[Show abstract][Hide abstract] ABSTRACT: A subset of patients with Hereditary Hemorrhagic Telangiectasia (HHT) develops pulmonary hypertension (PH) by mechanisms including pulmonary arterial hypertension, high flow, and elevated pulmonary arterial wedge pressure (PAWP). We aimed to describe echocardiographic and hemodynamic characteristics of patients with coexisting HHT and PH.
Single center cohort study of patients with confirmed HHT who underwent right heart catheterization (RHC) and transthoracic 2D echocardiography for suspected PH between 6/1/2003-9/1/2013 at Mayo Clinic Rochester.
Of 38 patients with confirmed HHT who underwent RHC and echocardiography, 28 (74%) had a MPAP ≥ 25 mmHg. Of those 28, 12 (43%) had pulmonary arterial hypertension. Two patients had normal PAWP and PVR, with PH secondary to either an atrial septal defect or high cardiac flow. Fourteen patients (50%) had elevated PAWP (≥ 15 mmHg), nine with evidence of high flow. RHC in all 28 patients demonstrated a MPAP of 41 ± 11 mmHg, PAWP of 17 ± 10 mmHg, and PVR of 4.5 ± 4.2 Wood Units. Echocardiography demonstrated moderate/severe right ventricular dysfunction in nine (32%) patients. The presence of PH trended towards worse survival (p = 0.06).
PH in patients with HHT occurs by different mechanisms, and there is a trend towards worse survival in patients that develop PH despite the mechanism. The equal predilection towards all subtypes of PH illustrates the necessity of RHC to clarify the hemodynamics.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right heart failure, decreasing functional status, and poor survival. The present study characterizes the 5-year survival in the United States of newly and previously diagnosed PAH patients stratified by baseline functional class (FC). The Registry to Evaluate Early And Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) is a 55-center, observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH.
The REVEAL Registry enrolled newly and previously diagnosed patients ≥3 months of age with WHO group 1 PAH, consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients ≥18 years of age.
Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I-IV had estimated 5-year survival rates of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I-IV, respectively.
Patient survival for advanced PAH remains poor at 5 years, despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH.
[Show abstract][Hide abstract] ABSTRACT: Background
Clinical studies of pulmonary arterial hypertension have used change in 6-minute walk distance as a clinical endpoint; however, its association with survival outcomes has not been well established. In this analysis, we examined the prognostic value of baseline 6-minute walk distance, absolute thresholds of 6-minute walk distance, and change in 6-minute walk distance.
Patients in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) with 6-minute walk distance at enrollment, with or without a follow-up assessment within the first year of observation, were included. Kaplan-Meier survival estimates were computed for subsets with baseline 6-minute walk distance that were above or below all possible thresholds, and for subsets with change in 6-minute walk distance 10 percentage points above or below all possible thresholds, including both improvement thresholds and worsening thresholds. Multivariable Cox regression models assessed the effect of both improvement and worsening in 6-minute walk distance on 1-year survival, adjusted for baseline factors.
One-year survival estimates were higher for patients with baseline 6-minute walk distance above versus below a threshold, although no specific threshold was more prognostic than others. In a model adjusted for baseline 6-minute walk distance and risk score, worsening of 6-minute walk distance over time significantly predicted decreased survival, but improvement in 6-minute walk distance did not affect survival.
No 6-minute walk distance improvement threshold carries particular prognostic value. Improvement in 6MWD was not associated with survival, but worsening of 6MWD was strongly and significantly associated with poor prognosis.
Full-text · Article · Aug 2014 · The Journal of Heart and Lung Transplantation
[Show abstract][Hide abstract] ABSTRACT: Background:Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population. Methods:The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations. Results:Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group. Conclusions:Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment. Registered at:www.clinicaltrials.gov #NCT00370214.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Hospitalization is an important outcome in pulmonary arterial hypertension (PAH), shown previously to correlate with survival. Using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), we sought to characterize first-time hospitalizations and their effect on subsequent hospitalization and survival in patients with newly diagnosed disease.
Patients with newly diagnosed PAH (n = 862, World Health Organization group 1) were evaluated for first-time hospitalization. The hospitalizations were categorized as PAH related or PAH unrelated based on the case report form. Categories for PAH-related and PAH-unrelated hospitalization were defined before independent review. Patient demographics and disease characteristics are described as well as freedom from hospitalization and survival.
Of 862 patients, 490 (56.8%) had one or more hospitalizations postenrollment: 257 (52.4%) PAH related, 214 (43.7%) PAH unrelated, and 19 (3.9%) of undetermined causes. The most common causes of PAH-related hospitalization were congestive heart failure and placement/removal of a central venous catheter. Patients with PAH-related hospitalizations were more likely to receive parenteral therapy, be in functional class III/IV, and have higher risk scores before hospitalization at enrollment. Following discharge, 25.4% ± 3.2% and 31.0% ± 4.0% of patients with PAH-related and PAH-unrelated first hospitalization, respectively, remained hospitalization-free for 3 years (P = .11). Survival estimates at 3 years postdischarge were 56.8% ± 3.5% and 67.8% ± 3.6% (P = .037) for patients with PAH-related and PAH-unrelated hospitalization, respectively.
In the REVEAL Registry, PAH-related hospitalization was associated with relatively more rehospitalizations and worse survival at 3 years.
ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov
[Show abstract][Hide abstract] ABSTRACT: In patients with pulmonary arterial hypertension (PAH) the relation of hemodynamic impairment experienced during daily activity and exercise test is not known.
Ten PAH patients received an implantable hemodynamic monitor that continuously recorded and stored right ventricular systolic (RVSP) and mean pulmonary artery pressure (MPAP). Before starting a new PAH treatment (baseline) and after 12-weeks on treatment (12W) a 6-min walk test (6MWT) and a maximal exercise test (MAXWT) were performed. Exercise pressure range was measured as the difference between rest before exercise and maximal pressure during 6MWT or MAXWT. Ambulatory range (AMB) was measured as the difference between the lowest (4th percentile) and highest (96th percentile) values recorded over 24-hours. One week of ambulatory ranges were averaged for each patient before each exercise test. Mean age was 54±18 years, 9 were female and all in WHO functional class 3. At baseline RVSP and MPAP increased 136±49% and 164±49% during AMB, 63±26% and 79±30% during MAXWT and 59±32% and 69±33% during 6MWT. There was no difference in pressure change at 12W.
Changes in RV and PA pressures during exercise tests were relatively small compared to the range seen during ambulatory conditions.
Full-text · Article · May 2014 · Journal of cardiac failure
[Show abstract][Hide abstract] ABSTRACT: The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments.
Full-text · Article · Dec 2013 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases.
Full-text · Article · Dec 2013 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Uncorrected congenital heart disease (CHD) frequently leads to pulmonary arterial hypertension (PAH), the most severe form of which is Eisenmenger syndrome (ES). We compared patients with idiopathic or heritable PAH (IPAH or HPAH; n = 1,626) against those with CHD-associated PAH (n = 353) who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL Registry). Of patients with CHD-associated PAH, 151 had ES. Compared with the IPAH or HPAH cohort, the ES cohort had greater systemic blood flow (2 ± 1 vs 3 ± 2 L/min/m(2), p <0.001), lower mean right atrial pressure (10 ± 6 vs 7 ± 4 mm Hg, p <0.001), higher mean pulmonary artery pressure (53 ± 14 vs 65 ± 17 mm Hg, p <0.001), higher pulmonary vascular resistance index (22 ± 12 vs 32 ± 31 Wood units × m(2), p <0.001), and lower systemic arterial oxygen saturation at rest (92 ± 11% vs 84 ± 13%, p <0.001). At 4 years from enrollment and 7 years from diagnosis, survival rate was similar between IPAH or HPAH and CHD-associated PAH cohorts. For the overall CHD-associated PAH cohort, longer 6-minute walk distance, lower mean right atrial pressure, brain natriuretic peptide level <50 pg/ml, and the presence of acute vasoreactivity were predictors of survival at 4 years from enrollment; younger age and lower mean right atrial pressure were predictors of survival at 7 years from diagnosis. In conclusion, these observations support predicted physiologic differences (e.g., hemodynamics) between patients with IPAH or HPAH and patients with CHD-associated PAH, with or without a systemic-pulmonary shunt. These differences, however, did not translate into significantly improved 4- and 7-year survival rates in patients with ES versus IPAH or HPAH and CHD-associated PAH.
Full-text · Article · Oct 2013 · The American journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: Current guidelines recommend intravenous prostacyclin as first-line therapy for patients with pulmonary arterial hypertension (PAH) in New York Heart Association/World Health Organization functional class (FC) IV, or combination therapy for patients in any FC who do not respond to monotherapy. We investigated the aggressiveness of therapy in patients enrolled in the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) Registry who deteriorated to FC IV or died.
Among 3,515 patients (age ≥ 18 years) in REVEAL with a mean pulmonary artery pressure ≥ 25 mm Hg and pulmonary capillary wedge pressure ≤ 15 mm Hg, we examined three sub-sets: the 487 patients who had a PAH-related death, the larger set of 908 patients who died from any cause (PAH-related, not PAH-related, or unknown), and the 294 patients who were FC I, II, or III at enrollment and later assessed as FC IV.
Among patients who died, 56% (n = 272 of 487) and 43% (n = 391 of 908) were receiving intravenous prostacyclin before death in the PAH-related death and all-cause death cohorts, respectively. In the PAH-related death cohort, 60% and 16% of patients were most recently assessed as FC III and IV, respectively; among those assessed as FC IV within 6 months of death, 57.7% (n = 15 of 26) had received intravenous prostacyclin. Because many patients died without an observed assessment of worsening to FC IV, we also evaluated medication use among the cohort of patients who worsened to FC IV during the study. One day before worsening to FC IV, 150 of 294 patients were not receiving intravenous prostacyclin and 70 were receiving only PAH-specific monotherapy; of these, 61% and 67%, respectively, received no additional therapy 90 days later.
Intravenous prostacyclin and combination therapy are not consistently used in the most seriously ill patients enrolled in REVEAL after being assessed as FC IV or at the time of death.
No preview · Article · Sep 2013 · The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation
[Show abstract][Hide abstract] ABSTRACT: The presence and size of a pericardial effusion in pulmonary arterial hypertension (PAH) and it's association with outcome remains unclear.
Single center cohort study of 577 patients with group 1 PAH seen between 1/1/1995 and 12/31/2005. All patients underwent transthoracic echocardiography and followed for ≥ five years. Echo-guided pericardiocentesis was performed as needed.
Pericardial effusions on index echocardiography occurred in 150 (26%) patients; 128 patients had small and 22 had ≥ moderate sized effusions. Most of the ≥ moderate or greater effusions occurred in patients who had connective tissue disease (82%). Mean right atrial pressure was 13.4 ± 4.4 mm Hg (no effusion), 15.1 ± 4.4 (small effusion), and 17.0 ± 4.0 (≥ moderate effusion) (p < 0.0001). Median survival for patients with ≥ moderate effusion, mild effusion, or no effusion was 11.3 months, 42.3 months, and 76.5 months respectively. Four of the 22 patients with ≥ moderate pericardial effusions eventually required echo-guided pericardiocentesis because of clinical and echocardiographic evidence of hemodynamic impact. When drained, the effusions were large (858 ± 469 mL) and generally serous. All pericardiocenteses were performed cautiously under echo-guidance by a vastly experienced echocardiologist with low immediate morbidity and mortality.
Pericardial effusions are relatively common but rarely of hemodynamic significance in patients with PAH. However, even modest degrees of pericardial fluid are associated with significant increase in mortality and appear to reflect the presence of associated collagen vascular disease and high right atrial pressure.
[Show abstract][Hide abstract] ABSTRACT: Time to clinical worsening has been proposed as a primary endpoint in clinical trials of pulmonary arterial hypertension (PAH); however, there are neither standardized nor validated definitions of clinical worsening across PAH trials. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy).
We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults (N=3,001) with hemodynamically defined PAH. Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥15% reduction in 6-minute walk distance (6MWD), all-cause hospitalization, or the introduction of a parenteral prostacyclin analogue therapy.
In the 2 years of follow-up, 583 deaths occurred; a total of 426 patients died after a documented clinical worsening event including FC worsening (n=128), a ≥15% reduction in 6MWD (n=118), all-cause hospitalization (n=370), or introduction of a prostacyclin analogue (n=91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival post-worsening than patients who did not worsen (P < .001).
Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary endpoint in clinical trial design.
[Show abstract][Hide abstract] ABSTRACT: Background:
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with LV filling patterns through speckle-tracking strain echocardiography.
Methods and results:
Echocardiography was performed in 71 adults with a new diagnosis of PAH. To analyze LV and RV function separately, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed >2 years. Patients had dilated right-sided chambers (right atrial volume index, 44 ± 19 mL/m(2); RV end-diastolic area, 34 ± 9 cm(2)), and reduced RV function (RV fractional area change, 28 ± 12%). Speckle-tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (-15 ± 3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension, 42 ± 6 mm; ejection fraction, 65 ± 8%; cardiac index, 2.6 ± 0.8 L/min per m(2)), patients had reduced LV free wall systolic strain (-15 ± 3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, P=0.0002. During 2-year follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted hazard ratio, 2.40 per 5% decrease in LV free wall strain, 1.22-4.68), which remained significant when adjusted for age, sex, World Health Organization functional class, and PAH pathogenesis (hazard ratio, 3.11, 1.38-7.20).
The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LV ejection fraction, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.
No preview · Article · May 2013 · Circulation Heart Failure
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT OBJECTIVE: New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival versus patients who remain at FC III or worsen to FC IV. METHODS: Patients aged ≥19 years with FC III PAH from the REVEAL Registry (N=982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-minute walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by etiology (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly and previously diagnosed [diagnostic right heart catheterization within or ≥3 months of enrollment, respectively]). RESULTS: Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84%±2%; n=263) versus those who remained unchanged (66%±2%; n=645) or worsened (29%±6%; n=74) (all P<.001). Survival was also better in patient subgroups whose FC improved versus those who remained unchanged (idiopathic/familial [P<.001], CTD-associated PAH [P=.009], whether newly [P=.004] or previously diagnosed [P<.001]. 6MWD improvements were greater in patients whose FC improved versus those who remained unchanged in the overall (P<.001) and CTD (P=.028) cohorts. CONCLUSION: Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH etiology, have better survival versus patients who remain FC III.ClinicalTrials.gov Registration Number: NCT00370214.