Mario Gerges

Diastolic Pulmonary Vascular Pressure Gradient: A Predictor of Prognosis in “Out-of-Proportion” Pulmonary Hypertension

BACKGROUND Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This “reactive” or “out-of-proportion” PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in “out-of-proportion” PH. METHODS A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed. RESULTS In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG ≥ 7 mm Hg compared with a DPG < 7 mm Hg (101 months, P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling. CONCLUSIONS DPG identifies patients with “out-of-proportion” PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

Original ResearchPulmonary Vascular DiseaseDiastolic Pulmonary Vascular Pressure Gradient: A Predictor of Prognosis in “Out-of-Proportion” Pulmonary Hypertension

BACKGROUND Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This “reactive” or “out-of-proportion” PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in “out-of-proportion” PH. METHODS A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed. RESULTS In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG ≥ 7 mm Hg compared with a DPG < 7 mm Hg (101 months, P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling. CONCLUSIONS DPG identifies patients with “out-of-proportion” PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

How to define pulmonary hypertension due to left heart disease

Current 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension (PH) [1, 2] have adopted new insights in the understanding of PH due to left heart disease (PH-LHD, group 2). Pulmonary vascular disease in heart failure comprises increased RV afterload, poor RV-PV coupling and worse survival http://ow.ly/4n622h

Hemodynamic phenotyping of pulmonary hypertension in left heart failure

Increased pulmonary venous pressure secondary to left heart disease is the most common cause of pulmonary hypertension (PH). The diagnosis of PH due to left heart disease relies on a clinical probability assessment followed by the invasive measurements of a mean pulmonary artery pressure (PAP) ≥25 mm Hg and mean wedged PAP (PAWP) >15 mm Hg. A combination of mean PAP and mean PAWP defines postcapillary PH. Postcapillary PH is generally associated with a diastolic pulmonary pressure gradient (diastolic PAP minus mean PAWP) <7 mm Hg, a transpulmonary pressure gradient (mean PAP minus mean PAWP) <12 mm Hg, and pulmonary vascular resistance ⩽3 Wood units (WU). This combination of criteria defines isolated postcapillary PH. Postcapillary PH with elevated vascular gradients and pulmonary vascular resistance defines combined post- and precapillary PH (Cpc-PH). Postcapillary PH is associated with a decreased survival in proportion to increased pulmonary vascular gradients, decreased pulmonary arterial compliance, and reduced right ventricular function. The Cpc-PH subcategory occurs in 12% to 13% of patients with PH due to left heart disease. Patients with Cpc-PH have severe PH, with higher diastolic pulmonary pressure gradient, transpulmonary pressure gradient, and pulmonary vascular resistance and more pronounced ventilatory responses to exercise, lower pulmonary arterial compliance, depressed right ventricular ejection fraction, and shorter life expectancy than isolated postcapillary PH. Cpc-PH bears similarities to pulmonary arterial hypertension. Whether Cpc-PH is amenable to therapies targeting the pulmonary circulation remains to be tested by properly designed randomized controlled trials.

Hemodynamic Thresholds for Precapillary Pulmonary Hypertension

BACKGROUND Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response. METHODS We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response. RESULTS Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) < 12 mm Hg and diastolic pulmonary vascular pressure gradient (DPG) ≥ 7 mm Hg as the best hemodynamic discriminators between idiopathic PAH and postcapillary PH. In our treatment study, only patients with mPAWP < 12 mm Hg, DPG > 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics. CONCLUSIONS mPAWP < 12 mm Hg and DPG > 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment.

Advanced Imaging Tools Rather Than Hemodynamics Should Be the Primary Approach for Diagnosing, Following, and Managing Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is currently defined based on invasive measurements: a resting pulmonary artery pressure ≥ 25 mm Hg. For pulmonary arterial hypertension, a pulmonary arterial wedge pressure ≤ 15 mm Hg and pulmonary vascular resistance > 3 Wood units are also required. Thus, right heart catheterization is inevitable at present. However, the diagnosis, follow-up, and management of PH by noninvasive techniques is progressing. Significant advances have been achieved in the imaging of pulmonary vascular disease and the right ventricle. We review the current sensitivities and specificities of noninvasive imaging of PH and discuss its role and future potential to replace hemodynamics as the primary approach to screening, diagnosing, and following/managing PH.

Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension

Objective To assess the efficacy and safety of subcutaneous treprostinil in adult patients with congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) after 12 months of treatment. Methods Consecutive adult patients with CHD–PAH received subcutaneous treprostinil to maximum tolerated doses in an observational study. Results Advanced CHD–PAH patients with WHO class III or IV disease (n=32, age 40±10 years, 20 females) received treprostinil for suboptimal response to bosentan (n=12), WHO functional class IV disease (FC, n=7) or prior to bosentan approval (n=13). In the multivariate mixed model, mean increase in 6 min walk distance (6-MWD) from baseline to 12 months was 114 m (76; 152) (P<0.001). WHO FC improved significantly (P=0.001) and B-type brain natriuretic peptide decreased from 1259 (375; 2368) pg/mL to 380 (144; 1468) pg/mL (P=0.02). In those 14 patients who had haemodynamic data before and after initiation of treprostinil, pulmonary vascular resistance decreased significantly (from 18.4±11.1 to 12.6±7.9 Wood units, P=0.003). The most common adverse events were infusion-site erythema and pain. One patient stopped treatment because of intolerable infusion-site pain after 8 months of treatment. No other major treatment-related complications were observed. Five patients died during early follow-up, having experienced a decrease in their 6-MWD prior. Conclusions Subcutaneous treprostinil therapy is generally safe and effective for at least 12 months and may be used in CHD-related PAH class III and IV.

In-depth haemodynamic phenotyping of pulmonary hypertension due to left heart disease

The commonest cause of pulmonary hypertension (PH) is left heart disease (LHD). The current classification system for definitions of PH-LHD is under review. We therefore performed prospective in-depth invasive haemodynamic phenotyping in order to assess the site of increased pulmonary vascular resistance (PVR) in PH-LHD subsets. Based on pulmonary artery occlusion waveforms yielding an estimate of the effective capillary pressure, we partitioned PVR in larger arterial (Rup, upstream resistance) and small arterial plus venous components (Rds, downstream resistance). In the case of small vessel disease, Rup decreases and Rds increases. Inhaled nitric oxide (NO) testing was used to assess acute vasoreactivity. Right ventricular afterload (PVR, pulmonary arterial compliance and effective arterial elastance) was significantly higher in combined post- and pre-capillary PH (Cpc-PH, n=35) than in isolated post-capillary PH (Ipc-PH, n=20). Right ventricular afterload decreased during inhalation of NO in Cpc-PH and idiopathic pulmonary arterial hypertension (n=31), but remained unchanged in Ipc-PH. Rup was similar in Cpc-PH (66.8±10.8%) and idiopathic pulmonary arterial hypertension (65.0±12.2%; p=0.530) suggesting small vessel disease, but significantly higher in Ipc-PH (96.5±4.5%; p<0.001) suggesting upstream transmission of elevated left atrial pressure. Right ventricular afterload is driven by elevated left atrial pressure in Ipc-PH and is further increased by elevated small vessel resistance in Cpc-PH. Cpc-PH is responsive to inhaled NO. Our data support current definitions of PH-LHD subsets. Combined post- and pre-capillary PH is characterised by pre-capillary pulmonary vascular disease and a positive response to inhaled NO http://ow.ly/G2nF30iYTeJ

Usefulness of thrombosis and inflammation biomarkers in chronic thromboembolic pulmonary hypertension—sampling plasma and surgical specimens

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) results from persistent pulmonary vascular obstructions, presumably due to inflammatory thrombosis. Because estimates of thrombus volume at diagnosis have no predictive value, we investigated the role of the thrombosis marker, D-dimer, and the inflammation marker, C-reactive protein (CRP), for predicting outcomes in CTEPH. METHODS A total 289 consecutive patients with CTEPH were followed for 57 (median 45 to 69) months. One hundred fifty-seven of these patients underwent surgical pulmonary endarterectomy (PEA). D-dimer and CRP were collected at the time of CTEPH diagnosis and their impact on outcome was analyzed using Cox and logistic regression models. Their association with thrombus composition was analyzed utilizing HistoQuest. RESULTS D-dimer and CRP levels were separately and independently predictive of death or need for lung transplantation (p = 0.012 and p = 0.025, respectively). For example, 5-year survival was 90% (confidence limits 84% to 96%) in patients with D-dimer levels <0.5 µg/ml and CRP <1 mg/dl at diagnosis, as compared with 50% (36% to 64%) for patients with D-dimer ≥0.5 µg/ml and CRP ≥1 mg/dl (p < 0.001). D-dimer and CRP both decreased significantly after PEA (p < 0.01). The amount of fresh red thrombus in thrombendarterectomy specimens correlated positively with D-dimer levels at diagnosis (r = 0.37, p = 0.003). CONCLUSIONS D-dimer and CRP at the time of diagnosis are independent and significant predictors of outcome in CTEPH, available at the time of diagnosis. This observation suggests an important role for fibrin turnover and inflammation in the pathogenesis of CTEPH and the associated complications.

Pulmonary Hypertension Due to Left Heart Disease

Pulmonary hypertension (PH) due to left heart disease (PH-LHD) is a significant predictor of outcome for patients with any type of heart failure (HF), and represents a subset of PH affecting a large number of patients. Because the condition is no standalone inherent pulmonary vascular disorder but the consequence of heart disease, its understanding is dependent on a thorough insight in current HF epidemiology, pathophysiology, diagnosis, and treatments. Although the age-specific incidence of HF is decreasing, this trend is less dramatic for HF with preserved ejection fraction than for HF with reduced ejection fraction. Both the current 2015 ESC/ERS guidelines for the diagnosis and treatment of PH, and the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic HF have adopted new insights in the current understanding of PH-LHD (PH group 2), but no consensus has been reached. Due to multimorbidity, advanced age, referral biases, and a large proportion of noncardiovascular deaths in this population, proper hemodynamic and clinical characterization of patients with and without significant pulmonary vascular disease is important. Definitions largely depend on fluid status which should be assessed prior to any hemodynamic assessment. Benefit from pulmonary arterial hypertension–targeted treatments appears unlikely from todays perspective, but there is an immense unmet need for any treatments of this condition, and proper trials still have to be done.