Jorge Silva Enciso

Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor α-converting enzyme

Angiotensin-converting enzyme 2 (ACE2) is a newly identified regulator of the renin-angiotensin system. This type I membrane-anchored protein has a catalytically active ectodomain that undergoes shedding. Tumor necrosis factor alpha-converting enzyme (TACE) has been shown to be involved in ACE2 shedding. Although pathophysiological significance of ACE2 shedding has been suggested, regulation of this process by TACE is not clearly defined. We characterized TACE-mediated constitutive ectodomain shedding of ACE2 using wild-type Chinese Hamster Ovary (WT-CHO), the TACE-mutant M2 (M2-CHO) cells, and EC-4 and EC-2 cells that are fibroblasts from wild-type and TACE-null mice, respectively. ACE2 was constitutively cleaved to release two distinct major soluble forms. The deglycosylated molecular masses of the larger (LSF) and smaller soluble form (SSF) were approximately 80 and 70 kDa, respectively. These forms had equivalent enzyme activities. Reduced shedding for the LSF from M2-CHO and EC-2 cells when compared with WT-CHO and EC-4 cells, respectively, was noted. TACE reconstitution in EC-2 cells expressing ACE2 resulted in increase in LSF but not SSF release, demonstrating a main role of TACE in LSF release and distinct regulations of release of the two soluble forms. Deletions of the juxtamembrane region of ACE2 reduced LSF release in CHO cell lines, whereas it abolished TACE-induced shedding in EC-2 cells. Analysis of TACE structural domains confirmed that the active site in the catalytic domain is essential for ACE2 shedding but that noncatalytic domains also play additional roles. These results demonstrate selective and specific regulation of constitutive shedding of ACE2 by TACE.

Detection and Management of Geographic Disparities in the TOPCAT Trial: Lessons Learned and Derivative Recommendations

Summary TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) was a multinational clinical trial of 3,445 heart failure with preserved ejection fraction patients that enrolled in 233 sites in 6 countries in North America, Eastern Europe, and South America. Patients with a heart failure hospitalization in the last 12 months or an elevated B-type natriuretic peptide were randomized to the mineralocorticoid receptor antagonist spironolactone versus placebo. Sites in Russia and the Republic of Georgia provided the majority of early enrollment, primarily based on the hospitalization criterion because B-type natriuretic peptide levels were initially unavailable there. With the emergence of country-specific aggregate event rate data indicating lower rates in Eastern Europe and differences in patient characteristics there, the Data Safety and Monitoring Board recommended relatively increasing enrollment in North America plus other corrective measures. Although final enrollment reflected the increased contribution from North America, a plurality of the final cohort came from Russia and Georgia (49% vs. 43% in North America). B-type natriuretic peptide measurements from Russia and Georgia, available later in the trial, suggested no or a mild level of heart failure consistent with low event rates. The primary results showed no significant spironolactone treatment effect overall (primary endpoint hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 0.77 to 1.04), with a significant hazard ratio in North and South America (HR: 0.82; 95% CI: 0.69 to 0.98; p = 0.026) but not in Russia and Georgia (HR: 1.10; 95% CI: 0.79 to 1.51; interaction p = 0.12). This report describes the Data Safety and Monitoring Board’s detection and management recommendations for regional differences in patient characteristics in TOPCAT and suggests methods of surveillance and corrective actions that may be useful for future trials. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial [TOPCAT]; NCT00094302)

Mechanical Circulatory Support: Current Status and Future Directions

Advance heart failure (AHF) is a growing epidemic with high morbidity and mortality. Left ventricular assist device (LVAD) has come to offer an opportunity to improve survival and quality of life. This form of therapy however, is not free of complications and poses a challenge to apply to a broader population. Adjunct therapies in combination with LVAD therapy and advances in device technology are in the near future, which may lessen the number of adverse events. This review summarizes the history, clinical outcomes and current challenges facing LVAD therapy. Finally, future directions of LVADs in the treatment of AHF are discussed.

Functional Improvement After Ventricular Assist Device Implantation: Is Ventricular Recovery More Common Than We Thought?

He whos down one day can be up the next, unless he really wants to stay in bed, that is …—Miguel de Cervantes Saavedra, Don Quixote ([1][1]) Of the roughly 5.8 million Americans with heart failure, approximately 10% will have Stage D heart failure, defined as symptoms at rest despite optimal

Right ventricular failure after left ventricular assist device implant: ‘towards finding common ground’

In patients with advanced heart failure (HF), left ventricular assist devices (LVADs) offer an important treatment option as they have been shown to effectively unload the left ventricle while providing adequate perfusion of vital organs. The generally favourable impact of LVADs on quality of life and survival has resulted in their being considered as an alternative to heart transplantation [i.e. destination therapy (DT)] as well as a bridge to transplant (BTT). To date, more than 15 000 devices have been implanted throughout the world.1,2 However, the expanding use of LVADs has been accompanied by a commensurate rise in the number of complications. As the right ventricle remains unsupported with an LVAD alone, it is not surprising that patients whose right ventricle has been damaged (either by the same process that affected the left ventricle or as a consequence of long-standing increases in load caused by left ventricular failure) experience right ventricular failure (RVF) after LVAD implantation.3 Observational studies have reported an incidence of RVF after LVAD implantation of between 10 and 40%4 and when it occurs the consequences can be devastating. When RVF is of the severity that a right ventricular assist device is needed early post-LVAD implant, in-hospital mortality has been reported to be in the range of 30–50% making RVF an important cause of death after LVAD implant.4,5 The relatively wide range in incidence and outcomes reported for RVF are due to differences in definition, patient selection, and management. Although several risk scores exist for predicting RVF, they are limited by the fact that they are derived from data obtained from a single or a small number of centres, information was entered from different implant eras in which diverse ventricular assist device (VAD) types (pulsatile vs. continuous flow) were used, or mixed patient populations (BTT vs. DT) were included. Limited

Original InvestigationEditorial CommentOften Talked About, Seldom Seen: Promoting Myocardial Recovery With Ventricular Assist Device∗

Ventricular assist devices (VADs) have fundamentally changed the treatment of end-stage heart failure. However, despite great advances, long-term VAD use is still associated with frequent hospitalizations, serious complications, and a 2-year survival of approximately 70% [(1)][1]. Although

Often talked about, seldom seen: promoting myocardial recovery with ventricular assist device.

Ventricular assist devices (VADs) have fundamentally changed the treatment of end-stage heart failure. However, despite great advances, long-term VAD use is still associated with frequent hospitalizations, serious complications, and a 2-year survival of approximately 70% [(1)][1]. Although