Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its ...pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council.
The aim of this study was to assess whether serial quantitative assessment of right ventricular (RV) function by speckle-based strain imaging is affected by pulmonary hypertension–specific therapies ...and whether there is a correlation between serial changes in RV strain and clinical status. RV longitudinal systolic function was assessed using speckle-tracking echocardiography in 50 patients with pulmonary arterial hypertension (PAH) before and after the initiation of therapy. The mean interval to follow-up was 6 ± 2 months. Subsequent survival was assessed over 4 years. Patients demonstrated a mean increase in RV systolic strain from −15 ± 5 before to −20 ± 7% (p = 0.0001) after PAH treatment. Persistence of or progression to a severe reduction in free wall systolic strain (<−12.5%) at 6 months was associated with greater disease severity (100% were in functional class III or IV vs 42%, p = 0.005), greater diuretic use (86% vs 40%, p = 0.02), higher mean pulmonary artery pressure (67 ± 20 vs 46 ± 17 mm Hg, p = 0.006), and poorer survival (4-year mortality 43% vs 23%, p = 0.002). After adjusting for age, functional class, and RV strain at baseline, patients with ≥5% improvement in RV free wall systolic strain had a greater than sevenfold lower mortality risk at 4 years (hazard ratio 0.13, 95% confidence interval 0.03 to 0.50, p = 0.003). In conclusion, serial echocardiographic assessment of RV longitudinal systolic function by quantitative strain imaging independently predicts clinical deterioration and mortality in patients with PAH after the institution of medical therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background In pulmonary arterial hypertension (PAH), survival predictions can be important for optimization of therapeutic strategies. The present study aimed to validate a quantitative algorithm for ...predicting survival derived from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) and develop a simplified calculator for everyday clinical use. Methods Prospectively collected data from patients with newly diagnosed (< 3 months) World Health Organization group I pulmonary hypertension enrolled in the REVEAL Registry were used to validate a predictive algorithm for 1-year survival. Model calibration was evaluated by comparing algorithm-predicted survival with observed Kaplan-Meier estimates for the overall validation cohort and for five risk groups. Similarly, the risk discriminators for the simplified calculator were compared with those of the quantitative algorithm. Results The validation cohort comprised 504 individuals with mean ± SD 6-min walk distance 308 ± 128 m, and 61.5% were functional class III. The proportion of patients surviving 1 year fell within the range predicted by the model (95.1%, 91.5%, 84.6%, 76.3%, and 58.2%, respectively) among patients in the low (predicted survival ≥ 95%), average (90% to < 95%), moderate (85% to < 90%), high (70% to < 85%), and very high (< 70%) risk strata. Predicted and observed 1-year survival were similar across risk stratum, and the c-index indicated good discrimination for both the full equation (0.726) and the simplified risk calculator (0.724). Conclusions The REVEAL Registry predictive algorithm and simplified risk score calculator are well calibrated and demonstrate good discriminatory ability in patients with newly or previously diagnosed PAH. Trial registry ClinicalTrials.gov ; No.: NCT00370214; URL: www.clinicaltrials.gov
Background 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/m2 ), 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 4-year 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 right-sided heart failure, clinical deterioration, and mortality in patients with PAH.
Objectives The purpose of this study was to determine the occurrence and causes of readmissions after implantation of axial flow left ventricular assist device (LVAD). Background Based on the REMATCH ...(Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) study experience, readmissions after LVAD implantation are thought to be frequent. Methods We retrospectively analyzed admissions to our facility in a cohort of 115 patients implanted between January 2008 and July 2011 with the HeartMate II axial flow LVAD, of whom 42 were bridged to transplant. To account for repeated events, Andersen-Gill models were used to determine possible predictors. Results The patients were followed for 1.4 ± 0.9 years. There were 224 readmissions in 83 patients. The overall readmission rate was 1.64 ± 1.97 per patient-year of follow-up. The readmission rate for the first 6 months was 2.0 ± 2.3 and decreased to 1.2 ± 2.1 during subsequent follow-up. Leading causes were bleeding (66 readmissions in 34 patients), mostly gastrointestinal bleed (51 in 27 patients), cardiac (51 in 36 patients, most for HF or arrhythmia), infections (32 in 25 patients) of which 6 were pump related, and thrombosis (20 in 15 patients) including 13 readmissions due to hemolysis. Preoperative variables associated with (fewer) readmissions in a multivariate model include residence within our hospital-extended referral zone of Minnesota and the neighboring states (hazard ratio: 0.66; 95% confidence interval: 0.48 to 0.91; p = 0.011), hemoglobin (hazard ratio: 0.91, 95% confidence interval: 0.84 to 0.99; p = 0.027) and N-terminal pro–B-type natriuretic peptide (hazard ratio: 0.98; 95% confidence interval: 0.96 to 1.0 per 1,000-unit increase, p = 0.022). C-statistic for the model: 0.63. Conclusions Readmission rates after axial flow LVAD implantation decrease during the first 6 months and then stabilize. The leading causes are bleeding, cardiac (heart failure and arrhythmia), infections, and thrombosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives The aim of this study was to determine renal outcomes after left ventricular assist device (LVAD) implantation. Background Renal dysfunction before LVAD placement is frequent, and it is ...unclear whether it is due to primary renal disease or to poor perfusion. Methods A retrospective single-center analysis was conducted in 83 consecutive patients implanted with HeartMate II continuous-flow LVADs (Thoratec Corp., Pleasanton, California). Calculated glomerular filtration rate (GFR) was assessed on admission and 1, 3, and 6 months after implantation. To define predictors for improvement in GFR, clinical variables were examined in patients with decreased renal function (GFR <60 ml/min/1.73 m2 ) before LVAD, surviving and dialysis-free at 1 month (n = 44). Results GFR significantly increased from admission (53.2 ± 21.4 ml/min/1.73 m2 ) to 1 month after LVAD implantation (87.4 ± 27.9 ml/min/1.73 m2 ) (p < 0.0001). Subsequently, at 3 and 6 months, GFR remained significantly (p < 0.0001) above pre-LVAD values. Of the 51 patients with GFRs <60 ml/min/1.73 m2 before LVAD surviving at 1 month, 34 (67%) improved to GFRs >60 ml/min/1.73 m2 . Univariate pre-operative predictors for improvement in renal function at 1 month included younger age (p = 0.049), GFR improvement with optimal medical therapy (p < 0.001), intra-aortic balloon pump use (p = 0.004), kidney length above 10 cm (p = 0.023), no treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (p = 0.029), higher bilirubin (p = 0.002), higher Lietz-Miller score (p = 0.019), and atrial fibrillation (p = 0.007). Multivariate analysis indicated pre-operative improved GFR (slope = 0.5 U per unit improved; 95% confidence interval: 0.2 to 0.8; p = 0.003), atrial fibrillation (slope = 27; 95% confidence interval: 8 to 46; p = 0.006), and intra-aortic balloon pump use (slope = 14; 95% confidence interval: 2 to 26; p = 0.02) as independent predictors. Conclusions In most patients with end-stage heart failure considered for LVAD implantation, renal dysfunction is reversible and likely related to poor renal perfusion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity ...in a controlled trial (Imatinib QTI571 in Pulmonary Arterial Hypertension, a Randomized Efficacy Study IMPRES), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies.
The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension.
Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study.
Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged.
Background The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated ...with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. Methods A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. Results Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days ( P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels ( r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months’ postimplantation ( P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions. Conclusions The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. Trial Registry ClinicalTrials.gov; No.: NCT01321073 ; URL: www.clinicaltrials.gov
Background 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. Methods We conducted a single-center cohort study of patients with confirmed HHT who underwent right-sided heart catheterization (RHC) and transthoracic two-dimensional echocardiography for suspected PH between June 1, 2003 and September 1, 2013 at Mayo Clinic Rochester, Minnesota. Results Of 38 patients with confirmed HHT who underwent RHC and echocardiography, 28 (74%) had a mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg. Of those 28, 12 (43%) had pulmonary arterial hypertension. Two patients had normal PAWP and pulmonary vascular resistance (PVR), with PH secondary to either an atrial septal defect or high cardiac flow. Fourteen patients (50%) had elevated PAWP (≥ 15 mm Hg), nine with evidence of high flow. RHC in all 28 patients demonstrated a MPAP of 41 ± 11 mm Hg, PAWP of 17 ± 10 mm Hg, and PVR of 4.5 ± 4.2 Wood units. Echocardiography demonstrated moderate/severe right ventricular dysfunction in nine patients (32%). The presence of PH trended toward worse survival ( P = .06). Conclusions PH in patients with HHT occurs by different mechanisms, and there is a trend toward worse survival in patients who develop PH despite the mechanism. The equal predilection toward all subtypes of PH illustrates the necessity of RHC to clarify the hemodynamics.
Background Current management guidelines for pulmonary arterial hypertension (PAH) recommend a treatment choice based primarily on World Health Organization (WHO) functional class. This study was ...designed to assess how the incorporation of readily obtained clinical and test-based information may significantly improve the prediction of outcomes over functional class alone. Methods Clinical and hemodynamic variables were assessed in 484 consecutive patients presenting with WHO group 1 PAH. The primary outcome measure was time to all-cause mortality over 5 years from the index presentation (data available in all). Follow-up was censored at the time of lung or heart/lung transplant in 21 patients or at 5 years. Predictors of mortality were assessed sequentially using Cox models, with the step-wise incorporation of clinical variables, echocardiographic, and catheterization findings. Results were further compared with the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) prediction score. Results Overall median survival was 237 weeks (95% CI, 196-266), corresponding to 1-year, 3-year, and 5-year survival rates of 81.1% (77.0, 84.7), 61.1% (56.5, 65.3), and 47.9% (43.2, 52.4), respectively. The prediction of mortality was improved incrementally by incorporating clinical and echocardiographic measures with a concordance index (c-index) of 0.84 compared with that of 0.60 with functional class alone. The REVEAL prediction score was validated independently in this cohort to predict both 1-year and 5-year mortality. It had a prediction c-index of 0.71. Conclusions The integration of routine PAH clinical (predominantly noninvasive) parameters predicts long-term outcome better than functional class and, hence, should be incorporated into medical management decisions.
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