Post Pulmonary Embolism Phenotypes Described by Invasive Cardiopulmonary Exercise Testing.

BACKGROUND: Post pulmonary embolism (PE) dyspnea is common. Existing non-invasive studies have demonstrated that post PE dyspnea is associated with elevations in right ventricular afterload, dead space ventilation, and deconditioning. We aimed to use invasive cardiopulmonary exercise testing (iCPET) parameters in patients with post PE dyspnea to identify unique physiologic phenotypes. RESEARCH QUESTION: Are there distinct post pulmonary embolism dyspnea physiologic phenotypes described with iCPET? STUDY DESIGN AND METHODS: Patients were enrolled at the time of acute PE and through our pulmonary hypertension and dyspnea clinic. ICPET was performed if there was high suspicion for pulmonary hypertension or if there was unexplained dyspnea. A hierarchical cluster analysis was performed to identify dyspnea phenotypes. ICPET parameters assessing pulmonary hemodynamics, ventilation, and peripheral oxygen utilization were then compared within and across each cluster and with iCPET controls against peak oxygen consumption (Peak VO2). RESULTS: 173 patients were enrolled. Sixty-seven patients underwent iCPET. All patients had reductions in Peak VO2 and peak cardiac index relative to controls. Three clusters were identified. Cluster one was defined by having elevated RV afterload and impaired ventilatory efficiency. Cluster two had elevated RV afterload with reductions in respiratory mechanics. Cluster three had mild derangement in RV afterload with mild reductions in peak cardiac output. INTERPRETATION: iCPET reveals significant heterogeneity in post PE dyspnea. Three phenotypes are characterized by differences in RV afterload, ventilatory efficiency, respiratory mechanics, and peripheral oxygen utilization.

Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension.

BACKGROUND: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. METHODS: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO2peak)>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. RESULTS: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P=0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P=0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P=0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. CONCLUSIONS: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.

Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension.

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RVFnRec). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. Methods: We evaluated 63 incident patients with PAH by right heart catheterization and cardiac MRI (CMR) at diagnosis and CMR and invasive cardiopulmonary exercise (CPET) following treatment (∻11 months). Sex, age, race/ethnicity matched healthy control subjects (n=62) with one-time CMR and non-invasive CPET were recruited from the PVDOMICS project. We examined therapeutic CMR changes relative to the evidence-based peak oxygen consumption (VO2 peak )>15mL/kg/min to define RVFnRec by receiver operating curve analysis. Afterload was measured in the as mean pulmonary artery pressure, resistance, compliance, and elastance. Results: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (AUC 0.87, P=0.0001) and neared upper 95% CI RVEDV of controls. 22/63 (35%) of subjects met this cutoff which was reinforced by freedom from clinical worsening, RVFnRec 1/21 (5%) versus no RVFnRec 17/42, 40%, (log rank P=0.006). A therapy-associated increase of 0.8 mL/mmHg in compliance had the best predictive value of RVFnRec (AUC 0.76, CI 0.64-0.88, P=0.001). RVFnRec subjects had greater increases in stroke volume, and cardiac output at exercise. Conclusions: RVFnRec defined by RVEDV therapeutic decrease of -15mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise. Clinical Perspective: What is new?: Right ventricular functional recovery (RVFnRec) represents a novel endpoint of therapeutic success in PAH. We define RVFnRec as treatment associated normative RV changes related to function (peak oxygen consumption). Normative RV imaging changes are compared to a well phenotyped age, sex, and race/ethnicity matched healthy control cohort from the PVDOMICS project. Previous studies have focused on RV ejection fraction improvements. However, we show that changes in RVEDV are perhaps more important in that improvements in LV function also occur. Lastly, RVFnRec is best predicted by improvements in pulmonary artery compliance versus pulmonary vascular resistance, a more often cited metric of RV afterload.What are the clinical implications?: RVFnRec represents a potential non-invasive assessment of clinical improvement and therapeutic response. Clinicians with access to cardiac MRI can obtain a limited scan (i.e., ventricular volumes) before and after treatment. Future study should examine echocardiographic correlates of RVFnRec.

Statin-Induced Triad of Autoimmune Myocarditis, Myositis, and Transaminitis.

Despite well-established cardiovascular benefits, statins have been associated with myopathic side effects ranging from myalgias to rhabdomyolysis and autoimmune necrotizing myositis. Statins have not been previously shown to cause myocarditis. Our case highlights this rare entity.

Clinical implications of idiopathic pulmonary arterial hypertension phenotypes defined by cluster analysis.

BACKGROUND: >Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters. METHODS: Patients with IPAH from 2 referral centers (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Patients were classified according to cluster analysis and followed for clinical worsening occurrence. RESULTS: The cluster analysis identified 4 IPAH phenotypes. Cluster 1 was characterized by young patients, mild pulmonary hypertension (PH), mild right ventricular (RV) dilation and high oxygen (O2) pulse; Cluster 2 by severe PH and RV dilation and high O2 pulse; and Cluster 3 by male patients, severe PH and RV dilation, and low O2 pulse. Cluster 4 patients were older and overweight, with mild PH and RV dilation and low O2 pulse. After a mean follow-up of 995 ± 623 days, 123 (48.8%) patients had clinical worsening. Cluster 1 patients presented the best prognosis, whereas Cluster 3 had the highest rates of clinical worsening. Compared with Cluster 1, risk of clinical worsening ranged from 4.12 (confidence interval [CI] 1.43-11.92; p = 0.009) for Cluster 4 to 7.38 (CI 2.80-19.40) for Cluster 2 and 13.8 (CI 5.60-34.0; p = 0.0001) for Cluster 3. CONCLUSIONS: Cluster analysis of clinical variables identified 4 distinct phenotypes of IPAH. Our findings underscore the high degree of disease heterogeneity that exists within patients with IPAH and the need for advanced clinical testing to define phenotypes to improve treatment strategy decision-making. CONDENSED ABSTRACT Idiopathic pulmonary arterial hypertension (IPAH) characterization is based on criteria that may not adequately capture disease heterogeneity. The aim of this study was to apply cluster analysis to improve phenotyping of IPAH. Patients with IPAH (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Within the umbrella category of IPAH, it was the combination of mean pulmonary arterial pressure, right ventricular size, and oxygen pulse that further stratified patients into novel IPAH phenotypes that significantly associate with clinical worsening. These findings underscore the need for novel multidimensional IPAH phenotyping for improved patient care and trial quality.

Methods for Evaluating Right Ventricular Function and Ventricular-Arterial Coupling.

Right ventricular function (RVF) carries great prognostic significance in heart failure and pulmonary hypertension (PH). Although there is considerable focus on RVF in pulmonary arterial hypertension, RVF is also of great importance in group 2 PH. This article will discuss assessment of RVF and evaluation of the Right Ventricle-Pulmonary Artery (RV-PA) coupling relationship. Cardiac imaging modalities allow direct visualization and assessment of RVF. Imaging modalities include the commonly utilized echo-Doppler imaging evaluating RV fractional area change, tricuspid annular plane systolic excursion and Tissue Doppler Imaging, in addition to the increasingly utilized cardiac magnetic resonance. Invasive hemodynamic assessment also plays an important role and can also be employed during exercise to help elucidate functional reserve. Cardiopulmonary exercise testing provides added insight into the mechanisms of cardiopulmonary disease. Cardiac imaging, invasive hemodynamics, and gas exchange stress testing can be combined to give a more sophisticated understanding of RVF. The RV-PA coupling relationship can be assessed using practical and clinically available metrics in order to gain clinically relevant understanding of the patients' physiologic state. RV-PA coupling assessments can be done using invasive, combined noninvasive-invasive, or non-invasive approaches. We also discuss our approaches in the assessment of the RV-PA coupling relationship.

Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor ß (TGFß) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like "Sma/Mab" signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development.

Developing the inner scientist: book club participation and the nature of science.

The leap from science student to scientist involves recognizing that science is a tentative, evolving body of knowledge that is socially constructed and culturally influenced; this is known as The Nature of Science (NOS). The aim of this study was to document NOS growth in first-year premedical students who participated in a science book club as a curricular option. The club read three acclaimed nonfiction works that connect biology to medicine via the history of scientific ideas. Students' NOS status was assessed as informed, transitional, or naïve at the beginning and end of the academic year using the Views of Nature of Science Questionnaire-Form C (VNOS-C). Focus group interviews and document analysis of assignments and exams provided qualitative evidence. VNOS-C scores improved over the academic year regardless of book club participation. Students who participated in book club had marginally better NOS status at the end of the year but also at the beginning, suggesting that book club may have attracted rather than produced students with higher NOS status. It is notable that an improvement in NOS understanding could be detected at all, as there have been few reports of NOS growth in the literature in which NOS was not an explicit topic of instruction.