiac evaluation, which should be performed in dedicated centers with expertize in HSCT for SSc. The current recommendations are based on pre-transplant cardiopulmonary evaluations combining pulmonary function tests, echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic testing, initiated at Northwestern University (Chicago) and subsequently discussed and endorsed within the EBMT ADWP in 2016.

CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry.

We evaluated the prevalence and prognostic value of CT-pulmonary angiographic (CTPA) measures in 292 treatment naive patients with pulmonary arterial hypertension (PAH). Pulmonary artery calcification (13%) and thrombus (10%) were exclusively seen in PAH-congenital heart disease. Oesophageal dilation (46%) was most frequent in PAH-systemic sclerosis. Ground glass opacification (GGO) (41%), pericardial effusion (38%), lymphadenopathy (19%) and pleural effusion (11%) were common. On multivariate analysis, inferior vena caval area, the presence of pleural effusion and septal lines predicted outcome. In PAH, CTPA provides diagnostic and prognostic information. In addition, the presence of GGO on a CT performed for unexplained breathlessness should alert the physician to the possibility of PAH.

MRI model-based non-invasive differential diagnosis in pulmonary hypertension.

Pulmonary hypertension(PH) is a disorder characterised by increased mean pulmonary arterial pressure. Currently, the diagnosis of PH relies upon measurements taken during invasive right heart catheterisation (RHC). This paper describes a process to derive diagnostic parameters using only non-invasive methods based upon MRI imaging alone. Simultaneous measurements of main pulmonary artery (MPA) anatomy and flow are interpreted by 0D and 1D mathematical models, in order to infer the physiological status of the pulmonary circulation. Results are reported for 35 subjects, 27 of whom were patients clinically investigated for PH and eight of whom were healthy volunteers. The patients were divided into 3 sub-groups according to the severity of the disease state, one of which represented a negative diagnosis (NoPH), depending on the results of the clinical investigation, which included RHC and complementary MR imaging. Diagnostic indices are derived from two independent mathematical models, one based on the 1D wave equation and one based on an RCR Windkessel model. Using the first model it is shown that there is an increase in the ratio of the power in the reflected wave to that in the incident wave (Wpb/Wptotal) according to the classification of the disease state. Similarly, the second model shows an increase in the distal resistance with the disease status. The results of this pilot study demonstrate that there are statistically significant differences in the parameters derived from the proposed models depending on disease status, and thus suggest the potential for development of a non-invasive, image-based diagnostic test for pulmonary hypertension.

Pulmonary hypertension in renal disease: epidemiology, potential mechanisms and implications.

Pulmonary hypertension (PH) is highly prevalent in end-stage renal disease. Several observational studies, based on an echocardiographic diagnosis of PH, have suggested a prevalence of 30-60% and an association with increased mortality and poorer outcome following renal transplantation. The pathogenesis of PH in this population remains poorly understood. Reported associations include arteriovenous fistulae, cardiac dysfunction, fluid overload, bone mineral disorder and non-biocompatible dialysis membranes. However, due to the small numbers, the cross-sectional nature of the majority of studies in this field, and the reliance on echocardiography for the diagnosis of PH, no consistent association with any individual risk factor has been demonstrated. There is no difference in prevalence between patients receiving different dialysis modalities and emerging evidence suggests that the onset of the condition may precede dialysis treatment in many patients. Furthermore, little is known about the impact of the 'uraemic vasculopathy' on the pulmonary vasculature. Given the similarities between vascular changes in uraemia and those seen in pulmonary arterial hypertension, it is possible that a pulmonary vasculopathy may be present in a proportion of patients. There is a need for better understanding of the natural history and the pathogenesis of the condition which would help to individualise treatment of PH in end-stage renal disease. To enable such understanding, prospective adequately powered studies with an integrated investigational approach including right heart catheterisation are needed.

Central venous catheter-related blood stream infections in patients receiving intravenous iloprost for pulmonary hypertension.

Catheter-related blood stream infection (CR-BSI) in patients with pulmonary hypertension (PH) receiving intravenous iloprost via an indwelling central line has previously not been fully described. Recent studies have suggested a link between the pH of prostanoid infusions and the rate and nature of CR-BSI. We have investigated CR-BSI in patients receiving intravenous iloprost at our unit. Databases and hospital records were interrogated for all patients receiving intravenous iloprost between September 2007 and June 2012. Fifty-nine patients received intravenous iloprost via an indwelling central catheter with a total of 23,072 treatment days. There were 15 episodes of CR-BSI, identified using a systematic screening protocol, involving 11 patients giving an overall CR-BSI rate of 0.65/1,000 treatment days. CR-BSI rate for Gram-positive organisms was 0.26/1,000 treatment-days and for Gram-negative organisms was 0.39/1,000 treatment-days. The pH of iloprost in typical dosing regimens was comparable to the pH used in standard-diluent treprostinil and dissimilar to alkaline epoprostenol infusions. The proportion of Gram-negative CR-BSI was similar to that reported for standard-diluent treprostinil. CRP was normal on admission in 33 % of cases of confirmed CR-BSI and remained normal in 13 % of cases. CR-BSI rates with intravenous iloprost are comparable to those observed for other prostanoids. The high proportion of Gram-negative organisms observed and the neutral pH of iloprost infusions support the previously hypothesised link between pH and antimicrobial activity. Although usually elevated during a CR-BSI, CRP may be normal in early infection and a normal result cannot completely exclude infection.

ASPIRE registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre.

Pulmonary hypertension (PH) is a heterogeneous condition. To date, no registry data exists reflecting the spectrum of disease across the five diagnostic groups encountered in a specialist referral centre. Data was retrieved for consecutive, treatment-naïve cases diagnosed between 2001 and 2010 using a catheter-based approach. 1,344 patients were enrolled, with a mean follow-up of 2.9 yrs. The 3-yr survival was 68% for pulmonary arterial hypertension (PAH), 73% for PH associated with left heart disease, 44% for PH associated with lung disease (PH-lung), 71% for chronic thromboembolic PH (CTEPH) and 59% for miscellaneous PH. Compared with PAH, survival was inferior in PH-lung and superior in CTEPH (p<0.05). Multivariate analysis demonstrated that diagnostic group independently predicted survival. Within PAH, Eisenmenger's survival was superior to idiopathic PAH, which was superior to PAH associated with systemic sclerosis (p<0.005). Within PH-lung, 3-yr survival in sleep disorders/alveolar hypoventilation (90%) was superior to PH-lung with chronic obstructive pulmonary disease (41%) and interstitial lung disease (16%) (p<0.05). In CTEPH, long-term survival was best in patients with surgically accessible disease undergoing pulmonary endarterectomy. In this large registry of consecutive, treatment-naïve patients identified at a specialist PH centre, outcomes and characteristics differed between and within PH groups. The current system of classification of PH has prognostic value even when adjusted for age and disease severity, emphasising the importance of systematic evaluation and precise classification.

Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach.

OBJECTIVE: Pregnancy in women with pulmonary hypertension (PH) is reported to carry a maternal mortality rate of 30-56%. We report our experience of the management of pregnancies using a strategy of early introduction of targeted pulmonary vascular therapy and early planned delivery under regional anaesthesia. DESIGN: Retrospective observational study. SETTING: Specialist quaternary referral pulmonary vascular unit. POPULATION: Nine women with PH who chose to proceed with ten pregnancies. METHODS: A retrospective review of the management of all women who chose to continue with their pregnancy in our unit during 2002-2009. MAIN OUTCOME MEASURES: Maternal and fetal survival. RESULTS: All women commenced nebulised targeted therapy at 8-34 weeks of gestation. Four women required additional treatment or conversion to intravenous prostanoid therapy. All women were delivered between 26 and 37 weeks of gestation. Delivery was by planned caesarean section in nine cases. All women received regional anaesthesia and were monitored during the peripartum period in a critical care setting. There was no maternal mortality during pregnancy and all infants were free from congenital abnormalities. One woman died 4 weeks after delivery following patient-initiated discontinuation of therapy. All remaining women and infants were alive after a median of 3.2 years (range, 0.8-6.5 years) of follow-up. CONCLUSION: Although the risk of mortality in pregnant women with PH remains significant, we describe improved outcomes in fully counselled women who chose to continue with pregnancy and were managed with a tailored multiprofessional approach involving early introduction of targeted therapy, early planned delivery and regional anaesthetic techniques.

Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension.

Several prognostic variables have previously been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Specific medical conditions have also been associated with the development and prognosis of CTEPH. Using a national registry, the current authors have assessed the prognostic value of a larger number of variables and have also attempted to validate the clinical importance of previously identified aetiological factors. Baseline information for all 469 CTEPH patients diagnosed in the UK pulmonary hypertension service between January 2001 and June 2006 was collected from hospital records. Although univariate analysis confirmed the prognostic importance of pulmonary resistance, in multivariate analysis gas transfer and exercise capacity predicted pulmonary endarterectomy perioperative mortality. Cardiac index and exercise capacity independently predicted outcome in patients with nonoperable disease. Previous splenectomy was noted in 6.7% of patients, being significantly more common in patients with nonoperable than operable disease (13.7 versus 3.6%). Medical risk factors were not found to predict mortality. In a large national cohort, predictors of outcome in patients with both operable and nonoperable chronic thromboembolic pulmonary hypertension have been identified. These may be useful in planning treatment. The aetiological importance of previously identified medical risk factors has been confirmed, although the current authors were unable to validate their prognostic strength.

Results of European post-marketing surveillance of bosentan in pulmonary hypertension.

After the approval of bosentan for the treatment of pulmonary arterial hypertension (PAH), European authorities required the introduction of a post-marketing surveillance system (PMS) to obtain further data on its safety profile. A novel, prospective, internet-based PMS was designed, which solicited reports on elevated aminotransferases, medical reasons for bosentan discontinuation and other serious adverse events requiring hospitalisation. Data captured included demographics, PAH aetiology, baseline functional status and concomitant PAH-specific medications. Safety signals captured included death, hospitalisation, serious adverse events, unexpected adverse events and elevated aminotransferases. Within 30 months, 4,994 patients were included, representing 79% of patients receiving bosentan in Europe. In total, 4,623 patients were naïve to treatment; of these, 352 had elevated aminotransferases, corresponding to a crude incidence of 7.6% and an annual rate of 10.1%. Bosentan was discontinued due to elevated aminotransferases in 150 (3.2%) bosentan-naïve patients. Safety results were consistent across subgroups and aetiologies. The novel post-marketing surveillance captured targeted safety data ("potential safety signals") from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials. These data complement those from randomised controlled clinical trials and provide important additional information on the safety profile of bosentan.

The role of vasopressin in cardiorespiratory arrest and pulmonary hypertension.

Vasopressin is a peptide synthesized in the hypothalamus whose primary role is in fluid homeostasis. It has recently gained interest as a potential agent in the treatment of cardiorespiratory arrest. Initial human studies have shown benefits with vasopressin in patients with out of hospital ventricular fibrillation and asystolic cardiac arrest. One subgroup of patients not included in these trials is patients with pulmonary hypertension, who have a five-year mortality rate of 50%. Animal studies have shown vasopressin to be a vasodilator in the pulmonary vascular system of rats, under normoxic and hypoxic conditions, with conflicting results in canines. Human studies have shown conflicting results with increases, decreases and no changes seen in pulmonary artery pressures of patients with a variety of clinical conditions. Research needs to be done in patients with pulmonary hypertension regarding the potential role of vasopressin during cardiac arrest in this subgroup.

The use of iloprost in early pregnancy in patients with pulmonary arterial hypertension.

In patients with pulmonary hypertension, pregnancy is associated with a high risk of maternal death. Such patients are counselled to avoid pregnancy, or if it occurs, are offered early interruption. Some patients, however, decide to continue with their pregnancy and others may present with symptoms for the first time whilst pregnant. Pulmonary vasodilator therapy provides a treatment option for these high-risk patients. The present study describes three patients with pulmonary arterial hypertension of various aetiologies who were treated with the prostacyclin analogue iloprost during pregnancy, and the post-partum period. Nebulised iloprost commenced as early as 8 weeks of gestation and patients were admitted to hospital between 24-36 weeks of gestation. All pregnancies were completed with a duration of between 25-36 weeks and all deliveries were by caesarean section under local anaesthetic. All patients delivered children free from congenital abnormalities, and there was no post-partum maternal or infant mortality. In conclusion, although pregnancy is strongly advised against in those with pulmonary hypertension, the current authors have achieved a successful outcome for mother and foetus with a multidisciplinary approach and targeted pulmonary vascular therapy.

Bedside tracer gas technique accurately predicts outcome in aspiration of spontaneous pneumothorax.

BACKGROUND: There is no technique in general use that reliably predicts the outcome of manual aspiration of spontaneous pneumothorax. We have hypothesised that the absence of a pleural leak at the time of aspiration will identify a group of patients in whom immediate discharge is unlikely to be complicated by early lung re-collapse and have tested this hypothesis by using a simple bedside tracer gas technique. METHODS: Eighty four episodes of primary spontaneous pneumothorax and 35 episodes of secondary spontaneous pneumothorax were studied prospectively. Patients breathed air containing a tracer (propellant gas from a pressurised metered dose inhaler) while the pneumothorax was aspirated percutaneously. Tracer gas in the aspirate was detected at the bedside using a portable flame ioniser and episodes were categorised as tracer gas positive (>1 part per million of tracer gas) or negative. The presence of tracer gas was taken to imply a persistent pleural leak. Failure of manual aspiration and the need for a further intervention was based on chest radiographic appearances showing either failure of the lung to re-expand or re-collapse following initial re-expansion. RESULTS: A negative tracer gas test alone implied that manual aspiration would be successful in the treatment of 93% of episodes of primary spontaneous pneumothorax (p<0.001) and in 86% of episodes of secondary spontaneous pneumothorax (p=0.01). A positive test implied that manual aspiration would either fail to re-expand the lung or that early re-collapse would occur despite initial re-expansion in 66% of episodes of primary spontaneous pneumothorax and 71% of episodes of secondary spontaneous pneumothorax. Lung re-inflation on the chest radiograph taken immediately after aspiration was a poor predictor of successful aspiration, with lung re-collapse occurring in 34% of episodes by the following day such that a further intervention was required. CONCLUSIONS: National guidelines currently recommend immediate discharge of patients with primary spontaneous pneumothorax based primarily on the outcome of the post-aspiration chest radiograph which we have shown to be a poor predictor of early lung re-collapse. Using a simple bedside test in combination with the post-aspiration chest radiograph, we can predict with high accuracy the success of aspiration in achieving sustained lung re-inflation, thereby identifying patients with primary spontaneous pneumothorax who can be safely and immediately discharged home and those who should be observed overnight because of a significant risk of re-collapse, with an estimated re-admission rate of 1%.

Iatrogenic pneumothorax: marker gas technique for predicting outcome of manual aspiration.

BACKGROUND: Although manual aspiration is used for treating pneumothorax, the post-aspiration radiograph may not be a reliable indicator of whether the pleural leak remains. We have previously shown that marker gas can identify an air leak in patients with spontaneous pneumothoraces. OBJECTIVE: This study examines whether a marker gas technique can be safely used to manage patients with iatrogenic pneumothoraces. METHODS: 10 patients with iatrogenic pneumothorax were identified among a cohort referred for manual aspiration of pneumothorax, using a marker gas technique, in which inspired metered-dose inhaler propellant gas is detectable in pneumothorax aspirate using a portable flame ioniser. The presence of marker gas was taken to imply a persistent air leak. RESULTS: Marker gas was detected in the aspirate from 3 out of 10 pneumothoraces. 2 required intercostal tube drainage because of lung collapse following initial aspiration and 1 was treated conservatively. Marker gas was not detected in 7 cases (2 post-pacemaker insertion, 5 pleural aspiration +/- biopsy), and in all these cases, manual aspiration resulted in sustained re-expansion of the lung. There was a trend towards a significant relationship between the presence or absence of marker gas and the need for a further intervention (p = 0.055). CONCLUSION: The presence or absence of a pleural leak during manual aspiration of iatrogenic pneumothorax can be demonstrated by this technique. The absence of marker gas in the aspirate implies that manual aspiration will be successful, whereas its presence, in most cases, predicts either failure of manual aspiration to expand the lung or early re-collapse of the lung.

The effect of nitric oxide inhibition on the renin response to frusemide, in man.

AIMS: We wished to see if renin release in man was inhibited by nitric oxide blockade, suggesting a role for nitric oxide in renin release. Evidence from animal studies has shown variable effects on renin release depending on the model and stimulus used. METHODS: Ten normal male volunteers, received either L-NMMA as a front loaded infusion (4 mg kg-1 bolus, with 4 mg kg-1 infusion), or placebo, followed by an intravenous bolus of 5 mg frusemide to stimulate renin. To investigate whether any alteration in renin release was due to the pressor effect of the L-NMMA, the experiment was repeated using an equipressor dose of phenylephrine (0.5 microg kg-1 min-1 ). RESULTS: L-NMMA caused the expected increase in mean arterial pressure (96+/-2.6 vs 89+/-3.3 mmHg P<0.05 [mean+/-s.e.mean]), and a reduction in heart rate (59+/-3.6 vs 67+/-2.5 beats min-1 P<0.05). L-NMMA completely blocked the renin rise following the bolus of frusemide (1.18+/-0.196 vs 1.96+/-0.333 ng ml-1 h-1 P<0.01). Phenylephrine 0.5 microg kg-1 min-1 produced very similar haemodynamic effects to L-NMMA, and also suppressed the renin response to frusemide (1.43+/-0.290 vs 2.67+/-0.342 ng ml-1 h-1 P<0. 01). CONCLUSIONS: In man, the renin inhibition seen with NO synthesis inhibition is similar to that seen with a standard pressor stimulus, hence inhibition of renin in man by L-NMMA, may be due to both direct effects on macula densa cells and indirect haemodynamic effects.

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man.

AIMS: The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N(G)-monomethyl-L-arginine (L-NMMA) on systemic and pulmonary haemodynamics. METHODS: Ten normal male volunteers 26 +/- 1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of L-NMMA (4 mg kg(-1) h(-1)) with a front loaded bolus (4 mg kg(-1)) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t0) and after 4, 8, and 12 min (t1, t2 and t3). RESULTS: Infusion of L-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t1 and persisted during the entire infusion period. CONCLUSIONS: These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.

Effects of frusemide and hypoxia on the pulmonary vascular bed in man.

AIMS: Diuretic therapy is conventionally used to treat oedema in patients with hypoxic cor pulmonale. This condition is associated with activation of the renin angiotensin system (RAS) with elevated levels of angiotensin II (ANG II), a potent pulmonary pressor agent. We explored the hypothesis that RAS activation by diuretic therapy might therefore worsen hypoxic pulmonary vasoconstriction via the effects of ANG II on the pulmonary vascular bed. METHODS: Eight normal volunteers were studied on 2 separate days. They either received 40 mg frusemide daily or placebo for 4 days and were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave doppler echocardiography was used to measure mean pulmonary artery pressure, cardiac output and hence pulmonary vascular resistance (PVR). RESULTS: Plasma renin activity (PRA) was significantly (P < 0.01) increased after prior treatment with frusemide compared with placebo at all time points. Prior treatment with frusemide significantly (P < 0.05) increased PVR compared with placebo at baseline: 185 +/- 17 vs 132 +/- 10 dyn s cm-5 at an SaO2 of 85-90%: 291 +/- 18 vs 229 +/- 16 dyn s cm-5 and at SaO2 of 75-80%: 356 +/- 12 vs 296 +/- 17 dyn s cm-5 respectively. However, the delta-PVR response to hypoxaemia was not significantly altered by frusemide compared with placebo. In contrast to its effect on the pulmonary vasculature prior treatment with frusemide did not significantly alter systemic haemodynamic parameters either at baseline or during hypoxia. CONCLUSIONS: Thus, prior treatment with frusemide increased baseline pulmonary vascular resistance and significantly augmented the hypoxaemic pulmonary vascular response in additive fashion. It is hypothesised that this effect of frusemide may be due to RAS activation with ANG II mediated pulmonary vasoconstriction.

Cardiopulmonary effects of endothelin-1 in man.

OBJECTIVES: Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vasoconstriction such as congestive cardiac failure and primary and secondary pulmonary hypertension. The aim of the present study was to assess the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal man. METHODS: Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study and received systemic infusions of either endothelin-1 (0.75, 1.5 and 3 pmol.kg-1.min-1 for 30 min each) or saline placebo. Systemic and pulmonary haemodynamic parameters were monitored non-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin-angiotensin and natriuretic peptide system activity were also measured. RESULTS: Endothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increased from 1156 +/- 57 to 1738 +/- 115 dyn.s.cm-5, and total pulmonary vascular resistance (TPR) increased from 142 +/- 12 to 329 +/- 22 dyn.s.cm-5. Endothelin-1 caused significant impairment of left and right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic pressor effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impaired. Activity of the renin-angiotensin system was suppressed by endothelin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were unchanged. CONCLUSIONS: Thus, in addition to systemic and pulmonary pressor effects our results suggest that endothelin-1 impairs overall cardiovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compensatory changes in the renin-angiotensin system.

Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale.

OBJECTIVES: Angiotensin II (ANG II) is known to be a potent vasoconstrictor agent in the pulmonary circulation. Furthermore, type 1 ANG II receptor blockade with losartan attenuates acute hypoxic pulmonary vasoconstriction in normal subjects. The aim of this study was therefore to evaluate the haemodynamic and endocrine sequelae of type 1 ANG II receptor blockade in patients with hypoxaemic cor pulmonale. METHODS: Nine patients with chronic obstructive pulmonary disease (COPD) age 67 +/- 3 years with pulmonary hypertension and normal left ventricular systolic function were studied on two separate occasions in a double-blind, placebo-controlled, crossover study. They were randomised to receive either 50 mg of oral losartan or matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Haemodynamic measurements and venous blood samples were taken at baseline and after 2 and 4 h. RESULTS: Maximal effects were observed at 4 h where losartan compared to placebo resulted in a significant reduction in both MPAP (28.6 +/- 2.0 vs 32.4 +/- 1.5 mmHg) and TPR (428 +/- 40 vs 510 +/- dyn.s.cm-5), respectively. Similarly losartan compared to placebo resulted in a significant reduction in MAP (87 +/- 4.5 vs 93 +/- 3.2 mmHg) and SVR (1293 +/- 94 vs 1462 +/- 112 dyn.s.cm-5), and significantly increased CO (5.58 +/- 0.43 vs 5.31 +/- 0.42 l/min). In addition, plasma aldosterone was significantly lower after treatment with losartan compared to placebo: 76 +/- 23 vs 164 +/- 43 pg/ml respectively. CONCLUSIONS: Thus, selective type 1 ANG II receptor blockade appears to have beneficial pulmonary and endocrine effects, suggesting a possible therapeutic role in the management of hypoxaemic cor pulmonale.