Chymase in Plasma and Urine Extracellular Vesicles: Novel Biomarkers for Primary Hypertension.

BACKGROUND: Extracellular vesicles (EVs) have emerged as a promising liquid biopsy for various diseases. For the first time, using plasma and urinary EVs, we assessed the activity of renin-angiotensin system (RAS), a central regulator of renal, cardiac, and vascular physiology, in patients with control (Group I) or uncontrolled (Group II) primary hypertension. METHODS: EVs were isolated from 34 patients with history of hypertension, and characterized for size and concentration by nanoparticle tracking analyses, exosomal biomarkers by immunogold labeling coupled with transmission electron microscopy, flow cytometry and immunoblotting. EVs were analyzed for the hydrolytic activity of chymase, angiotensin converting enzyme (ACE), ACE2, and neprilysin (NEP) by HPLC. RESULTS: Plasma and urinary EVs were enriched for small EVs and expressed exosomal markers (CD63, CD9, and CD81). The size of urinary EVs (but not plasma EVs) was significantly larger in Group II compared to Group I. Differential activity of RAS enzymes was observed, with significantly higher chymase activity compared to ACE, ACE2, and NEP in plasma EVs. Similarly, urinary EVs exhibited higher chymase and NEP activity compared to ACE and ACE2 activity. Importantly, compared to Group I, significantly higher chymase activity was observed in urinary EVs (p = 0.03) from Group II, while no significant difference in activity was observed for other RAS enzymes. CONCLUSIONS: Bioactive RAS enzymes are present in plasma and urinary EVs. Detecting chymase in plasma and urinary EVs uncovers a novel mechanism of angiotensin II-forming enzyme and could also mediate cell-cell communication and modulate signaling pathways in recipient cells.

Does the Naked Emperor Parable Apply to Current Perceptions of the Contribution of Renin Angiotensin System Inhibition in Hypertension?

PURPOSE OF REVIEW: To address contemporary hypertension challenges, a critical reexamination of therapeutic accomplishments using angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, and a greater appreciation of evidence-based shortcomings from randomized clinical trials are fundamental in accelerating future progress. RECENT FINDINGS: Medications targeting angiotensin II mechanism of action are essential for managing primary hypertension, type 2 diabetes, heart failure, and chronic kidney disease. While the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to control blood pressure is undisputed, practitioners, hypertension specialists, and researchers hold low awareness of these drugs' limitations in preventing or reducing the risk of cardiovascular events. Biases in interpreting gained knowledge from data obtained in randomized clinical trials include a pervasive emphasis on using relative risk reduction over absolute risk reduction. Furthermore, recommendations for clinical practice in international hypertension guidelines fail to address the significance of a residual risk several orders of magnitude greater than the benefits. We analyze the limitations of the clinical trials that have led to current recommended treatment guidelines. We define and quantify the magnitude of the residual risk in published hypertension trials and explore how activation of alternate compensatory bioprocessing components within the renin angiotensin system bypass the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to achieve a significant reduction in total and cardiovascular deaths. We complete this presentation by outlining the current incipient but promising potential of immunotherapy to block angiotensin II pathology alone or possibly in combination with other antihypertensive drugs. A full appreciation of the magnitude of the residual risk associated with current renin angiotensin system-based therapies constitutes a vital underpinning for seeking new molecular approaches to halt or even reverse the cardiovascular complications of primary hypertension and encourage investigating a new generation of ACE inhibitors and ARBs with increased capacity to reach the intracellular compartments at which Ang II can be generated.

Feast or famine? The variable impact of coexisting fellowships on general surgery resident operative volumes.

OBJECTIVES: Nearly 80% of general surgery residents (GSR) pursue Fellowship training. We hypothesized that fellowships coexisting with general surgery residencies do not negatively impact GSR case volumes and that fellowship-bound residents (FBR) preferentially seek out cases in their chosen specialty ("early tracking"). METHODS: To test our hypotheses, we analyzed the Accreditation Council for Graduate Medical Education Surgical Operative Log data from 2009 American Board of Surgery qualifying examination applicants (N = 976). General surgery programs coexisted with 35 colorectal (CR), 97 vascular (Vasc), 80 minimally invasive (MIS), and 12 Endocrine (Endo) fellowships. We analyzed (1) operative cases for general surgery residency programs with and without coexisting Fellowships, comparing caseloads for FBR and all GSR and (2) operative cases of FBR in their chosen specialties compared to all other GSR. Group means were compared using ANOVA with significance set at P < 0.01. RESULTS: Coexisting fellowships had minimal impact on GSR caseloads. Endocrine fellowships actually enhanced case volumes for all residents. CR impact was neutral while MIS and vascular fellowships resulted in small declines. Endo, CR, and Vasc but not MIS FBR performed significantly more cases in their future specialties than their GSR counterparts, consistent with self-directed, prefellowship tracking. Tracking seems to be additive and FBR do not sacrifice other GSR cases. CONCLUSIONS: Our data establish that the impact of Fellowships on GSR caseloads is minimal. Our data confirm that FBR seek out cases in their future specialties ("early tracking").