Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy.

BACKGROUND: Positron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. OBJECTIVES: The authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. METHODS: Adults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. RESULTS: A total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: -6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = -0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. CONCLUSIONS: The 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786).

Frailty and outcomes in heart failure patients from high-, middle-, and low-income countries.

BACKGROUND AND AIMS: There is little information on the incremental prognostic importance of frailty beyond conventional prognostic variables in heart failure (HF) populations from different country income levels. METHODS: A total of 3429 adults with HF (age 61 ± 14 years, 33% women) from 27 high-, middle- and low-income countries were prospectively studied. Baseline frailty was evaluated by the Fried index, incorporating handgrip strength, gait speed, physical activity, unintended weight loss, and self-reported exhaustion. Mean left ventricular ejection fraction was 39 ± 14% and 26% had New York Heart Association Class III/IV symptoms. Participants were followed for a median (25th to 75th percentile) of 3.1 (2.0-4.3) years. Cox proportional hazard models for death and HF hospitalization adjusted for country income level; age; sex; education; HF aetiology; left ventricular ejection fraction; diabetes; tobacco and alcohol use; New York Heart Association functional class; HF medication use; blood pressure; and haemoglobin, sodium, and creatinine concentrations were performed. The incremental discriminatory value of frailty over and above the MAGGIC risk score was evaluated by the area under the receiver-operating characteristic curve. RESULTS: At baseline, 18% of participants were robust, 61% pre-frail, and 21% frail. During follow-up, 565 (16%) participants died and 471 (14%) were hospitalized for HF. Respective adjusted hazard ratios (95% confidence interval) for death among the pre-frail and frail were 1.59 (1.12-2.26) and 2.92 (1.99-4.27). Respective adjusted hazard ratios (95% confidence interval) for HF hospitalization were 1.32 (0.93-1.87) and 1.97 (1.33-2.91). Findings were consistent among different country income levels and by most subgroups. Adding frailty to the MAGGIC risk score improved the discrimination of future death and HF hospitalization. CONCLUSIONS: Frailty confers substantial incremental prognostic information to prognostic variables for predicting death and HF hospitalization. The relationship between frailty and these outcomes is consistent across countries at all income levels.

Right Ventricular Maladaptation to Pressure Overload in Fischer Rats Is Associated With Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics.

BACKGROUND: We explored the mechanism of maladaptive right ventricular (RV) remodeling in Fischer compared with Sprague-Dawley (SD) rats exposed to pressure overload. METHODS: Pulmonary hypertension was induced by injection of the VEGFR antagonist, SU5416, followed by a 3-week exposure to hypoxia (Sugen chronic hypoxia). In vivo oxidative metabolism was assessed by RV/left ventricle ratio of [11C]acetate positron emission tomography clearance (kmono). Unbiased, global transcriptional and proteomic profiling was performed in Fischer and SD rats at baseline and after Sugen chronic hypoxia. RESULTS: All Fischer rats succumbed to RV failure by 5 weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (P<0.0001). Fischer rats exhibited increased oxidative metabolism at 4 weeks (P<0.05) and impaired RV efficiency compared with SD (work metabolic index: 52±10 versus 91±27 mmHg·mL/cm2, respectively; P<0.05), but no differences in mitochondrial complex activity. AK1 (adenylate kinase 1) was among the top 10 differentially expressed genes between Fischer and SD rats, with markedly lower RV expression in Fischer rats (FC: 3.36, P<0.05), confirmed by proteomic analysis and validated by Western blotting (>10-fold reduction, P<0.001). While whole-genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region likely involved in the regulation of AK1 expression. CONCLUSIONS: Therefore, Fischer rats exhibit profound AK1 deficiency and inefficient cardiac energetics likely related to reduced adenosine triphosphate shuttling from the mitochondria to the contractile fibers. This represents a novel mechanism for RV failure in response to chronic increases in afterload.

A standardized definition for right ventricular failure in cardiac surgery patients.

Right ventricular failure (RVF) is a significant cause of mortality and morbidity after cardiac surgery. Despite its prognostic importance, RVF remains under investigated and without a universally accepted definition in the perioperative setting. We foresee that the provision of a standardized perioperative definition for RVF based on practical and objective criteria will help to improve quality of care through early detection and facilitate the generalization of RVF research to advance this field. This article provides an overview of RVF aetiology, pathophysiology, current diagnostic modalities, as well as a summary of existing RVF definitions. This is followed by our proposal for a standardized definition of perioperative RVF, one that captures RV structural and functional abnormalities through a multimodal approach based on anatomical, echocardiographic, and haemodynamic criteria that are readily available in the perioperative setting (Central Image).

Increased myocardial oxygen consumption rates are associated with maladaptive right ventricular remodeling and decreased event-free survival in heart failure patients.

BACKGROUND: Reduced left ventricular (LV) function is associated with increased myocardial oxygen consumption rate (MVO2) and altered sympathetic activity, the role of which is not well described in right ventricular (RV) dysfunction. METHODS AND RESULTS: 33 patients with left heart failure were assessed for RV function/size using echocardiography. Positron emission tomography (PET) was used to measure 11C-acetate clearance rate (kmono), 11C-hydroxyephedrine (11C-HED) standardized uptake value (SUV), and retention rate. RV MVO2 was estimated from kmono. 11C-HED SUV and retention indicated sympathetic neuronal function. A composite clinical endpoint was defined as unplanned cardiac hospitalization within 5 years. Patients with (n = 10) or without (n = 23) RV dysfunction were comparable in terms of sex (male: 70.0 vs 69.5%), LV ejection fraction (39.6 ± 9.0 vs 38.6 ± 9.4%), and systemic hypertension (70.0 vs 78.3%). RV dysfunction patients were older (70.9 ± 13.5 vs 59.4 ± 11.5 years; P = .03) and had a higher prevalence of pulmonary hypertension (60.0% vs 13.0%; P = .01). RV dysfunction was associated with increased RV MVO2 (.106 ± .042 vs .068 ± .031 mL/min/g; P = .02) and decreased 11C-HED SUV and retention (6.05 ± .53 vs 7.40 ± 1.39 g/mL (P < .001) and .08 ± .02 vs .11 ± .03 mL/min/g (P < .001), respectively). Patients with an RV MVO2 above the median had a shorter event-free survival (hazard ratio = 5.47; P = .01). Patients who died within the 5-year follow-up period showed a trend (not statistically significant) for higher RV MVO2 (.120 ± .026 vs .074 ± .038 mL/min/g; P = .05). CONCLUSIONS: RV dysfunction is associated with increased oxygen consumption (also characterized by a higher risk for cardiac events) and impaired RV sympathetic function.

Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis.

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease.

Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement on Heart Transplantation: Patient Eligibility, Selection, and Post-Transplantation Care.

Significant practice-changing developments have occurred in the care of heart transplantation candidates and recipients over the past decade. This Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement provides evidence-based, expert panel recommendations with values and preferences, and practical tips on: (1) patient selection criteria; (2) selected patient populations; and (3) post transplantation surveillance. The recommendations were developed through systematic review of the literature and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The evolving areas of importance addressed include transplant recipient age, frailty assessment, pulmonary hypertension evaluation, cannabis use, combined heart and other solid organ transplantation, adult congenital heart disease, cardiac amyloidosis, high sensitization, and post-transplantation management of antibodies to human leukocyte antigen, rejection, cardiac allograft vasculopathy, and long-term noncardiac care. Attention is also given to Canadian-specific management strategies including the prioritization of highly sensitized transplant candidates (status 4S) and heart organ allocation algorithms. The focus topics in this position statement highlight the increased complexity of patients who undergo evaluation for heart transplantation as well as improved patient selection, and advances in post-transplantation management and surveillance that have led to better long-term outcomes for heart transplant recipients.

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis.

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

Medical Therapy for Heart Failure Associated With Pulmonary Hypertension.

The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction. 1 This success has coincided with the stepwise availability of drugs that target neurohormonal activation: ß-adrenergic receptor blockers (ß-blockers), ACE (angiotensin-converting enzyme) inhibitors and ANG (angiotensin) II blockers, neprilysin inhibitors, and aldosterone antagonists. Our understanding of right heart failure (RHF) has lagged behind and many proven targeted therapies for left heart failure do not appear to provide similar benefits for RHF. Until recently, the right ventricle (RV) has often been viewed as less important than the left ventricle and in contemporary literature received the moniker "The Forgotten Ventricle". Recent advances in echocardiography and magnetic resonance imaging have enabled detailed assessments of RV anatomy and physiology in both health and disease allowing us to more accurately describe the clinical sequelae and end-organ manifestations of RHF. RV function is now recognized as one of the most important predictors of prognosis in many cardiovascular disease states. 2 Despite the significance of RV function to survival, there are no clinically approved therapies that directly nor selectively improve RV function. As well, relative to our understanding of left heart failure, the basis for RHF remains poorly understood. This article aims to condense the current knowledge on RV adaptation and failure, review current management strategies for RHF, and explore evolving therapeutic approaches.

Biomarkers in the Diagnosis, Management, and Prognostication of Perioperative Right Ventricular Failure in Cardiac Surgery-Are We There Yet?

Right ventricular failure (RVF) is a major risk factor for end organ morbidity and mortality following cardiac surgery. Perioperative RVF is difficult to predict and detect, and to date, no convenient, accurate, or reproducible measure of right ventricular (RV) function is available. Few studies have examined the use of biomarkers in RVF, and even fewer have examined their utility in the perioperative setting of patients undergoing cardiac surgery. Of the available classes of biomarkers, this review focuses on biomarkers of (1) inflammation and (2) myocyte injury/stress, due to their superior potential in perioperative RV assessment, including Galectin 3, ST2/sST2, CRP, cTN/hs-cTn, and BNP/NT-proBNP. This review was performed to help highlight the importance of perioperative RV function in patients undergoing cardiac surgery, to review the current modalities of RV assessment, and to provide a review of RV specific biomarkers and their potential utilization in the clinical and perioperative setting in cardiac surgery. Based on current evidence, we suggest the potential utility of ST2, sST2, Gal-3, CRP, hs-cTn, and NT-proBNP in predicting and detecting RVF in cardiac surgery patients, as they encompass the multifaceted nature of perioperative RVF and warrant further investigation to establish their clinical utility.

Myocardial viability: from PARR-2 to IMAGE HF - current evidence and future directions / Viabilidade miocárdica: de PARR-2 a IMAGE HF - evidências atuais e futuras direções

Ischemic heart failure is a growing disease with high morbidity and mortality. Several studies suggest the benefit of viability imaging to assist revascularization decision, but there is controversy. Multiple imaging modalities can be used to accurately define hibernating myocardium; however, the best approach remains uncertain. This review will highlight current evidence and future directions of viability imaging assessment

Utility of Novel Cardiorenal Biomarkers in the Prediction and Early Detection of Congestive Kidney Injury Following Cardiac Surgery.

Acute Kidney Injury (AKI) in the context of right ventricular failure (RVF) is thought to be largely congestive in nature. This study assessed the utility of biomarkers high sensitivity cardiac troponin T (hs-cTnT), N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and neutrophil gelatinase-associated lipocalin (NGAL) for prediction and early detection of congestive AKI (c-AKI) following cardiac surgery. This prospective nested case-control study recruited 350 consecutive patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. Cases were patients who developed (1) AKI (2) new or worsening RVF, or (3) c-AKI. Controls were patients free of these complications. Biomarker levels were measured at baseline after anesthesia induction and immediately postoperatively. Patients with c-AKI had increased mean duration of mechanical ventilation and length of stay in hospital and in the intensive care unit (p < 0.01). For prediction of c-AKI, baseline NT-proBNP yielded an area under the curve (AUC) of 0.74 (95% CI, 0.60⁻0.89). For early detection of c-AKI, postoperative NT-proBNP yielded an AUC of 0.78 (0.66⁻0.91), postoperative hs-cTnT yielded an AUC of 0.75 (0.58⁻0.92), and ∆hs-cTnT yielded an AUC of 0.80 (0.64⁻0.96). The addition of baseline creatinine to ∆hs-cTnT improved the AUC to 0.87 (0.76⁻0.99), and addition of diabetes improved the AUC to 0.93 (0.88⁻0.99). Δhs-cTnT alone, or in combination with baseline creatinine or diabetes, detects c-AKI with high accuracy following cardiac surgery.

Double-Valve Surgery After Cardiac Retransplantation.

We provide an update on Canada's first neonatal heart transplant recipient who, after cardiac retransplantation, underwent a mitral valve replacement and tricuspid valve repair. Twenty-seven years after his initial heart surgery and 13 years after his most recent transplant, this patient developed heart failure with severe mitral regurgitation secondary to a calcified mitral valve. The patient was highly sensitized with no evidence of allograft rejection; therefore, mitral and tricuspid surgery was performed. The patient did well perioperatively and remains well 18 months after surgery. To our knowledge, this novel case represents the first double-valve surgery in a patient who underwent cardiac retransplantation.

Heart failure and palliative care in the emergency department.

OBJECTIVES: Heart failure is a common ED presentation that is underserved by palliative care services and is associated with significant morbidity and mortality. We sought to evaluate use of palliative care services in patients with heart failure presenting to the ED. The primary outcome studied was palliative care involvement. Secondary outcomes of the study were: (1) 1-year mortality, (2) ED visits, (3) hospital admissions and (4) heart failure clinic involvement. METHODS: We conducted a health records review of 500 patients with heart failure who presented to two Canadian academic hospital EDs from January to August 2013. RESULTS: Patients were of mean age 80.7 years, women (53.2%) and had significant comorbidities. Only 41% of all deceased patients at 1 year had any palliative care involvement. Of those with palliative care, 44 (76%) patients had less than 2 weeks of palliative care involvement prior to death. Compared with those with no palliative care, the 79 (15.8%) patients with palliative care involvement had a higher 1-year mortality rate (70.9% vs 18.8%) and more hospital admissions/year (1.4 vs 0.85) for heart failure. CONCLUSIONS: We found that few patients with heart failure had palliative care services. Additionally, the majority of those who have palliative care involvement do not meet current recommendations for early palliative care involvement in heart failure. This study suggests that the ED may be an appropriate setting to identify and refer high-risk patients with heart failure who could benefit from earlier palliative care involvement.

Barriers to Goals of Care Discussions With Patients Who Have Advanced Heart Failure: Results of a Multicenter Survey of Hospital-Based Cardiology Clinicians.

BACKGROUND: Conversations about goals of care in hospital are important to patients who have advanced heart failure (HF). METHODS: We conducted a multicenter survey of cardiology nurses, fellows, and cardiologists at 8 Canadian teaching hospitals. The primary outcome was the importance of barriers to goals-of-care discussions in hospital (1 = extremely unimportant; 7 = extremely important). We also elicited perspectives on roles of different practitioners in having these conversations. RESULTS: Questionnaires were returned by 770/1024 (75.2%) eligible clinicians. The most important perceived barriers were: family members' and patients' difficulty in accepting a poor prognosis (mean [SD] score 5.9 [1.1] and 5.7 [1.2], respectively), family members' and patients' lack of understanding about the limitations and harms of life-sustaining treatments (5.8 [1.1] and 5.7 [1.2], respectively), and lack of agreement among family members about goals of care (5.8 [1.2]). Interprofessional team members were viewed as having different but important roles in goals-of-care discussions. CONCLUSIONS: Cardiology clinicians perceive family and patient-related factors as the most important barriers to goals-of-care discussions in hospital. Many members of the interprofessional team were viewed as having important roles in addressing goals of care. These findings can inform the design of future interventions to improve communication about goals of care in advanced HF.

Cardiac Amyloidosis Phenotype Associated With a Glu89Lys Transthyretin Mutation.

We report a 45-year-old man with rapidly progressive cardiac amyloidosis, who required heart transplantation within 2 years of symptomatic onset. Hematologic testing and initial tissue biopsy results confirmed amyloid infiltration but were inconclusive for the amyloidogenic protein source. Mass spectroscopy and transthyretin (TTR) sequencing were required to reach a diagnosis of TTR amyloidosis resulting from a Glu89Lys mutation. Although a predominantly neuropathic phenotype has previously been described with this mutation, the present kinship documents a primarily cardiac presentation. This case report highlights the diagnostic challenge of TTR amyloidosis and the marked variability of the genotype-phenotype correlation.

Pulmonary Artery Abnormalities in Ex-smokers with and without Airflow Obstruction.

Pulmonary vascular disease is a common complication of chronic obstructive pulmonary disease (COPD), and an important risk factor for COPD exacerbations and death. We explored the relationship between pulmonary artery volumes measured using thoracic computed tomography (CT) and lung structure-function measured using spirometry, CT and magnetic resonance imaging (MRI) in 124 ex-smokers with (n = 68) and without (n = 56) airflow obstruction, and a control group of 35 never-smokers. We observed significantly greater main (p = .01), right (p = .001) and total (p = .003) pulmonary artery volumes in ex-smokers with airflow obstruction as compared to ex-smokers without airflow obstruction. There were also significantly greater pulmonary artery volumes in both ex-smoker subgroups, compared to the never-smoker subgroup (p = .008). For all participants, there were significant correlations for pulmonary artery volumes with the ratio of the forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), the diffusing capacity of the lung for carbon monoxide (DLCO%pred), airway count, MRI ventilation defect percent and MRI apparent diffusion coefficients. In ex-smokers, ventilation defect percent was significantly correlated with right (r = 0.27, p = .02) and total (r = 0.25, p = .03) pulmonary artery volumes. Multivariate zero-inflated Poisson regression analysis showed that FEV1%pred (p = .004), DLCO%pred (p = .03), the six minute walk distance (p = .04) and total pulmonary artery volume (p = .03) were significant predictors of acute exacerbations of COPD, while the number of previous exacerbations was not. In conclusion, pulmonary artery enlargement measured using thoracic CT was observed even in ex-smokers without airflow obstruction and was predictive of COPD exacerbations in ex-smokers with airflow obstruction.

An evidence-based approach to screening and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) continues to be a devastating disease, with a poor prognosis and high mortality rate if not treated early. Unfortunately, most patients are still diagnosed late in the course of the disease. Therefore, it is crucial to have a low threshold for suspecting PH and to refer patients early to specialized centres for diagnostic workup and management. In this article we focus on updated evidence-based screening and diagnosis in adults, based on the fifth World Symposium on Pulmonary Hypertension in 2013. The updated hemodynamic definition of PH includes a pulmonary vascular resistance > 3 Wood units. A new component to the hemodynamic definition of PH has been proposed in left heart disease, based on a diastolic pulmonary gradient (diastolic pulmonary arterial pressure - mean pulmonary artery wedge pressure), > 7 mm Hg. The term "borderline PH" for mean pulmonary artery pressures 21-24 mm Hg is discouraged, with emphasis on its significance for careful follow-up in high-risk patients, especially in systemic sclerosis. Annual pulmonary arterial hypertension (PAH) screening with a 2-step algorithm is recommended in asymptomatic systemic sclerosis patients. An updated simplified PH diagnostic algorithm approach is proposed. Genetic testing reveals mutations in bone morphogenic protein receptor type II in 70% of familial PAH, and is useful for screening asymptomatic family members. Important associated conditions that should be considered include thyroid disease, left heart disease, toxic causes, lung diseases (including pulmonary thromboembolism), hemolytic anemia, and human immunodeficiency virus infection. Biomarkers have been identified that correlate with PAH severity and mortality and are useful in follow-up.