Pulmonary Hypertension and the Gut Microbiome.

The gut microbiome and its associated metabolites are integral to the maintenance of gut integrity and function. There is increasing evidence that its alteration, referred to as dysbiosis, is involved in the development of a systemic conditions such as cardiovascular disease (e.g., systemic hypertension, atherosclerosis). Pulmonary hypertension (PH) is a condition characterised by progressive remodelling and vasoconstriction of the pulmonary circulation, ultimately leading to right ventricular failure and premature mortality if untreated. Initial studies have suggested a possible association between dysbiosis of the microbiome and the development of PH. The aim of this article is to review the current experimental and clinical data with respect to the potential interaction between the gut microbiome and the pathophysiology of pulmonary hypertension. It will also highlight possible new therapeutic targets that may provide future therapies.

Cardioprotective medication in Duchenne muscular dystrophy: a single-centre cohort study.

Background: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder characterised by progressive muscle wasting impacting mobility, ventilation and cardiac function. Associated neuromuscular cardiomyopathy remains a major cause of morbidity and mortality. We investigated the effects of cardioprotective medications [angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers] on clinical outcomes in DMD patients. Methods: This was a retrospective cohort study (reference: 2021/12469) of DMD patients at a tertiary centre between 1993-2021 screening the electronic records for demographics, comorbidities, medication, disease specific features, echocardiography, hospitalisations, and ventilator use. Results: A total of 68 patients were identified aged 27.4 (6.6) years, of which 52 were still alive. There was a difference in body mass index (BMI) between survivors and deceased patients [23.8 (5.9) vs. 19.9 (3.8) kg/m2, P=0.03]. Home mechanical ventilation (HMV) was required in 90% of patients, 85% had DMD associated cardiomyopathy. About 2/3 of all hospitalisations during the observation period were secondary to cardiopulmonary causes. The left ventricular ejection fraction (LVEF) at initial presentation was 44.8% (10.6%) and declined by 3.3% [95% confidence interval (CI): 0.4% to -7.0%] over the follow up period (P=0.002). A total of 61 patients were established on ACE-I for 75.9% (35.1%), and 62 were on beta-blockers for 73.6% (33.5%) of the follow up period. There was a significant LVEF decline in those taking ACE-I for limited periods compared to those permanently on ACE-I (P=0.002); a similar effect was recorded with beta-blockers (P=0.02). Conclusions: Long-term use of ACE-I and beta-blockers is associated with a reduced decline in LVEF in patients with DMD and may be protective of adverse cardiovascular ill health.

Diagnosis and management of pulmonary hypertension related to chronic respiratory disease.

Pulmonary hypertension (PH) is a recognised and significant complication of chronic lung disease (CLD) and hypoxia (referred to as group 3 PH) that is associated with increased morbidity, decreased quality of life and worse survival. The prevalence and severity of group 3 PH varies within the current literature, with the majority of CLD-PH patients tending to have non-severe disease. The aetiology of this condition is multifactorial and complex, while the prevailing pathogenetic mechanisms include hypoxic vasoconstriction, parenchymal lung (and vascular bed) destruction, vascular remodelling and inflammation. Comorbidities such as left heart dysfunction and thromboembolic disease can further confound the clinical picture. Noninvasive assessment is initially undertaken in suspected cases (e.g. cardiac biomarkers, lung function, echocardiogram), while haemodynamic evaluation with right heart catheterisation remains the diagnostic gold standard. For patients with suspected severe PH, those with a pulmonary vascular phenotype or when there is uncertainty regarding further management, referral to specialist PH centres for further investigation and definitive management is mandated. No disease-specific therapy is currently available for group 3 PH and the focus of management remains optimisation of the underlying lung therapy, along with treating hypoventilation syndromes as indicated.

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

BACKGROUND: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death. METHODS: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research. RESULTS: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning. CONCLUSIONS: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

Long-term adherence to home mechanical ventilation: a 10-year retrospective, single-centre cohort study.

BACKGROUND: Sleep-disordered breathing (SBD) can be associated with hypercapnic respiratory failure (HRF). Home Mechanical Ventilation (HMV) is the preferred long-term treatment for patients with chronic HRF. We reviewed the database of a large tertiary referral centre for HMV to study the long-term adherence to HMV in chronic hypercapnic patients. METHODS: Data on adherence and characteristics of patients who received HMV for the treatment of SDB were collected over a decade using electronic patient records. The primary outcome parameter in this study was annual non-adherence rate (patients with HMV usage of <4 hours/night in the service divided by the number of all new patients of the same year), secondary outcomes were patients' characteristics and reasons for low adherence. HMV adherence clinics were established to improve uptake. RESULTS: Two thousand and two hundred twenty-eight patients with HRF were under active follow-up on HMV at the end of the recording period. In contrast, a total of 1,900 patients had their HMV contracts terminated over the course of a decade (due to non-adherence, transfer to other services or death). Out of those, 222 patients {62 [52-72] years, body-mass index, BMI 40 [35-43] kg/m2, 58.1% male, Epworth Sleepiness Scale, ESS 9 [4-15] points, 4% oxygen desaturation index, 4%ODI 32 [20-71] × hour-1, TcCO2 6.6 [6.0-7.2] kPa} met the non-adherence criteria (nocturnal usage 0-4 hours). The annual non-adherence rate was 25.5% of all new setups in 2010, and declined to 3.4% in 2019 (relative reduction of 86%, P<0.001). Patients with Obstructive Sleep Apnoea/Obesity Hypoventilation Syndrome (58.2%), Neuromuscular Diseases (NMD) (26.8%) and COPD (13.6%) accounted for most cases of this non-adherent cohort. The vast majority of the patients (96.1%) were established on full-face masks. In 23.4% of patients, substantial weight loss (>10%) was the most common reason for low adherence; general displeasure (21.3%), uncontrolled symptoms (12.8%), claustrophobia (6.7%), mood (4.8%) and mask intolerance (4.3%) caused problems as well. CONCLUSIONS: Non-adherence to HMV in patients with chronic HRF can affect significant proportions of patients. However, the non-adherent rate substantially decreases when individual treatment solutions are offered in multi-disciplinary clinics.

Long-term survival following initiation of home non-invasive ventilation: a European study.

INTRODUCTION: Although home non-invasive ventilation (NIV) is increasingly used to manage patients with chronic ventilatory failure, there are limited data on the long-term outcome of these patients. Our aim was to report on home NIV populations and the long-term outcome from two European centres. METHODS: Cohort analysis including all patients established on home NIV from two European centres between 2008 and 2014. RESULTS: Home NIV was initiated in 1746 patients to treat chronic ventilatory failure caused by (1) obesity hypoventilation syndrome±obstructive sleep apnoea (OHS±OSA) (29.5%); (2) neuromuscular disease (NMD) (22.7%); and (3) obstructive airway diseases (OAD) (19.1%). Overall cohort median survival following NIV initiation was 6.6 years. Median survival varied by underlying aetiology of respiratory failure: rapidly progressive NMD 1.1 years, OAD 2.7 years, OHS±OSA >7 years and slowly progressive NMD >7 years. Multivariate analysis demonstrated higher mortality in patients with rapidly progressive NMD (HR 4.78, 95% CI 3.38 to 6.75), COPD (HR 2.25, 95% CI 1.64 to 3.10), age >60 years at initiation of home NIV (HR 2.41, 95% CI 1.92 to 3.02) and NIV initiation following an acute admission (HR 1.38, 95% CI 1.13 to 1.68). Factors associated with lower mortality were NIV adherence >4 hours per day (HR 0.64, 95% CI 0.51 to 0.79), OSA (HR 0.51, 95% CI 0.31 to 0.84) and female gender (HR 0.79, 95% CI 0.65 to 0.96). CONCLUSION: The mortality rate following initiation of home NIV is high but varies significantly according to underlying aetiology of respiratory failure. In patients with chronic respiratory failure, initiation of home NIV following an acute admission and low levels of NIV adherence are poor prognostic features and may be amenable to intervention.

Time-to-death in chronic respiratory failure on home mechanical ventilation: A cohort study.

BACKGROUND AND OBJECTIVE: Home mechanical ventilation (HMV) is used in heterogeneous conditions underlying chronic hypercapnic respiratory failure, but there are sparse data on long-term clinical outcomes. The aim was to systematically analyse the time and the circumstances of death on HMV. METHODS: All-cause mortality data of HMV patients were prospectively collected between 2008 and 2018 in a large tertiary centre. Data were categorised into diagnostic groups including neuromuscular disease (NMD), chest wall disease (CWD), chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS), overlap syndrome of COPD and OSA (overlap) and other group. The primary outcome was time-to-death from initiation of HMV. RESULTS: 1210 deaths were recorded over a 10-year period. Median time-to-death was 19.5 [6-55] months and differed between groups (Kruskal Wallis p < 0.001). CWD (98.5 [23.5-120] months) and slowly progressive NMD (64.5 [28-120] months) had the longest time-to-death on HMV, while OHS (33 [13-75] months) and overlap syndrome (30.5 [14.5-68.5] months) had a longer median time-to-death than COPD (19.5 [7-42.5] months) and motor neurone disease (7 [3-14] months). Daily adherence to HMV of greater than 4 h/night was associated with better outcomes (10 [3-24] vs. 30 [10-76] months; p < 0.001). 43% with confirmed location of death died outside the hospital. CONCLUSIONS: The time-to-death on home mechanical ventilation varies widely across disease groups with chronic respiratory failure and seems to be associated with daily usage time. TRIAL REGISTRATION: researchregistry.com UIN: researchregistry4122.

Neural respiratory drive and cardiac function in patients with obesity hypoventilation syndrome following initiation of non-invasive ventilation.

BACKGROUND: Chronic hypercapnic respiratory failure (HRF) in obesity hypoventilation syndrome (OHS) is commonly treated using non-invasive ventilation (NIV). We hypothesised that treatment of OHS would improve neural respiratory drive index (NRDI) and cardiac function. METHODS: Fourteen patients (8 females) with OHS, who were admitted for initiation of domiciliary NIV, were prospectively studied. Patients had (mean ± SD): age (53±10 years), body mass index (BMI) (50.1±10.8 kg/m2), and pCO2 (7.3±0.9 kPa). NRDI was assessed by surface electromyogram of the parasternal intercostals. Cardiac function was assessed by transthoracic echocardiography (TTE). All measurements were performed at baseline, 6 weeks, and 3 months. RESULTS: NRDI improved on day one following NIV set-up comparing to baseline (484.2±214.8 vs. 316.5±106.5 AU) and this improvement was maintained at 6 weeks (369.1±173.2 AU) and at 3 months (351.2±167.1 AU) (P=0.004). No significant differences were identified in terms of cardiac function between baseline and 3 months [tricuspid annular plane systolic excursion (TAPSE) (24.6±5.8 vs. 23.0±4.0 mm, P=0.317); systolic pulmonary artery (PA) pressures (36.7±15.2 vs. 44.5±23.9 mmHg, P=0.163]. CONCLUSIONS: NIV improves NRDI in patients with OHS, while the cardiac function over a three-month period remains unchanged.

The CRASH report: emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension.

Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the 'most common' emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis ('CRASH'), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate.

Association of haemodynamic changes measured by serial central venous saturation during ultrafiltration for acutely decompensated heart failure with diuretic resistance and change in renal function.

BACKGROUND: Patients with acute decompensated heart failure with diuretic resistance (ADHF-DR) have a poor prognosis. The aim of this study was to assess in patients with ADHF-DR, whether haemodynamic changes during ultrafiltration (UF) are associated with changes in renal function (Δcreatinine) and whether Δcreatinine post UF is associated with mortality. METHODS: Seventeen patients with ADHF-DR underwent 20 treatments with UF. Serial bloods (4-6 hourly) from the onset of UF treatment were measured for renal function, electrolytes and central venous saturation (CVO2). Univariate and multivariate analysis were performed to assess the relationship between changes in markers of haemodynamics [heart rate (HR), systolic blood pressure (SBP), packed cell volume (PCV) and CVO2] and Δcreatinine. Patients were followed up and mortality recorded. Cox-regression survival analysis was performed to determine covariates associated with mortality. RESULTS: Renal function worsened after UF in 17 of the 20 UF treatments (baseline vs. post UF creatinine: 164±58 vs. 185±69µmol/l, P<0.01). ΔCVO2 was significantly associated with Δcreatinine [ß-coefficient of -1.3 95%CI (-1.8 to -0.7), P<0.001] and remained significantly associated with Δcreatinine after considering changes in SBP, HR and PCV [P<0.001]. Ten (59%) patients died at 1-year and 15(88%) by 2-years. Δcreatinine was independently associated with mortality (adjusted-hazard ratio 1.03 (1.01 to 1.07) per 1µmol/l increase in creatinine; P=0.02). CONCLUSIONS: Haemodynamic changes during UF as measured by the surrogate of cardiac output was associated with Δcreatinine. Worsening renal function at end of UF treatment occurred in the majority of patients and was associated with mortality.

Prospective observational cohort study of patients with weaning failure admitted to a specialist weaning, rehabilitation and home mechanical ventilation centre.

OBJECTIVES: According to National Health Service England (NHSE) specialist respiratory commissioning specification for complex home ventilation, patients with weaning failure should be referred to a specialist centre. However, there are limited data reporting the clinical outcomes from such centres. SETTING: Prospective observational cohort study of patients admitted to a UK specialist weaning, rehabilitation and home mechanical ventilation centre between February 2005 and July 2013. PARTICIPANTS: 262 patients admitted with a median age of 64.2 years (IQR 52.6-73.2 years). 59.9% were male. RESULTS: 39.7% of patients had neuromuscular and/or chest wall disease, 21% were postsurgical, 19.5% had chronic obstructive pulmonary disease (COPD), 5.3% had obesity-related respiratory failure and 14.5% had other diagnoses. 64.1% of patients were successfully weaned, with 38.2% weaned fully from ventilation, 24% weaned to nocturnal non-invasive ventilation (NIV), 1.9% weaned to nocturnal NIV with intermittent NIV during the daytime. 21.4% of patients were discharged on long-term tracheostomy ventilation. The obesity-related respiratory failure group were most likely to wean (relative risk (RR) for weaning success=1.48, 95% CI 1.35 to 1.77; p<0.001), but otherwise weaning success rates did not significantly vary by diagnostic group. The median time-to-wean was 19 days (IQR 9-33) and the median duration of stay was 31 days (IQR 16-50), with no difference observed between the groups. Weaning centre mortality was 14.5%, highest in the COPD group (RR=2.15, 95% CI 1.19 to 3.91, p=0.012) and lowest in the neuromuscular and/or chest wall disease group (RR=0.34, 95% CI 0.16 to 0.75, p=0.007). Of all patients discharged alive, survival was 71.7% at 6 months and 61.8% at 12 months postdischarge. CONCLUSIONS: Following NHSE guidance, patients with weaning delay and failure should be considered for transfer to a specialist centre where available, which can demonstrate favourable short-term and long-term clinical outcomes.

Physiological differences between various types of Eisenmenger syndrome and relation to outcome.

BACKGROUND: Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) related to congenital heart disease. Several studies have suggested that the presence and location of the shunt defines the natural history of these patients by influencing right ventricular adaptation to PAH. We aimed to echocardiographically assess differences in cardiac physiology and outcome between various types of ES. METHODS AND RESULTS: In this longitudinal cohort study, 191 patients with ES and non-complex congenital heart disease were recruited, 36 with pre-tricuspid and 155 with post-tricuspid shunts. Patients with pre-tricuspid shunts were older, had higher BNP concentrations and lower exercise tolerance compared to patients with post-tricuspid shunts. Right ventricular (RV) function was impaired in patients with atrial septal defects, with larger right ventricles, impaired systolic function and adaptation. The left ventricular eccentricity index was significantly higher in pre-tricuspid defects. Within post-tricuspid shunts, patients with atrio-ventricular septal defects had better right ventricular function compared to ventricular septal defects, while in those with a patent ductus arteriosus this was worse. There was a trend towards lower mortality in patients with post versus pre-tricuspid shunts, which was significant for patients above the age of 48 years. CONCLUSION: The presence of a post-tricuspid shunt appears to carry physiological and possibly prognostic benefits in ES compared to patients with pre-tricuspid shunts. This should be borne in mind when management decisions and advanced therapies are considered.

Treatment of sarcoidosis-associated pulmonary hypertension: A single centre retrospective experience using targeted therapies.

BACKGROUND: Pulmonary hypertension (PH), an increasingly recognised complication of pulmonary sarcoidosis, is associated with increased morbidity and mortality Evidence of benefit with targeted therapies in sarcoidosis associated pulmonary hypertension (SAPH) is limited. METHODS: We conducted a retrospective review of patients with sarcoidosis and right heart catheter proven PH who received treatment with targeted therapies (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, or combination) at our hospital. Six minute walk test (6MWT), World Health Organisation (WHO) functional class, echocardiography, pulmonary function test (PFT) and serum brain natriuretic peptide (BNP) data were collected at baseline and during follow-up. RESULTS: Thirty-three patients (16 men) with a mean age of 55.5 ± 10.7 years and mean pulmonary artery pressure of 44.0 ± 8.6 mm Hg received treatment with targeted PH therapies (sildenafil=29, bosentan=4). At six months, median six minute walk distance improved from 227 (88-526) meters to 240 (140-380) metres (p=0.04), median serum BNP levels improved from 35 (2-424) pmol/L to 26 (4-255) pmol/L (p<0.01), and at echocardiography, median tricuspid annular plane systolic excursion (TAPSE) improved from 17.5 (8.0-27.0) mm to 20.0 (15.0-27.0) mm (p=0.03). WHO functional class improved in 14 patients. Two patients developed side-effects attributed to sildenafil (n=1) or bosentan (n=1), requiring conversion to alternative PH therapies. Ten patients died, and one patient underwent lung transplantation, a median of 13.5 (3-37) months after commencing targeted therapies. CONCLUSIONS: Our results suggest that targeted therapies are safe in patients with SAPH. Controlled trials are warranted before therapeutic recommendations can be made.

Donation after circulatory death: a national survey of current practice in England in 2012.

OBJECTIVE: In recent years, England has seen renewed interest in donation after circulatory death. Many national and local initiatives have been implemented to encourage and support donation after circulatory death. To assess whether practice is in line with published guidance, we conducted a national survey with regard to current donation after circulatory death practices, local guidelines, and views on the need to further develop a national standardized protocol for donation after circulatory death. DESIGN: Online survey. SUBJECTS: Lead physicians for intensive care or organ donation for every acute National Health Service trust in England delivering adult care between April and June 2012. INTERVENTIONS: Physicians were e-mailed a link to a structured online questionnaire regarding their experience and practice of donation after circulatory death, including local protocols, use of organ optimization, and the need for a national protocol. MEASUREMENTS AND MAIN RESULTS: We received replies from 119 of 156 eligible trusts (76.3%) in England. Of these, 112 trusts (94%) have performed donation after circulatory death. Ninety-three trusts (78.1%) have a local donation after circulatory death protocol, and 89 trusts (74.7%) felt there should be a national donation after circulatory death protocol. All responding transplant centers had performed donation after circulatory death, 14 of 17 (82.3%) had a donation after circulatory death protocol with 14 of 17 respondents (82.3%) supporting a national protocol. Regarding organ optimization, 92 institutions (77.3%) used vasoactive drugs to achieve a target mean arterial blood pressure with 82 centers (68.9%) employing positive end-expiratory pressure and FIO2 to optimize oxygenation. Eight centers (6.7%) used heparin premortem compared with two of 17 transplant centers (11.8%). Two centers have used phentolamine to facilitate organ retrieval, with another five centers (4.2%) cannulating vessels premortem. CONCLUSIONS: Our survey revealed varying approaches and views toward donation after circulatory death across England. A greater than expected percentage use premortem cannulation, heparinization, and phentolamine despite current guidance in England to the contrary. The majority of institutions practicing donation after circulatory death with protocols in place favor the development of national guidelines, particularly with respect to organ optimization. We believe that such a protocol would help to address potential barriers to donation after circulatory death, which may lead to increased donation rates and improved outcomes.

Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia.

RATIONALE: Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. OBJECTIVES: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. METHODS: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. MEASUREMENTS AND MAIN RESULTS: Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m(2) and reduced cardiac index of 2.21 (± 0.5) L/min/m(2) were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). CONCLUSIONS: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).

C-reactive protein in adults with pulmonary arterial hypertension associated with congenital heart disease and its prognostic value.

OBJECTIVES: To assess the relationship of C-reactive protein (CRP) to clinical outcome and mortality in adults with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). BACKGROUND: Approximately 5-10% of adults with congenital heart disease (ACHD) develop PAH, which in turn is associated with substantial morbidity and mortality. Although CRP is known to predict outcome in idiopathic PAH, little is known regarding its prognostic value in CHD-PAH. METHODS: We obtained and analysed 1936 CRP values in a total of 225 adults with CHD-PAH (median age at study entry 34.0 years (27.0-41.7); 32.9% male, 35% with Down syndrome), performed over a 12-year period. High CRP values related to infection or blood transfusions were excluded from the analysis. RESULTS: During a median follow-up of 4.8 years (1149 patients-years), 50 patients died. The median CRP concentration on the last assessment was 5.0 mg/L (IQR 2.0-10.0), higher in deceased patients compared with survivors (11.5 mg/L (6.0-23.0) vs 4.0 mg/L (1.5-8.0), p<0.0001). Following univariate Cox regression analysis, CRP emerged as a strong predictor of mortality (HR 1.18; 95% CI 1.11 to 1.26, p<0.0001) and remained significant after adjustment for age, presence of Down syndrome and advanced PAH therapy. Survival-receiver-operator characteristic analysis identified an optimal cut-off value of 10 mg/L. Patients with CRP >10 mg/L had more than a threefold increased risk of death (HR 3.63, 95% CI 2.07 to 6.38, p<0.0001). CONCLUSIONS: Serum CRP is a simple but powerful marker of mortality in CHD-PAH patients and should be incorporated in the risk stratification and routine assessment of these patients.

Six-minute walk test distance and resting oxygen saturations but not functional class predict outcome in adult patients with Eisenmenger syndrome.

BACKGROUND: Eisenmenger syndrome (ES) represents the extreme manifestation of pulmonary arterial hypertension in patients with congenital heart disease, associated with significant exercise intolerance and mortality. Even though of six-minute-walk-test (6MWT) is routinely used in these patients, little is known about its prognostic value in comparison to functional class. METHODS AND RESULTS: We included 210 adult patients with ES who underwent a total of 822 6MWTs. Median walking distance (6MWD) was 330 m [IQR 260-395], oxygen saturation (SO2) at baseline 86% [IQR 82-91%] and SO2 at peak-exercise 69% [IQR 60-80%]. In patients commenced on advanced therapy for pulmonary hypertension, but not in the reminder, there was a significant improvement in walking distance (297±97 m vs. 325±87 m,P=0.0019), SO2 at rest (84.9±7.1 vs. 86.8±5.9%,P=0.003), SO2 at peak exercise (69.1±12.7 vs. 72.3±12.2%,P=0.04) and NYHA functional class (P=0.0047). During a follow up of 3.3 years, 29 patients died. On time-dependent Cox analysis, 6MWD (HR 0.94 per 10 m, 95%CI: 0.91-0.97,P<0.001) and baseline SO2 (HR 0.90, 95%CI:0.86-0.94,P<0.0001) were predictors of death. In contrast, age, functional class, peak-exercise SO2 and SO2 change were not related to mortality. A three-fold increased risk of death was identified in patients not reaching a 6MWD of 350 m or with baseline SO2 below 85%. CONCLUSIONS: The 6MWD and resting SO2, but not functional class were predictive of outcome in this contemporary cohort of Eisenmenger patients and should be incorporated in both risk stratification and management algorithms for these patients.

Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival.

BACKGROUND: Restrictive lung defects are associated with higher mortality in patients with acquired chronic heart failure. We investigated the prevalence of abnormal lung function, its relation to severity of underlying cardiac defect, its surgical history, and its impact on outcome across the spectrum of adult congenital heart disease. METHODS AND RESULTS: A total of 1188 patients with adult congenital heart disease (age, 33.1±13.1 years) undergoing lung function testing between 2000 and 2009 were included. Patients were classified according to the severity of lung dysfunction based on predicted values of forced vital capacity. Lung function was normal in 53% of patients with adult congenital heart disease, mildly impaired in 17%, and moderately to severely impaired in the remainder (30%). Moderate to severe impairment of lung function related to complexity of underlying cardiac defect, enlarged cardiothoracic ratio, previous thoracotomy/ies, body mass index, scoliosis, and diaphragm palsy. Over a median follow-up period of 6.7 years, 106 patients died. Moderate to severe impairment of lung function was an independent predictor of survival in this cohort. Patients with reduced force vital capacity of at least moderate severity had a 1.6-fold increased risk of death compared with patients with normal lung function (P=0.04). CONCLUSIONS: A reduced forced vital capacity is prevalent in patients with adult congenital heart disease; its severity relates to the complexity of the underlying heart defect, surgical history, and scoliosis. Moderate to severe impairment of lung function is an independent predictor of mortality in contemporary patients with adult congenital heart disease.