BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by... more BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.MethodsTo identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant associa...
BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Ra... more BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.MethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.FindingsA locus atHLA-DPA1/DPB1within the class II major histocompatibility (MHC) region and a second nearSOX17were significantly associated with PAH. TheSOX17locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants n...
Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recen... more Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH. By statistical association of rare deleterious variants, we found tissue kallikrein 1 and gamma glutamyl carboxylase as new candidate risk genes for idiopathic PAH associated with a later age-of-onset and relatively moderate disease phenotype compared to bone morphogenetic receptor type 2. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data su...
Hemodynamic and echocardiographic data, including right atrial pressure (RAP), pulmonary capillar... more Hemodynamic and echocardiographic data, including right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), left ventricular end diastolic diameter (LVIDd) were collected and divided into tertiles. The relationship between these variables and VA hospitalizations was evaluated using unadjusted Cox proportional regression analysis and Kaplan Meier survival curves. VA-free survival analysis was censored at time of death, transplant, or explant. Results: Median time between LVAD implant and RHC was 126 days. Following RHC, 14/123 subjects were hospitalized for VA within one year. Elevated PCWP was associated with an increased risk of hospitalization for VA, and lower event free survival at one year of follow up (HR 2.65, p = 0.012; Fig. 1). Other variables, including RAP, CI, and LVIDd were not statistically significant predictors of VA (Table 1). Conclusion: Ventricular arrhythmias at one year are more common among patients with LVADs who have elevated PCWP. This unadjusted univariate analysis suggests inadequate LV unloading on LVAD support may contribute to risk of VA. Further studies are needed to clarify this relationship and to determine whether this risk can be alleviated with medical therapy or pump speed optimization.
Journal of cardiovascular pharmacology and therapeutics, 2014
Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative t... more Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil. In this multicenter, prospective, 6-month study, patients with PAH were instructed to take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). Of the 35 patients who met the study criteria, 56% were receiving ≥2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d, with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, a...
Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized ... more Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized by the abnormal accumulation of Langerhans' cells around small airways and other distal lung compartments. Although pulmonary hypertension (PH) is a frequent complication of PLCH, the role of advanced PH therapies for PLCH-related PH is not well-established. We describe a PLCH patient with severe, disease-related PH that responded unexpectedly well to advanced PH therapy with sustained improvement over a 10 year follow-up period. This case indicates that PLCH-associated PH may, in certain instances, be highly responsive to advanced PH therapies and emphasizes the importance of trialing these therapies among patients with PLCH-related PH.
SummaryPulmonary arterial hypertension (PAH) is characterised by increased pressure in the pulmon... more SummaryPulmonary arterial hypertension (PAH) is characterised by increased pressure in the pulmonary arteries leading to right-sided ventricular failure, and death. Identification of factors that affect patient survival is important to improve patient management and outcomes. The first registry to evaluate survival and develop a prognostic model was the National Institutes of Health (NIH) registry in 1981. Importantly this prognostic model is based on data collected prior to availability of PAH-targeted therapies and does not reflect survival rates for treated patients. Since the 1980s, however, four modern registries of PAH now exist which compensate for the NIH equations shortcomings and include the French National registry, Pulmonary Hypertension Connection registry, the Mayo registry, and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). The similarities and difference in these registries are highlighted in this review and although similar in many res...
Journal of the American College of Cardiology, 2013
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure !25 mm Hg at rest, mea... more Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure !25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone. (J Am Coll Cardiol 2013;62: D42-50) ª 2013 by the American College of Cardiology Foundation Diagnosis and assessment of patients with pulmonary arterial hypertension (PAH) have been major topics at all previous world meetings on pulmonary hypertension (PH), with the last update coming from the 4th World Symposium on Pulmonary Hypertension (WSPH) held in 2008 in Dana Point, California (1). The recommendations from that conference were incorporated into the most recent international guidelines (2-4). During the 5th WSPH in 2013 in From the
Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, ... more Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, right-sided heart failure, and limited survival. Whether strain-based measures of right ventricular (RV) systolic function predict future right-sided heart failure and/or death is untested. Methods RV longitudinal systolic strain and strain rate were evaluated by echocardiography in 80 patients with World Health Organization group 1 pulmonary hypertension (PH) (72% were functional class [FC] III or IV). Survival status was assessed over 4 years. Results All patients had a depressed RV systolic strain (-15% ± 5%) and strain rate (-0.80 ± 0.29 s-1). Of the parameters assessed, average RV free wall systolic strain worse than-12.5% identified a cohort with greater severity of disease (82% were FC III/IV), greater RV systolic dysfunction (RV stroke volume index 26 ± 9 mL/m 2), and higher right atrial pressure (12 ± 5 mm Hg). Patients with an RV free wall strain worse than-12.5% were associated with a greater degree of disease progression within 6 months, a greater requirement for loop diuretics, and/or a greater degree of lower extremity edema, and it also predicted 1-, 2-, 3-, and 4year mortality (unadjusted 1-year hazard ratio, 6.2; 2.1-22.3). After adjusting for age, sex, PH cause, and FC, patients had a 2.9-fold higher rate of death per 5% absolute decline in RV free wall strain at 1 year. Conclusions Noninvasive assessment of RV longitudinal systolic strain and strain rate independently predicts future rightsided heart failure, clinical deterioration, and mortality in patients with PAH. 40 Champion HC, Michelakis ED, Hassoun PM: Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications.
Background: Cardiac index is an important determinant of outcome in patients with idiopathic pulm... more Background: Cardiac index is an important determinant of outcome in patients with idiopathic pulmonary artery hypertension (IPAH). An implantable hemodynamic monitor (IHM) [Chronicle; Medtronic; Minneapolis, MN; a system limited to investigational use only] that records right ventricular (RV) pressure waveforms continuously may increase our understanding of IPAH and improve therapeutic selections and outcomes. The aim of this study was to investigate whether the RV pressure waveform utilizing an IHM can be used to estimate the magnitude of pressure wave reflection and cardiac index in patients with IPAH in acute settings. Methods: In eight patients with pulmonary arterial hypertension, RV pressure waveforms were recorded utilizing the IHM, and breath-by-breath cardiac index was recorded during acute IV epoprostenol infusion at 3, 6 and 9 ng/kg/min. Late systolic pressure augmentation and cardiac index were estimated using the RV pressure waveforms and correlated with direct measurement of cardiac index. Results: At baseline, the cardiac index was 2.1 ؎ 0.2 L/min/m 2 , total pulmonary resistance index was 38 ؎ 2 Wood U/m 2 , and RV systolic pressure was 92 ؎ 4 mm Hg. Wave reflection accounted for 29 ؎ 1 mm Hg of the RV systolic pressure. During epoprostenol infusion, total pulmonary resistance index and wave reflection decreased (؊ 15 ؎ 4 Wood U/m 2 , p < 0.001, and ؊ 5 ؎ 2 mm Hg, p < 0.05, respectively). The breath-by-breath cardiac index correlated with the RV pressure waveform cardiac index estimates (r 2 ؍ 0.95). Conclusions: RV pressure waveform analysis provides continuous hemodynamic assessments including cardiac index in acute settings. Once confirmed in long-term settings, this information may prove useful in optimizing a treatment regimen in patients with IPAH.
PURPOSE: PAH is a life-threatening disease with poor prognosis. Imatinib inhibits the PDGF signal... more PURPOSE: PAH is a life-threatening disease with poor prognosis. Imatinib inhibits the PDGF signaling pathway, which appears important in PAH pathogenesis. METHODS: 59 patients symptomatic on approved PAH-specific therapies entered a 24-week, randomized, double-blind, placebo-controlled, pilot study (imatinib 200-400mg daily, n=28; placebo, n=31). 42 patients completed the 24week study, and 22 entered an open-label extension (OLE) with imatinib. 31 patients received compassionate use imatinib for 4-26 months between 24-week study completion and OLE entry. Only serious AEs were reported during the compassionate use phase. Compassionate use patients considered clinically stable or improved continued into the OLE. 6 minute walk distance (6MWD) and safety are assessed in the OLE. RESULTS: By 18 May 2011, 15 patients continued the OLE (discontinuations: lack of efficacy, n=2; AEs, n=3; death, n=2). Mean±SD 6MWD change from 24week study baseline was 47±59 (n=20), 53±66 (n=14), 54±63 (n=16), 63±49 (n=15) and 53±62m (n=15) at OLE screening and following 6, 12, 18, and 24 months OLE treatment, respectively. Improvements were comparable to 24-week study completion with imatinib (mean change from baseline: 52m). OLE AEs in ≥20% patients included nasopharyngitis (55%), respiratory infection (46%), vertigo (36%), edema (32%), nausea (27%), cough (23%), edema peripheral
Objective To establish an expert consensus on which criteria are the most appropriate in clinical... more Objective To establish an expert consensus on which criteria are the most appropriate in clinical practice to refer patients with systemic sclerosis (SSc) for right heart catheterisation (RHC) when pulmonary hypertension (PH) is suspected. Methods A three stage internet based Delphi consensus exercise involving worldwide PH experts was designed. In the first stage, a comprehensive list of domains and items combining evidence based indications and expert opinions were obtained. In the second and third stages, experts were asked to rate each item selected in the list. After each of stages 2 and 3, the number of items and criteria were reduced according to a cluster analysis. Results A literature search and the opinions of 47 experts participating in Delphi stage 1 provided a list of seven domains containing 142 criteria. After stages 2 and 3, these domains and tools were reduced to three domains containing eight tools: clinical (progressive dyspnoea over the past 3 months, unexplained dyspnoea, worsening of WHO dyspnoea functional class, any finding on physical examination suggestive of elevated right heart pressures and any sign of right heart failure), echocardiography (systolic pulmonary artery pressure >45 mm Hg and right ventricle dilation) and pulmonary function tests (diffusion lung capacity for carbon monoxide <50% without pulmonary fibrosis). Conclusions Among experts in pulmonary arterial hypertension-SSc, a core set of criteria for clinical practice to refer SSc patients for RHC has been defined by Delphi consensus methods. Although these indications are recommended by this expert group to be used as an interim tool, it will be necessary to formally validate the present tools in further studies.
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Previous Registry studies have reported that heart transplantation with older donor hearts is ass... more Previous Registry studies have reported that heart transplantation with older donor hearts is associated with a more than twofold increase in early mortality. An analysis of 77 consecutive patients undergoing heart transplantations at our institution between June 1988 and July 1994 was performed to assess the effect of donor age on mortality and morbidity. Recipients were grouped into those receiving hearts from younger donors (aged < 40 years, n = 60) and those receiving hearts from older donors (aged > 40 years, n = 17). There were two deaths within the first 30 days in the younger donor group and no deaths in the other group. One-year survival rate was 95% and 100% for the "younger" and "older" groups, respectively. The mean recipient age of the younger donor group was lower (46 +/- 14 years) compared with the older donor group (57 +/- 7 years). Morbidity was compared between the two groups; the length of hospital stay (22.6 +/- 15.8 days versus 21.3 +/-...
Background-We evaluated whether combined heart liver transplant can protect the heart graft from ... more Background-We evaluated whether combined heart liver transplant can protect the heart graft from the development of Cardiac allograft vasculopathy (CAV) using coronary 3D volumetric IVUS. Methods-From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 combined heart liver transplant (H+Liver Tx) recipients in whom two coronary 3D IVUS studies were performed one year apart. Baseline 3D IVUS was performed at 0.22 [0.17, 1.16] years after transplant with follow up 3D IVUS exams performed 0.96 [0.83, 1.08] after baseline exam. Results-Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+Liver Tx group (0.3±1.1 mm 3 /mm vs. 1.5±2.9 mm 3 /mm; P=0.08, and 0.01±0.03 vs. 0.1±0.1; P=0.004 respectively). Rejection burden was much lower in the H+Liver
Background-Although a link between donor-specific antibodies against human leukocyte antigens typ... more Background-Although a link between donor-specific antibodies against human leukocyte antigens type II (DSA II+) and transplant glomerulopathy has been clearly established, its role in cardiac allograft vasculopathy (CAV) is unclear. Methods-DSA were evaluated using solid phase Single Antigen Bead assay before transplant in 51 heart transplant (HTX) recipients. Coronary angiography and three-dimensional intravascular ultrasound (3D IVUS) were performed at baseline and approximately one year after the baseline exam. Results-There were 4 (7.8 %), 11 (21.5%), and 2 (3.9%) patients who had DSA against donor Class I (DSA I+), DSA II+, or both respectively. All patients had negative complement dependent cytotoxic cross match. There was accelerated progression of CAV in the DSA II+ group demonstrated by accelerated progression in plaque index (plaque volume/vessel volume) compared to patients with no DSA II+ antibodies (13.8±12% vs. −7.9±37%; p=0.01). The development of any angiographic CAV was also more common in DSA II+ patients as compared
BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by... more BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.MethodsTo identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant associa...
BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Ra... more BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.MethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.FindingsA locus atHLA-DPA1/DPB1within the class II major histocompatibility (MHC) region and a second nearSOX17were significantly associated with PAH. TheSOX17locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants n...
Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recen... more Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH. By statistical association of rare deleterious variants, we found tissue kallikrein 1 and gamma glutamyl carboxylase as new candidate risk genes for idiopathic PAH associated with a later age-of-onset and relatively moderate disease phenotype compared to bone morphogenetic receptor type 2. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data su...
Hemodynamic and echocardiographic data, including right atrial pressure (RAP), pulmonary capillar... more Hemodynamic and echocardiographic data, including right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), left ventricular end diastolic diameter (LVIDd) were collected and divided into tertiles. The relationship between these variables and VA hospitalizations was evaluated using unadjusted Cox proportional regression analysis and Kaplan Meier survival curves. VA-free survival analysis was censored at time of death, transplant, or explant. Results: Median time between LVAD implant and RHC was 126 days. Following RHC, 14/123 subjects were hospitalized for VA within one year. Elevated PCWP was associated with an increased risk of hospitalization for VA, and lower event free survival at one year of follow up (HR 2.65, p = 0.012; Fig. 1). Other variables, including RAP, CI, and LVIDd were not statistically significant predictors of VA (Table 1). Conclusion: Ventricular arrhythmias at one year are more common among patients with LVADs who have elevated PCWP. This unadjusted univariate analysis suggests inadequate LV unloading on LVAD support may contribute to risk of VA. Further studies are needed to clarify this relationship and to determine whether this risk can be alleviated with medical therapy or pump speed optimization.
Journal of cardiovascular pharmacology and therapeutics, 2014
Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative t... more Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil. In this multicenter, prospective, 6-month study, patients with PAH were instructed to take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). Of the 35 patients who met the study criteria, 56% were receiving ≥2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d, with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, a...
Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized ... more Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized by the abnormal accumulation of Langerhans' cells around small airways and other distal lung compartments. Although pulmonary hypertension (PH) is a frequent complication of PLCH, the role of advanced PH therapies for PLCH-related PH is not well-established. We describe a PLCH patient with severe, disease-related PH that responded unexpectedly well to advanced PH therapy with sustained improvement over a 10 year follow-up period. This case indicates that PLCH-associated PH may, in certain instances, be highly responsive to advanced PH therapies and emphasizes the importance of trialing these therapies among patients with PLCH-related PH.
SummaryPulmonary arterial hypertension (PAH) is characterised by increased pressure in the pulmon... more SummaryPulmonary arterial hypertension (PAH) is characterised by increased pressure in the pulmonary arteries leading to right-sided ventricular failure, and death. Identification of factors that affect patient survival is important to improve patient management and outcomes. The first registry to evaluate survival and develop a prognostic model was the National Institutes of Health (NIH) registry in 1981. Importantly this prognostic model is based on data collected prior to availability of PAH-targeted therapies and does not reflect survival rates for treated patients. Since the 1980s, however, four modern registries of PAH now exist which compensate for the NIH equations shortcomings and include the French National registry, Pulmonary Hypertension Connection registry, the Mayo registry, and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). The similarities and difference in these registries are highlighted in this review and although similar in many res...
Journal of the American College of Cardiology, 2013
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure !25 mm Hg at rest, mea... more Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure !25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone. (J Am Coll Cardiol 2013;62: D42-50) ª 2013 by the American College of Cardiology Foundation Diagnosis and assessment of patients with pulmonary arterial hypertension (PAH) have been major topics at all previous world meetings on pulmonary hypertension (PH), with the last update coming from the 4th World Symposium on Pulmonary Hypertension (WSPH) held in 2008 in Dana Point, California (1). The recommendations from that conference were incorporated into the most recent international guidelines (2-4). During the 5th WSPH in 2013 in From the
Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, ... more Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, right-sided heart failure, and limited survival. Whether strain-based measures of right ventricular (RV) systolic function predict future right-sided heart failure and/or death is untested. Methods RV longitudinal systolic strain and strain rate were evaluated by echocardiography in 80 patients with World Health Organization group 1 pulmonary hypertension (PH) (72% were functional class [FC] III or IV). Survival status was assessed over 4 years. Results All patients had a depressed RV systolic strain (-15% ± 5%) and strain rate (-0.80 ± 0.29 s-1). Of the parameters assessed, average RV free wall systolic strain worse than-12.5% identified a cohort with greater severity of disease (82% were FC III/IV), greater RV systolic dysfunction (RV stroke volume index 26 ± 9 mL/m 2), and higher right atrial pressure (12 ± 5 mm Hg). Patients with an RV free wall strain worse than-12.5% were associated with a greater degree of disease progression within 6 months, a greater requirement for loop diuretics, and/or a greater degree of lower extremity edema, and it also predicted 1-, 2-, 3-, and 4year mortality (unadjusted 1-year hazard ratio, 6.2; 2.1-22.3). After adjusting for age, sex, PH cause, and FC, patients had a 2.9-fold higher rate of death per 5% absolute decline in RV free wall strain at 1 year. Conclusions Noninvasive assessment of RV longitudinal systolic strain and strain rate independently predicts future rightsided heart failure, clinical deterioration, and mortality in patients with PAH. 40 Champion HC, Michelakis ED, Hassoun PM: Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications.
Background: Cardiac index is an important determinant of outcome in patients with idiopathic pulm... more Background: Cardiac index is an important determinant of outcome in patients with idiopathic pulmonary artery hypertension (IPAH). An implantable hemodynamic monitor (IHM) [Chronicle; Medtronic; Minneapolis, MN; a system limited to investigational use only] that records right ventricular (RV) pressure waveforms continuously may increase our understanding of IPAH and improve therapeutic selections and outcomes. The aim of this study was to investigate whether the RV pressure waveform utilizing an IHM can be used to estimate the magnitude of pressure wave reflection and cardiac index in patients with IPAH in acute settings. Methods: In eight patients with pulmonary arterial hypertension, RV pressure waveforms were recorded utilizing the IHM, and breath-by-breath cardiac index was recorded during acute IV epoprostenol infusion at 3, 6 and 9 ng/kg/min. Late systolic pressure augmentation and cardiac index were estimated using the RV pressure waveforms and correlated with direct measurement of cardiac index. Results: At baseline, the cardiac index was 2.1 ؎ 0.2 L/min/m 2 , total pulmonary resistance index was 38 ؎ 2 Wood U/m 2 , and RV systolic pressure was 92 ؎ 4 mm Hg. Wave reflection accounted for 29 ؎ 1 mm Hg of the RV systolic pressure. During epoprostenol infusion, total pulmonary resistance index and wave reflection decreased (؊ 15 ؎ 4 Wood U/m 2 , p < 0.001, and ؊ 5 ؎ 2 mm Hg, p < 0.05, respectively). The breath-by-breath cardiac index correlated with the RV pressure waveform cardiac index estimates (r 2 ؍ 0.95). Conclusions: RV pressure waveform analysis provides continuous hemodynamic assessments including cardiac index in acute settings. Once confirmed in long-term settings, this information may prove useful in optimizing a treatment regimen in patients with IPAH.
PURPOSE: PAH is a life-threatening disease with poor prognosis. Imatinib inhibits the PDGF signal... more PURPOSE: PAH is a life-threatening disease with poor prognosis. Imatinib inhibits the PDGF signaling pathway, which appears important in PAH pathogenesis. METHODS: 59 patients symptomatic on approved PAH-specific therapies entered a 24-week, randomized, double-blind, placebo-controlled, pilot study (imatinib 200-400mg daily, n=28; placebo, n=31). 42 patients completed the 24week study, and 22 entered an open-label extension (OLE) with imatinib. 31 patients received compassionate use imatinib for 4-26 months between 24-week study completion and OLE entry. Only serious AEs were reported during the compassionate use phase. Compassionate use patients considered clinically stable or improved continued into the OLE. 6 minute walk distance (6MWD) and safety are assessed in the OLE. RESULTS: By 18 May 2011, 15 patients continued the OLE (discontinuations: lack of efficacy, n=2; AEs, n=3; death, n=2). Mean±SD 6MWD change from 24week study baseline was 47±59 (n=20), 53±66 (n=14), 54±63 (n=16), 63±49 (n=15) and 53±62m (n=15) at OLE screening and following 6, 12, 18, and 24 months OLE treatment, respectively. Improvements were comparable to 24-week study completion with imatinib (mean change from baseline: 52m). OLE AEs in ≥20% patients included nasopharyngitis (55%), respiratory infection (46%), vertigo (36%), edema (32%), nausea (27%), cough (23%), edema peripheral
Objective To establish an expert consensus on which criteria are the most appropriate in clinical... more Objective To establish an expert consensus on which criteria are the most appropriate in clinical practice to refer patients with systemic sclerosis (SSc) for right heart catheterisation (RHC) when pulmonary hypertension (PH) is suspected. Methods A three stage internet based Delphi consensus exercise involving worldwide PH experts was designed. In the first stage, a comprehensive list of domains and items combining evidence based indications and expert opinions were obtained. In the second and third stages, experts were asked to rate each item selected in the list. After each of stages 2 and 3, the number of items and criteria were reduced according to a cluster analysis. Results A literature search and the opinions of 47 experts participating in Delphi stage 1 provided a list of seven domains containing 142 criteria. After stages 2 and 3, these domains and tools were reduced to three domains containing eight tools: clinical (progressive dyspnoea over the past 3 months, unexplained dyspnoea, worsening of WHO dyspnoea functional class, any finding on physical examination suggestive of elevated right heart pressures and any sign of right heart failure), echocardiography (systolic pulmonary artery pressure >45 mm Hg and right ventricle dilation) and pulmonary function tests (diffusion lung capacity for carbon monoxide <50% without pulmonary fibrosis). Conclusions Among experts in pulmonary arterial hypertension-SSc, a core set of criteria for clinical practice to refer SSc patients for RHC has been defined by Delphi consensus methods. Although these indications are recommended by this expert group to be used as an interim tool, it will be necessary to formally validate the present tools in further studies.
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Previous Registry studies have reported that heart transplantation with older donor hearts is ass... more Previous Registry studies have reported that heart transplantation with older donor hearts is associated with a more than twofold increase in early mortality. An analysis of 77 consecutive patients undergoing heart transplantations at our institution between June 1988 and July 1994 was performed to assess the effect of donor age on mortality and morbidity. Recipients were grouped into those receiving hearts from younger donors (aged < 40 years, n = 60) and those receiving hearts from older donors (aged > 40 years, n = 17). There were two deaths within the first 30 days in the younger donor group and no deaths in the other group. One-year survival rate was 95% and 100% for the "younger" and "older" groups, respectively. The mean recipient age of the younger donor group was lower (46 +/- 14 years) compared with the older donor group (57 +/- 7 years). Morbidity was compared between the two groups; the length of hospital stay (22.6 +/- 15.8 days versus 21.3 +/-...
Background-We evaluated whether combined heart liver transplant can protect the heart graft from ... more Background-We evaluated whether combined heart liver transplant can protect the heart graft from the development of Cardiac allograft vasculopathy (CAV) using coronary 3D volumetric IVUS. Methods-From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 combined heart liver transplant (H+Liver Tx) recipients in whom two coronary 3D IVUS studies were performed one year apart. Baseline 3D IVUS was performed at 0.22 [0.17, 1.16] years after transplant with follow up 3D IVUS exams performed 0.96 [0.83, 1.08] after baseline exam. Results-Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+Liver Tx group (0.3±1.1 mm 3 /mm vs. 1.5±2.9 mm 3 /mm; P=0.08, and 0.01±0.03 vs. 0.1±0.1; P=0.004 respectively). Rejection burden was much lower in the H+Liver
Background-Although a link between donor-specific antibodies against human leukocyte antigens typ... more Background-Although a link between donor-specific antibodies against human leukocyte antigens type II (DSA II+) and transplant glomerulopathy has been clearly established, its role in cardiac allograft vasculopathy (CAV) is unclear. Methods-DSA were evaluated using solid phase Single Antigen Bead assay before transplant in 51 heart transplant (HTX) recipients. Coronary angiography and three-dimensional intravascular ultrasound (3D IVUS) were performed at baseline and approximately one year after the baseline exam. Results-There were 4 (7.8 %), 11 (21.5%), and 2 (3.9%) patients who had DSA against donor Class I (DSA I+), DSA II+, or both respectively. All patients had negative complement dependent cytotoxic cross match. There was accelerated progression of CAV in the DSA II+ group demonstrated by accelerated progression in plaque index (plaque volume/vessel volume) compared to patients with no DSA II+ antibodies (13.8±12% vs. −7.9±37%; p=0.01). The development of any angiographic CAV was also more common in DSA II+ patients as compared
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Papers by Robert Frantz