HIV Promotes Atherosclerosis via Circulating Extracellular Vesicle MicroRNAs.

People living with HIV (PLHIV) are at a higher risk of having cerebrocardiovascular diseases (CVD) compared to HIV negative (HIVneg) individuals. The mechanisms underlying this elevated risk remains elusive. We hypothesize that HIV infection results in modified microRNA (miR) content in plasma extracellular vesicles (EVs), which modulates the functionality of vascular repairing cells, i.e., endothelial colony-forming cells (ECFCs) in humans or lineage negative bone marrow cells (lin- BMCs) in mice, and vascular wall cells. PLHIV (N = 74) have increased atherosclerosis and fewer ECFCs than HIVneg individuals (N = 23). Plasma from PLHIV was fractionated into EVs (HIVposEVs) and plasma depleted of EVs (HIV PLdepEVs). HIVposEVs, but not HIV PLdepEVs or HIVnegEVs (EVs from HIVneg individuals), increased atherosclerosis in apoE-/- mice, which was accompanied by elevated senescence and impaired functionality of arterial cells and lin- BMCs. Small RNA-seq identified EV-miRs overrepresented in HIVposEVs, including let-7b-5p. MSC (mesenchymal stromal cell)-derived tailored EVs (TEVs) loaded with the antagomir for let-7b-5p (miRZip-let-7b) counteracted, while TEVs loaded with let-7b-5p recapitulated the effects of HIVposEVs in vivo. Lin- BMCs overexpressing Hmga2 (a let-7b-5p target gene) lacking the 3'UTR and as such is resistant to miR-mediated regulation showed protection against HIVposEVs-induced changes in lin- BMCs in vitro. Our data provide a mechanism to explain, at least in part, the increased CVD risk seen in PLHIV.

MicroRNA-146a Induces Lineage-Negative Bone Marrow Cell Apoptosis and Senescence by Targeting Polo-Like Kinase 2 Expression.

OBJECTIVE: Lineage-negative bone marrow cells (lin- BMCs) are enriched in endothelial progenitor cells and mediate vascular repair. Aging-associated senescence and apoptosis result in reduced number and functionality of lin- BMCs, impairing their prorepair capacity. The molecular mechanisms underlying lin- BMC senescence and apoptosis are poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin- BMCs is a critical step in understanding the process of vascular repair. The aim of this study was to characterize the role of the miR-146a-Polo-like kinase 2 (Plk2) network in regulating lin- BMC senescence, apoptosis, and their angiogenic capability. APPROACH AND RESULTS: Transcriptome analysis in lin- BMCs isolated from young and aged wild-type and ApoE-/- (apolipoprotein E) mice showed a significant age-associated increase in miR-146a expression. In silico analysis, expression study and Luciferase reporter assay established Plk2 as a direct target of miR-146a. miR-146a overexpression in young lin- BMCs inhibited Plk2 expression, resulting in increased senescence and apoptosis, via p16Ink4a/p19Arf and p53, respectively, as well as impaired angiogenic capacity in vitro and in vivo. Conversely, suppression of miR-146a in aged lin- BMCs increased Plk2 expression and rejuvenated lin- BMCs, resulting in decreased senescence and apoptosis, leading to improved angiogenesis. CONCLUSIONS: (1) miR-146a regulates lin- BMC senescence and apoptosis by suppressing Plk2 expression that, in turn, activates p16Ink4a/p19Arf and p53 and (2) modulation of miR-146a or its target Plk2 may represent a potential therapeutic intervention to improve lin- BMC-mediated angiogenesis and vascular repair.

Long-term outcomes associated with the transaortic approach to transcatheter Aortic valve replacement.

OBJECTIVE: We investigated the long-term safety, efficacy and clinical outcomes associated with transaortic (TAO) transcatheter aortic valve replacement (TAVR) in the United States. BACKGROUND: We previously reported the technical feasibility and short-term safety of TAO TAVR. Compared to transapical (TAP) access, the TAO approach was associated with shorter median intensive care unit (ICU) length of stay (LOS) and more favorable technical learning curve. However, outcomes data beyond 30 days were lacking and the longer-term clinical consequences of this strategy were unknown. METHODS: Mortality outcomes at 1 year (and longer) of 44 consecutive patients who underwent TAO TAVR in our institution were compared with that of 76 consecutive patients who underwent TAP TAVR at our site. Risk-adjusted analysis was performed in propensity-matched patients (25 from each group) to account for baseline differences. RESULTS: TAO TAVR was associated with a trend towards lower all-cause mortality at 1 year compared to TAP TAVR (18% vs. 34%, P=0.09 in the overall sample; 12% vs. 40%, P=0.05 in the matched cohort). The higher probability of survival with TAO TAVR persisted after a median follow-up period of 23 months (hazard ratio [HR]=1.96, P=0.06 in the overall sample; HR=3.4, P=0.01 in the matched cohort). Cardiovascular mortality at 1 year was lower with TAO TAVR (2% vs. 22%, P=0.01 in the overall sample; 4% vs. 28%, P=0.05 in the matched cohort). ICU LOS (shorter in the TAO group) and implantation of second prosthetic valve (higher incidence in the TAP group) were independent predictors of long-term mortality. CONCLUSION: The outcomes associated with TAO TAVR compare favorably with TAP TAVR. Our results appear to corroborate the long-term safety and efficacy of the TAO approach in TAVR patients with inadequate iliofemoral access.

Clinical outcomes with on-label and off-label use of the transcatheter heart valve in the United States.

OBJECTIVE: We explored the efficacy, safety, and clinical consequences of on-label and off-label transcatheter aortic valve replacement (TAVR) in the real-world setting. BACKGROUND: The transcatheter heart valve (THV) was initially approved only for transfemoral (TF) delivery (on-label use) during TAVR in inoperable patients with severe aortic stenosis (AS). Because of lack of alternative options in TAVR-eligible patients with inadequate TF access, other routes have been utilized for THV implantation (off-label use), outcomes of which were previously unknown. METHODS: Consecutive patients with severe inoperable AS who underwent clinical TAVR at our site were enrolled in a prospective database. Fifty subjects underwent TF-TAVR (on-label group), while non-TF routes were utilized in 60 subjects (off-label group). Procedural events, 30-day clinical outcomes, and 1-year all-cause mortality data were analyzed. RESULTS: Technical device success was similar between on-label and off-label groups (88% vs. 87%, respectively; P = 0.92), as was the incidence of procedural complications and 30-day clinical events. The on-label group had lower 1-year all-cause death rate (12%) compared to the off-label group (32%; P = 0.02). The 1-year all-cause mortality in the off-label group was comparable to published clinical trial and registry data on TAVR, and appeared lower than historical outcomes with conservative medical therapy. CONCLUSION: On-label use of the THV in the real-world setting was associated with favorable survival outcomes compared to off-label TAVR and historical data. Off-label use of the THV appeared to be safe and effective when used in select patients with inoperable AS who are not eligible for TAVR via TF approach.

ECG-gated MDCT after aortic and mitral valve surgery.

OBJECTIVE: The purpose of this article is to review the utility of ECG-gated MDCT in evaluating postsurgical findings in aortic and mitral valves. Normal and pathologic findings after aortic and mitral valve corrective surgery are shown in correlation with the findings of the traditionally used imaging modalities echocardiography and fluoroscopy to assist in accurate noninvasive anatomic and dynamic evaluation of postsurgical valvular abnormalities. CONCLUSION: Because of its superior spatial and adequate temporal resolution, ECG-gated MDCT has emerged as a robust diagnostic tool in the evaluation and treatment of patients with postsurgical valvular abnormalities.

Mitral Regurgitation Complicated by Cardiogenic Shock: Reassessing Risk Stratification and Therapeutic Strategies.

Mitral regurgitation complicated by cardiogenic shock creates a unique and devastating risk profile for patients and poses significant difficulties for physicians who lack a comprehensive range of effective management strategies. Supportive measures such as intravenous vasodilators, intra-aortic balloon pumps, and percutaneous ventricular assist devices are often necessary to stabilize patients prior to definitive treatment with surgical mitral valve replacement or trans-catheter edge-to-edge repair. This review evaluates the evidence for the available supportive and definitive management strategies in patients with mitral regurgitation complicated by cardiogenic shock and presents a framework to aid clinicians in navigating the complex clinical decision-making process. Additionally, the authors review emerging transcatheter mitral valve replacement technologies that hold promise for expanding the therapeutic armamentarium and improving patient outcomes.

Functional Mitral Regurgitation: Patient Selection and Optimization.

Functional mitral regurgitation appears commonly among all heart failure phenotypes and can affect symptom burden and degree of maladaptive remodeling. Transcatheter mitral valve edge-to-edge repair therapies recently became an important part of the routine heart failure armamentarium for carefully selected and medically optimized candidates. Patient selection is considering heart failure staging, relevant comorbidities, as well as anatomic criteria. Indications and device platforms are currently expanding.

Contrast Ultrasound Assessment of Skeletal Muscle Recruitable Perfusion after Permanent Left Ventricular Assist Device Implantation: Implications for Functional Recovery.

BACKGROUND: In heart failure with reduced ejection fraction (HFrEF), abnormal regulation of skeletal muscle perfusion contributes to reduced exercise tolerance. The aim of this study was to test the hypothesis that improvement in functional status after permanent left ventricular assist device (LVAD) implantation in patients with HFrEF is related to improvement in muscle perfusion during work, which was measured using contrast-enhanced ultrasound (CEUS). METHODS: CEUS perfusion imaging of calf muscle at rest and during low-intensity plantar flexion exercise (20 W, 0.2 Hz) was performed in patients with HFrEF (n = 22) at baseline and 3 months after placement of permanent LVADs. Parametric analysis of CEUS data was used to quantify muscle microvascular blood flow (MBF), blood volume index, and red blood cell flux rate. For subjects alive at 3 months, comparisons were made between those with New York Heart Association functional class I or II (n = 13) versus III or IV (n = 7) status after LVAD. Subjects were followed for a median of 5.7 years for mortality. RESULTS: Echocardiographic data before and after LVAD placement and LVAD parameters were similar in subjects classified with New York Heart Association functional class I-II versus functional class III-IV after LVAD. Skeletal muscle MBF at rest and during exercise before LVAD implantation was also similar between groups. After LVAD placement, resting MBF remained similar between groups, but during exercise those with New York Heart Association functional class I or II had greater exercise MBF (111 ± 60 vs 52 ± 38 intensity units/sec, P = .03), MBF reserve (median, 4.45 [3.95 to 6.80] vs 2.22 [0.98 to 3.80]; P = .02), and percentage change in exercise MBF (median, 73% [-28% to 83%] vs -45% [-80% to 26%]; P = .03). During exercise, increases in MBF were attributable to faster microvascular flux rate, with little change in blood volume index, indicating impaired exercise-mediated microvascular recruitment. The only clinical or echocardiographic feature that correlated with post-LVAD exercise MBF was a history of diabetes mellitus. There was a trend toward better survival in patients who demonstrated improvement in muscle exercise MBF after LVAD placement (P = .05). CONCLUSIONS: CEUS perfusion imaging can quantify peripheral vascular responses to advanced therapies for HFrEF. After LVAD implantation, improvement in functional class is seen in patients with improvements in skeletal muscle exercise perfusion and flux rate, implicating a change in vasoactive substances that control resistance arteriolar tone.

Trends and Outcomes of Coronary Angiography and Percutaneous Coronary Intervention After Out-of-Hospital Cardiac Arrest Associated With Ventricular Fibrillation or Pulseless Ventricular Tachycardia.

Importance: The 2015 cardiopulmonary resuscitation and emergency cardiovascular care guidelines recommend performing coronary angiography in resuscitated patients after cardiac arrest with or without ST-segment elevation (STE). Objective: To assess the temporal trends, predictors, and outcomes of performing coronary angiography and percutaneous coronary intervention (PCI) in patients resuscitated after out-of-hospital cardiac arrest (OHCA) with initial rhythms of ventricular tachycardia or pulseless ventricular fibrillation (VT/VF). Design, Setting, and Participants: An observational analysis of the use of coronary angiography and PCI in 407 974 patients hospitalized after VT/VF OHCA from January 1, 2000, through December 31, 2012, from the Nationwide Inpatient Sample database. Multivariable analysis was used to assess factors associated with coronary angiography and PCI use. Data analysis was performed from December 12, 2015, to January 5, 2016. Main Outcomes and Measures: Temporal trends of coronary angiography, PCI, and survival to discharge in patients with VT/VF OHCA. Results: Among the 407 974 patients hospitalized after VT/VF OHCA, 143 688 (35.2%) were selected to undergo coronary angiography. The mean (SD) age of the total population was 65.7 (14.9) years, 37.9% were female, and 74.1% were white, 13.4% black, 6.8% Hispanic, and 5.7% other race. Use of coronary angiography increased from 27.2% in 2000 to 43.9% in 2012 (odds ratio, 2.47; 95% CI, 2.25-2.71; P for trend < .001), and PCI increased from 9.5% in 2000 to 24.1% in 2012 (odds ratio, 4.80; 95% CI, 4.21-5.66; P for trend < .001). From 2000 to 2012, coronary angiography and PCI after VT/VF OHCA increased in patients with STE (53.7% to 87.2%, P for trend < .001, and 29.7% to 77.3%, P for trend < .001, respectively) and those without STE (19.3% to 33.9%, P for trend < .001, and 3.5% to 11.8%, P for trend < .001, respectively). There was an associated increasing trend in survival to discharge in the overall population of patients with VT/VF OHCA (46.9% to 60.1%, P for trend < .001) in those with STE (59.2% to 74.3%, P for trend < .001) or without STE (43.3% to 56.8%, P for trend < .001). Conclusions and Relevance: Coronary angiography, PCI, and survival to discharge have increased in VT/VF OHCA survivors from event to hospitalization. However, a significant proportion of patients with VT/VF OHCA, especially those without STE, do not undergo coronary angiography and revascularization. Prospective studies are needed to determine whether this limitation has a survival effect.

New-onset atrial fibrillation after aortic valve replacement: comparison of transfemoral, transapical, transaortic, and surgical approaches.

OBJECTIVES: This study sought to determine the incidence of new-onset atrial fibrillation (AF) associated with different methods of isolated aortic valve replacement (AVR)-transfemoral (TF), transapical (TA), and transaortic (TAo) catheter-based valve replacement and conventional surgical approaches. BACKGROUND: The relative incidences of AF associated with the various access routes for AVR have not been well characterized. METHODS: In this single-center, retrospective cohort study, we evaluated a total of 231 consecutive patients who underwent AVR for degenerative aortic stenosis (AS) between March 2010 and September 2012. Patients with a history of paroxysmal, persistent, or chronic AF, with bicuspid aortic valves, and patients who died within 48 h after AVR were excluded. A total of 123 patients (53% of total group) qualified for inclusion. Data on documented episodes of new-onset AF, along with all clinical, echocardiographic, procedural, and 30-day follow-up data, were collated. RESULTS: AF occurred in 52 patients (42.3%). AF incidence varied according to the procedural method. AF occurred in 60% of patients who underwent surgical AVR (SAVR), in 53% after TA-TAVR, in 33% after TAo-TAVR cases, and 14% after TF-TAVR. The episodes occurred at a median time interval of 53 (25th to 75th percentile, 41 to 87) h after completion of the procedure. Procedures without pericardiotomy had an 82% risk reduction of AF compared with those with pericardiotomy (adjusted odds ratio: 0.18; 95% confidence interval: 0.05 to 0.59). CONCLUSIONS: AF was a common complication of AVR with a cumulative incidence of >40% in elderly patients with degenerative AS who underwent either SAVR or TAVR. AF was most common with SAVR and least common with TF-TAVR. Procedures without pericardiotomy were associated with a lower incidence of AF.

Transcatheter aortic valve replacement: techniques, complications, and bailout strategies.

Transcatheter aortic valve replacement has emerged as an alternative option for inoperable or very high-risk patients with severe aortic stenosis-however, there are serious complications associated with the procedure, such as patient mortality, stroke, conduction disturbances, paravalvular regurgitation, and vascular concerns. Our review focuses on the most common complications related to transcatheter aortic valve replacement procedures and potential bailout strategies and techniques.

Cholinergic neurons in the mouse rostral ventrolateral medulla target sensory afferent areas.

The rostral ventrolateral medulla (RVLM) primarily regulates respiration and the autonomic nervous system. Its medial portion (mRVLM) contains many choline acetyltransferase (ChAT)-immunoreactive (ir) neurons of unknown function. We sought to clarify the role of these cholinergic cells by tracing their axonal projections. We first established that these neurons are neither parasympathetic preganglionic neurons nor motor neurons because they did not accumulate intraperitoneally administered Fluorogold. We traced their axonal projections by injecting a Cre-dependent vector (floxed-AAV2) expressing either GFP or mCherrry into the mRVLM of ChAT-Cre mice. Transduced neurons expressing GFP or mCherry were confined to the injection site and were exclusively ChAT-ir. Their axonal projections included the dorsal column nuclei, medullary trigeminal complex, cochlear nuclei, superior olivary complex and spinal cord lamina III. For control experiments, the floxed-AAV2 (mCherry) was injected into the RVLM of dopamine beta-hydroxylase-Cre mice. In these mice, mCherry was exclusively expressed by RVLM catecholaminergic neurons. Consistent with data from rats, these catecholaminergic neurons targeted brain regions involved in autonomic and endocrine regulation. These regions were almost totally different from those innervated by the intermingled mRVLM-ChAT neurons. This study emphasizes the advantages of using Cre-driver mouse strains in combination with floxed-AAV2 to trace the axonal projections of chemically defined neuronal groups. Using this technique, we revealed previously unknown projections of mRVLM-ChAT neurons and showed that despite their close proximity to the cardiorespiratory region of the RVLM, these cholinergic neurons regulate sensory afferent information selectively and presumably have little to do with respiration or circulatory control.

The transaortic approach for transcatheter aortic valve replacement: initial clinical experience in the United States.

OBJECTIVES: This study sought to investigate the technical feasibility and safety of the transaortic (TAO) transcatheter aortic valve replacement (TAVR) approach in patients not eligible for transfemoral (TF) access by using a device commercially available in the United States. BACKGROUND: A large proportion of candidates for TAVR have inadequate iliofemoral vessels for TF access. The transapical route (TAP) is the current alternative but is associated with less favorable outcomes. Other access options need to be explored. METHODS: Forty-four consecutive patients with inoperable, severe aortic stenosis underwent TAO TAVR in our institution. Procedural and 30-day clinical outcomes data were compared with data from 76 consecutive patients who underwent TAP TAVR at our site. Technical learning curves were assessed by comparing outcomes of the first 20 cases with the subsequent patients who underwent each procedure. RESULTS: The TAO and TAP TAVR groups were similar in terms of device success according to Valve Academic Research Consortium criteria (89% vs. 84%; p = 0.59) and rates of the 30-day combined safety endpoint of all-cause mortality, myocardial infarction, major stroke, disabling bleeding, severe acute kidney injury, and valve reintervention (20% vs. 33%; p = 0.21). The TAO approach, compared with TAP TAVR, was associated with lower combined bleeding and vascular event rate (27% vs. 46%; p = 0.05), shorter median intensive care unit length of stay (3 vs. 6 days; p = 0.01), and a favorable learning curve. CONCLUSIONS: TAVR via the TAO approach is technically feasible, seems to be associated with favorable outcomes, and expands the current alternative options for access sites in patients with inoperable aortic stenosis who are ineligible for TF TAVR.