Laith Alkukhun

Sublingual microcirculation in pulmonary arterial hypertension

RATIONALE Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that leads to failure of the right ventricle and premature death. OBJECTIVES To determine whether the sublingual microcirculation is affected in patients with PAH compared with healthy age- and sex-matched control subjects. METHODS Using the CapiScope Handheld Video Capillaroscope we measured the sublingual microvasculature density, flow index, tortuosity, and curvature. Videos were acquired immediately after right heart catheterization, and determinations were made off-line by investigators blinded to the group assignment or hemodynamics. MEASUREMENTS AND MAIN RESULTS In this cross-sectional pilot study, we included 26 patients with PAH (age, mean ± SD, 56.7 ± 10 yr; 77% women) and 14 healthy control subjects (age, 53.1 ± 12 yr; 71% women). Sublingual microvasculature flow index was lower (2 ± 0.66 vs. 2.7 ± 0.37, P < 0.001) with higher heterogeneity index (0.63 ± 0.63 vs. 0.25 ± 0.25, P = 0.04) in patients with PAH than control subjects. Microvasculature density was similar between the groups, but tortuosity was more pronounced in patients than control subjects (tort 0: 45 ± 19 vs. 23.6 ± 12, P = 0.001 and tort 1: 0.2 ± 0.16 vs. 0.06 ± 0.04, P < 0.001). CONCLUSIONS Patients with PAH showed lower sublingual microvasculature flow index and higher tortuosity compared with healthy age- and sex-matched control subjects. Further investigations are needed to assess whether this methodology can provide information on disease prognosis and/or response to therapy in this condition.

Electrocardiography at diagnosis and close to the time of death in pulmonary arterial hypertension.

Scarce information exits on the electrocardiographic (ECG) characteristics of pulmonary arterial hypertension (PAH) patients close to their death and whether observed abnormalities progress from the time of PAH diagnosis.

Value of Impedance Cardiography during 6-Minute Walk Test in Pulmonary Hypertension

Methods that predict prognosis and response to therapy in pulmonary hypertension (PH) are lacking. We tested whether the noninvasive estimation of hemodynamic parameters during 6‐minute walk test (6MWT) in PH patients provides information that can improve the value of the test.

Non-invasive screening for pulmonary hypertension in idiopathic pulmonary fibrosis

BACKGROUND Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that is associated with poor prognosis. Noninvasive screening for PH in IPF patients is challenging and a combination of several noninvasive determinations can improve discrimination. METHODS We included 235 IPF patients who underwent right heart catheterization (RHC) as part of the lung transplant evaluation. We measured electrocardiographic (ECG) and echocardiographic variables as well as the pulmonary artery (PA) and ascending aorta (AA) diameters on chest CT. We recorded results of arterial blood gases (ABG), pulmonary function (PFT) and 6-min walk tests (6MWT). RESULTS Several variables were predictors of PH in IPF patients in univariable models including a lower arterial oxygenation and 6MWT distance; worse right ventricular (RV) function, rightward deviation of the QRS axis and a higher FVC/DLCOc ratio, PA/AA diameter ratio, and estimated RV systolic pressure. In multivariable analysis, a worse RV function and higher PA/AA ratio remained predictors of PH (c-index 0.75 (0.65-0.84)). Similarly, a worse RV function, a higher PA/AA ratio and a rightward QRS axis deviation were independent predictors of precapillary PH (c-index 0.86 (0.76-0.92)). A combination of PA/AA diameter ratio <1.1, a QRS axis <90° and normal RV function showed a negative predictive value of 85% for precapillary PH. CONCLUSIONS There are significant differences in ECG, echocardiographic, chest CT, PFT and ABG parameters between IPF patients with and without PH. However, these noninvasive tests alone or combination have limited discrimination ability for PH screening in IPF.

Treprostinil Iontophoresis in Idiopathic Pulmonary Arterial Hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a progressive disease without identifiable etiology and is characterized by elevated pulmonary vascular resistance that can lead to right heart failure and death (1). Initial studies characterized idiopathic PAH (IPAH) as a disease of the pulmonary circulation; however, recent data from us (2, 3) and other investigators (4–6) showed evidence of extrapulmonary vascular involvement. The extrapulmonary microcirculation can be studied in vivo, using cutaneous laser Doppler flowmetry (7), a methodology that can measure changes in skin flow in response to vasoactive stimuli. One stimulus is the cutaneous administration of prostacyclin (PGI2), using iontophoresis. Patients with IPAH have a marked reduction in PGI2 synthase (8) and expression of prostaglandin I2 receptors (9) in the lungs. More important, PGI2 analogs are potent medications to treat IPAH. Treprostinil is a PGI2 analog that increases cutaneous blood flow when administered by cathodal iontophoresis to healthy volunteers (10) and patients with systemic sclerosis (11). We hypothesize that patients with IPAH have systemic abnormalities in the PGI2 pathway that can be tested in vivo by cutaneous treprostinil iontophoresis. The research protocol was approved by the Cleveland Clinic Institutional Review Board, and all subjects provided written informed consent. We conducted this cross-sectional study between February 2013 and February 2015.We included consecutive patients who met hemodynamic criteria for PAH (12) and had the idiopathic or heritable (HPAH) forms of the disease. In addition, we studied ageand sex-matched control subjects without clinical evidence of pulmonary hypertension. We used the PeriFlux system 5000 (Perimed, Järfälla, Sweden) to test the effects of treprostinil iontophoresis and local thermal hyperemia. Treprostinil iontophoresis in patients was performed within 1 hour after right heart catheterization. Treprostinil (Remodulin 1 mg/ml) and its placebo (only treprostinil buffer) were iontophoresed for 30 minutes at 20 mA with a negative polarity. Measures were expressed as arbitrary perfusion units (PUs) (Figure 1). A detailed description of the methods is presented in the online supplement. Safety of the methodology was ascertained by recording local and/or systemic adverse effects in all subjects and by measuring treprostinil levels in plasma (at 20 minutes of iontophoresis) in a subset of individuals (n = 5). Patients (n = 24; IPAH = 22, HPAH = 2) and controls (n = 25) were ageand sex-matched. We also matched conditions known to be associated with systemic microvascular dysfunction. Patients were in New York Heart Association functional class I (n = 4, 17%), II (n = 7, 29%), III (n = 12, 50%), and IV (n = 1, 4%). Three quarters of patients were receiving PAHspecific therapies at the time of iontophoresis. Five (21%) and 7 (29%) received inhaled or parenteral PGI2 analogs, respectively. Patients had a mean pulmonary artery pressure of 44.56 14 mm Hg, cardiac index (thermodilution) of 2.86 0.79 L/min/m, and pulmonary vascular resistance of 7.56 4.3 Wood units. A total of 17 patients underwent inhaled nitric oxide challenge. With treprostinil iontophoresis, peak PUs, percentage change in PUs, and the percentage of peak PUs relative to the maximum value obtained by local hyperthermia were significantly reduced in patients compared with matched controls (Table 1). These relationships persisted after adjusting for skin resistance. The treprostinil buffer only minimally increased these determinations (n = 6), supporting the idea that the vasoactive effects are mostly a result of treprostinil. The receiver operating characteristic curve that tested the ability of the percentage change in PUs with treprostinil iontophoresis to discriminate between patients and controls showed an area under the curve of 0.75 (95% confidence interval [CI], 0.60–0.86; P = 0.0007). Patients treated with PGI2 analogs had higher baseline PUs (median [interquartile range], 7 [4–10] vs. 3 [2–6]; P = 0.04) and higher cardiac indexes (3.2 [2.8–3.6] vs. 2.4 [1.8–3.1] L/min/m; P = 0.01) than those not receiving this treatment. In addition, those receiving PGI2 analogs had a higher percentage change in PUs (517 [202–672] vs. 225 [86–274]%; P = 0.004) during treprostinil iontophoresis compared with individuals not receiving this treatment. In patients with IPAH not receiving PGI2 analogs (n = 12), the receiver operating characteristic curve of percentage change in PUs for discriminating patients versus controls showed an area under the curve of 0.87 (95% CI, 0.72–0.96; P , 0.0001). In this analysis, a cutoff of <300% had sensitivity of 83% and specificity of 87% to identify patients with IPAH from controls. The peak PUs during treprostinil iontophoresis was associated with New York Heart Association functional class (R =20.35; P = 0.01) and the number of PAH-specific therapies (R = 0.48; P = 0.02). We also noted a significant association between peak PU and cardiac index (R = 0.57; P = 0.004). We did not find an association between pulmonary vascular resistance, pulmonary vascular response to inhaled NO during right heart Supported by Clinical and Translational Science Collaborative KL2 (grant TR000440 to A.R.T.) from the National Center for Research Resources, a component of the National Institutes of Health, National Institutes of Health Roadmap for Medical Research. M.K.A. is supported by the Egyptian Cultural and Educational Research Scholar Program.

Heart rate slopes during 6‐min walk test in pulmonary arterial hypertension, other lung diseases, and healthy controls

Six‐minute walk test (6MWT) continues to be a useful tool to determine the functional capacity in patients with vascular and other lung diseases; nevertheless, it has a limited ability to predict prognosis in this context. We tested whether the heart rate (HR) acceleration and decay slopes during the 6‐m walk test are different in patients with pulmonary arterial hypertension (PAH), other lung diseases, and healthy controls. In addition, we assessed whether the HR slopes are associated with clinical worsening. Using a portable, signal‐morphology‐based, impedance cardiograph (PhysioFlow Enduro, Paris, France) with real‐time wireless monitoring via a Bluetooth USB adapter we determined beat‐by‐beat HR. We included 50 subjects in this pilot study, 20 with PAH (all on PAH‐specific treatment), 17 with other lung diseases (obstructive [n = 12, 71%] or restrictive lung diseases [5, 29%]), and 13 healthy controls. The beat‐by‐beat HR curves were significantly different among all three groups of subjects either during the activity or recovery of the 6MWT. HR curves were less steep in PAH than the other two groups (P < 0.001). HR acceleration rates were slower in patients with PAH or other lung diseases with progression of their disease (P < 0.001). In conclusion, the acceleration and decay slopes during 6MWT are different among patients with PAH, other lung diseases, and healthy controls. The HR slopes during 6MWT were steeper in patients without clinical worsening.

Subcutaneous to Intravenous Prostacyclin Analog Transition in Pulmonary Hypertension

Introduction: Prostacyclin analogs are Food and Drug Administration–approved therapies for the treatment of pulmonary arterial hypertension and can be administered by inhalational, intravenous (IV), or subcutaneous (SQ) routes. Because there are limited data to guide the transition between SQ to IV prostacyclin analogs, we describe our experience. Methods: We performed a retrospective review of patients with pulmonary hypertension diagnosed by right heart catheterization, who underwent transition from SQ to IV prostacyclin analogs. Results: We included 7 patients with pulmonary arterial hypertension and 2 with chronic thromboembolic pulmonary hypertension in this retrospective study. Median (interquartile range) age was 54 (39–63) years, and 67% were women. The reasons for the SQ to IV switch were site pain (n = 6, 67%), major surgery (n = 2, 22%), and septic shock (n = 1, 11%). SQ treprostinil was converted to IV treprostinil (n = 5, 56%) or IV epoprostenol (n = 4, 44%). When SQ treprostinil was converted to IV treprostinil, the initial mean (range) dose decreased from 84.9 (36.5–167) to 70.8 (24–114) ng·kg−1·min−1. When SQ treprostinil was converted to IV epoprostenol, the dose decreased from 24.5 (17.5–30) to 13.3 (9–20) ng·kg−1·min−1. The patient transitioned from SQ to IV treprostinil in the context of septic shock died a month after hospitalization. No deteriorations were observed in the remaining patients during the first year. Conclusions: Under careful monitoring, SQ treprostinil was transitioned to IV treprostinil or epoprostenol without complications. Dosing downadjustment was needed in some patients who were switched over from SQ to IV prostacyclin analogs.

Changes in main pulmonary artery diameter during follow‐up have prognostic implications in pulmonary arterial hypertension

A dilated pulmonary artery (PA) is a common finding in patients with pulmonary arterial hypertension (PAH). Little is known on the variations in PA size over time and whether these changes track with disease severity and/or predict long‐term survival.

Predictors of mortality after transjugular portosystemic shunt

AIM To investigate if echocardiographic and hemodynamic determinations obtained at the time of transjugular intrahepatic portosystemic shunt (TIPS) can provide prognostic information that will enhance risk stratification of patients. METHODS We reviewed medical records of 467 patients who underwent TIPS between July 2003 and December 2011 at our institution. We recorded information regarding patient demographics, underlying liver disease, indication for TIPS, baseline laboratory values, hemodynamic determinations at the time of TIPS, and echocardiographic measurements both before and after TIPS. We recorded patient comorbidities that may affect hemodynamic and echocardiographic determinations. We also calculated Model for End-stage Liver Disease (MELD) score and Child Turcotte Pugh (CTP) class. The following pre- and post-TIPS echocardiographic determinations were recorded: Left ventricular ejection fraction, right ventricular (RV) systolic pressure, subjective RV dilation, and subjective RV function. We recorded the following hemodynamic measurements: Right atrial (RA) pressure before and after TIPS, inferior vena cava pressure before and after TIPS, free hepatic vein pressure, portal vein pressure before and after TIPS, and hepatic venous pressure gradient (HVPG). RESULTS We reviewed 418 patients with portal hypertension undergoing TIPS. RA pressure increased by a mean ± SD of 4.8 ± 3.9 mmHg (P < 0.001), HVPG decreased by 6.8 ± 3.5 mmHg (P < 0.001). In multivariate linear regression analysis, a higher MELD score, lower platelet count, splenectomy and a higher portal vein pressure were independent predictors of higher RA pressure (R = 0.55). Three variables predicted 3-mo mortality after TIPS in a multivariate analysis: Age, MELD score, and CTP grade C. Change in the RA pressure after TIPS predicted long-term mortality (per 1 mmHg change, HR = 1.03, 95%CI: 1.01-1.06, P < 0.012). CONCLUSION RA pressure increased immediately after TIPS particularly in patients with worse liver function, portal hypertension, emergent TIPS placement and history of splenectomy. The increase in RA pressure after TIPS was associated with increased mortality. Age, splenectomy, MELD score and CTP grade were independent predictors of long-term mortality after TIPS.

Electrocardiographic Differences between COPD Patients Evaluated for Lung Transplantation With and without Pulmonary Hypertension

Abstract Introduction: Pulmonary hypertension (PH) is an indicator of poor prognosis in COPD patients; particularly in those with mean pulmonary artery pressure ≥ 40 mm Hg. Electrocardiography (ECG) might be useful for screening of this condition. Methods: Retrospective study of COPD patients evaluated for lung transplantation in whom we analyzed the 12-lead ECG performed closest to the time of right heart catheterization. Results: We included 142 patients. PH was present in 90 patients (63%) and 16 (11%) had a mean PAP ≥ 40 mmHg. The PR interval was longer in PH patients (151 (29) versus 139 (22) ms, p = 0.01) and T wave axis had a left shift (56.9 (32) versus 68.7 (19) degrees, p = 0.006). PR interval was longer (178.5 (35) versus 142.2 (23) ms, p = 0.001), T wave axis had a leftward deflection (63.6 (24) versus 42.8 (46) degrees, p = 0.005) and S wave in lead I was larger (0.19 (0.13) versus 0.12 (0.12) mV, p = 0.03) in patients with mean PAP ≥ 40 mmHg. A PR interval > 137 ms and S wave in DI > 0.02 mV had a sensitivity of 100% and a specificity of 59.5% to identify COPD patients with a mean PAP ≥ 40 mmHg. Conclusion: There are significant ECG differences between advanced COPD patients with and without PH; however the ECG is an inadequate tool to differentiate between the groups. A prolonged PR interval suggests the presence of severe PH.