Recurrent Aortic Thromboembolism Associated With TET2 Mutation in Chronic Myelomonocytic Leukemia.

Ten-eleven translocation 2 (TET2) plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional regulation for inflammatory cytokines, particularly interleukin-6. While loss-of-function mutation in TET2 has been associated with hematological malignancies, it has been increasingly recognized to cause atherosclerotic disease. The increased atherogenicity is thought to be the result of increased production of pro-inflammatory interleukin-1ß cytokines following activation of NLRP3 inflammasomes. We present a unique case of recurrent atherothrombosis in an elderly man who was diagnosed with chronic myelomonocytic leukemia in the setting of TET2 mutation.

Rebalancing Work and Life for the Busy Physician.

Many argue that the concept of "work-life balance" is impossible to achieve for busy physicians. After spending years in medical training and building a career in health care, physicians often find their work encroaching upon other aspects of day-to-day life. Over the past decade, studies have shown that physician burnout, stress, depression, mental health, and general lack of well-being affect productivity, efficiency, and patient care. In this article, we will discuss the concept of "work-life balance" and recommend strategies to strive for a meaningful balance.

Mixed Venous Oxygen Saturation Is a Better Prognosticator Than Cardiac Index in Pulmonary Arterial Hypertension.

BACKGROUND: European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines include thermodilution cardiac index (TDCI) and mixed venous oxygen saturation (SvO2) as two of the three hemodynamic determinations used in risk assessment of patients with pulmonary arterial hypertension (PAH). SvO2 may be a better measurement than TDCI to assess prognosis in patients with either idiopathic or heritable PAH. RESEARCH QUESTION: What is the concordance between TDCI and SvO2 ESC/ERS risk group allocation and their prognostic value in patients with PAH? STUDY DESIGN AND METHODS: In this retrospective study, we assessed the correlation between SvO2 and TDCI in patients with idiopathic and heritable PAH. We determined concordance in the ESC/ERS risk group allocation and association with survival, both at baseline and follow-up. RESULTS: A total of 158 patients (mean age, 58 ± 17 years; 72% women) with idiopathic (91%) and heritable (9%) PAH were included. There was moderate association between TDCI and SvO2 (r = 0.50; 95% CI, 0.37-0.62). Weighted kappa revealed a fair agreement between TDCI and SvO2 (κ = 0.30; 95% CI, 0.18-0.42), with concordance in risk group allocation in 49% of patients. During a median follow-up of 45 months (interquartile range, 23-105), 62 patients (39%) died. Using Kaplan-Meier analysis, survival was impacted by the SvO2 (log rank = 0.002) but not by the TDCI risk group allocation (log-rank = 0.51). Using the Cox proportional hazard model, adjusted for age and sex, SvO2 (but not TDCI) was associated with mortality (hazard ratio per 1% change, 0.94; 95% CI, 0.91-0.97; P < .001). INTERPRETATION: When using the cutoffs proposed by the ESC/ERS guidelines, we noted poor concordance in risk score allocation between TDCI and SvO2. In patients with idiopathic or heritable PAH, SvO2 measurements are superior to TDCI in predicting long-term mortality.

A pilot study on the kinetics of metabolites and microvascular cutaneous effects of nitric oxide inhalation in healthy volunteers.

RATIONALE: Inhaled nitric oxide (NO) exerts a variety of effects through metabolites and these play an important role in regulation of hemodynamics in the body. A detailed investigation into the generation of these metabolites has been overlooked. OBJECTIVES: We investigated the kinetics of nitrite and S-nitrosothiol-hemoglobin (SNO-Hb) in plasma derived from inhaled NO subjects and how this modifies the cutaneous microvascular response. FINDINGS: We enrolled 15 healthy volunteers. Plasma nitrite levels at baseline and during NO inhalation (15 minutes at 40 ppm) were 102 (86-118) and 114 (87-129) nM, respectively. The nitrite peak occurred at 5 minutes of discontinuing NO (131 (104-170) nM). Plasma nitrate levels were not significantly different during the study. SNO-Hb molar ratio levels at baseline and during NO inhalation were 4.7E-3 (2.5E-3-5.8E-3) and 7.8E-3 (4.1E-3-13.0E-3), respectively. Levels of SNO-Hb continued to climb up to the last study time point (30 min: 10.6E-3 (5.3E-3-15.5E-3)). The response to acetylcholine iontophoresis both before and during NO inhalation was inversely associated with the SNO-Hb level (r: -0.57, p = 0.03, and r: -0.54, p = 0.04, respectively). CONCLUSIONS: Both nitrite and SNO-Hb increase during NO inhalation. Nitrite increases first, followed by a more sustained increase in Hb-SNO. Nitrite and Hb-SNO could be a mobile reservoir of NO with potential implications on the systemic microvasculature.

Treatment Barriers in Portopulmonary Hypertension.

Portopulmonary hypertension (PoPH) is a form of pulmonary arterial hypertension (PAH) that can develop as a complication of portal hypertension. Treatment of PoPH includes PAH-specific therapies, and in certain cases, such therapies are necessary to facilitate a successful liver transplantation. A significant number of barriers may limit the adequate treatment of patients with PoPH and explain the poorer survival of these patients when compared to patients with other types of PAH. Until recently, only one randomized controlled trial has included PoPH patients, and the majority of treatment data have been derived from relatively small observational studies. In the present article, we review some of the barriers in the treatment of patients with PoPH and implications for liver transplantation.

Effect of abnormal right heart structures on the diagnosis of pulmonary hypertension.

The diagnosis of pulmonary hypertension (PH) requires a right heart catheterization (RHC) that reveals a mean pulmonary artery pressure ≥ 25 mmHg. The pulmonary artery catheter traverse the right atrium and ventricle on its way to the pulmonary artery. The presence of abnormal right heart structures, i.e. thrombus, vegetation, benign or malignant cardiac lesions, can lead to complications during this procedure. On the other hand, avoidance of RHC delays the diagnosis and treatment of PH, an approach that might be associated with worse outcomes. This paper discusses the impact of right heart lesions on the diagnosis of PH and suggests an approach on how to manage this association.

Serum Chloride Levels Track With Survival in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Serum chloride is an important homeostatic biomarker in left heart failure, with significant prognostic implications. The impact of serum chloride in the long-term survival of patients with pulmonary arterial hypertension (PAH) is unknown. We tested whether serum chloride levels are associated with long-term survival in patients with PAH. METHODS: We included patients with idiopathic or heritable PAH who had a basic metabolic panel performed at the time of their diagnostic right heart catheterization. Laboratory results were recorded both at diagnosis and 6-month follow-up. RESULTS: We included 277 patients, mean age 51 ± 18 years and 73% women, of whom 254 had a follow-up electrolyte determination at 6 months. Serum chloride was 102.9 ± 3.9 mM/L at diagnosis. A serum chloride ≤ 100 mM/L was noted in 65 (24%) and 53 (21%) patients at diagnosis and 6 months, respectively. Patients with serum chloride ≤ 100 mM/L at 6 months tracked with increase mortality when adjusted by age, sex, pulmonary vascular resistance, diuretics or prostacyclin analogs usage, and serum creatinine and sodium at 6 months (hazard ratio, 1.83; 95% CI, 1.11-3.00). This group of patients was older, with decreased functional capacity, had worse renal function, took more diuretics, had higher pulmonary artery wedge pressure but lower mean pulmonary artery pressure, transpulmonary gradient, and pulmonary vascular resistance. CONCLUSIONS: Serum chloride at 6 months from the PAH diagnosis is a strong and independent predictor of mortality in patients with idiopathic or heritable PAH, even after adjusting serum sodium, renal function, diuretic, and prostacyclin analog usage.

Hypoxemia in patients with idiopathic or heritable pulmonary arterial hypertension.

BACKGROUND: The prevalence and prognostic implications of hypoxemia either at rest or during six-minute walk test (6MWT) in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH or HPAH) have not been systemically studied. OBJECTIVES: We sought to determine the prevalence, phenotypic and prognostic implications of hypoxemia in patients with IPAH and HPAH. METHODS: Patients with IPAH or HPAH were identified from the Cleveland Clinic Pulmonary Hypertension Registry. Pulse oximetry (SpO2) at rest and during 6MWT was used to define hypoxemia at rest or during activities when measurements were lower than 90%, respectively. RESULTS: A total of 292 patients (age 50.6 ± 18.0 years, 73% females) with IPAH (88%) and HPAH (12%) were included. Of them, 143 (49%) had SpO2 >90% at rest and during 6MWT, 89 (31%) subjects had hypoxemia during 6MWT and 60 (20%) had hypoxemia at rest. Patients with hypoxemia had older age, greater body mass index, higher prevalence of cardiovascular risk factors, worse functional capacity and pulmonary function tests but less severe pre-capillary pulmonary hypertension. Individuals with hypoxemia either at rest or during the initial 6MWT had worse long-term survival when compared to subjects without hypoxemia, even when adjusting for a great number of potential confounders. (HR: 2.5 (95% CI: 1.54-3.98)). CONCLUSIONS: Hypoxemia in patients with IPAH and HPAH is associated with more comorbidities, less severe pre-capillary pulmonary hypertension and worse survival.

Different efficacy of inhaled and oral medications in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is progressive disorder characterized by elevated pulmonary vascular resistance that can lead to right heart failure and death. One of the main therapeutic options for PAH are medications targeting the prostacyclin pathway. Treprostinil is a prostacyclin analogue and selexipag is a selective IP receptor agonist. Treprostinil can be delivered by a variety of routes including oral, inhaled, subcutaneous and intravenous. Selexipag is currently approved as an oral formulation. The impact of the route of delivery and the optimal dosing for transitioning inhaled treprostinil to oral treprostinil or selexipag is unknown. More importantly, given the different selectivity for prostacyclin receptors, it is uncertain whether treprostinil and selexipag can be substituted. We present two patients with PAH who received medications targeting the prostacyclin pathway and were transitioned from inhaled treprostinil to either oral treprostinil or selexipag. In both cases, we noted clinical, functional and hemodynamic deterioration. These cases highlight that the route of delivery (inhaled versus oral) and/or the specific PH medication (treprostinil versus selexipag) matter; therefore close monitoring during transitions is imperative.