Estrogen receptor-α prevents right ventricular diastolic dysfunction and fibrosis in female rats.

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ERα-regulated pathways in RV pressure overload.

Patterns of opioid use in dialysis access procedures.

BACKGROUND: Overprescription of opioids after surgical procedures is recognized as an important contributor to opioid misuse. Dialysis access procedures are commonly performed outpatient operations with few data or guidelines to inform prescription pain management practices. We sought to characterize opioid pain medication use after dialysis access surgery to promote a conservative approach to postoperative opioid prescriptions. METHODS: We performed a retrospective review of patients who underwent surgical dialysis access procedures from August 2018 through January 2019. Patient-reported opioid use information was captured in a brief questionnaire administered during routine follow-up appointments or phone calls and recorded in the electronic medical record. The procedure, type of intraoperative anesthesia or analgesia, postoperative prescription provided, and patient factors (including age, sex, dialysis type, history of chronic pain, and preoperative opioid or benzodiazepine use) were recorded. All procedures were classified by type (arteriovenous fistula or graft with a short incision [AVF-S], arteriovenous fistula or graft with a long incision [AVF-L], or peritoneal dialysis [PD] catheter), and descriptive statistics were performed using R (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Eighty-six patients underwent dialysis access procedures in the study time frame, of whom 63 were administered the pain questionnaire and 58 quantified opioid use; 85% of patients received a prescription, but 31% took no opioids and 71% used opioids for ≤2 days. Interquartile ranges (25th-75th percentile) of prescription and consumption quantities for patients who underwent AVF-L procedures were 10 to 28 pills and 2.5 to 20 pills; for patients who underwent AVF-S, quantities were 4.0 to 8.4 pills and 0 to 4.3 pills; and PD quantities were 10 pills and 3.3 to 9 pills. Thirty-one patients (53%) reported receiving more pain medication than they used, which resulted in a median of 8 excess pills per patient with an unused pill interquartile range of 0 to 22 pills for AVF-L procedures, 0 to 4.2 pills for AVF-S procedures, and 1.3 to 6.7 pills for PD procedures. Patients who were prescribed oxycodone or had a repeated operation had significantly increased opioid use. CONCLUSIONS: This investigation of opioid use after surgical dialysis access procedures suggests that most patients use relatively few opioid pills after surgery, which translates into overprescription and leftover medication for >50% of patients. A conservative approach to postoperative prescription guidelines using lower prescription quantities would encourage opioid-related risk reduction while providing adequate postoperative analgesia. Recommended quantities for postoperative prescriptions were generated using the 80th percentile consumed and were 0 to 6 pills for brachiobasilic or brachiocephalic fistulas, 0 to 5 pills for basilic vein transposition, 0 to 5 pills for radiocephalic AVF, 0 to 15 pills for upper arm grafts, and 0 to 10 pills for PD catheter placement.

Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function.

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.

Characteristics and Timing of Interhospital Transfers of Emergency General Surgery Patients.

BACKGROUND: Transferred emergency general surgery (EGS) patients have increased morbidity, mortality, and costs, yet little is known about the characteristics of such transfers. Increasing specialization and a decreasing general surgery workforce have led to concerns about access to care, which may lead to increased transfers. We sought to evaluate the reasons for and timing of transfers for EGS diagnoses. METHODS: We performed a retrospective medical record review of patients transferred to a tertiary academic medical center between January 4, 2014 and March 31, 2016 who had an EGS diagnosis (bowel obstruction, appendicitis, cholecystitis/cholangitis/choledocholithiasis, diverticulitis, mesenteric ischemia, perforated viscus, or postoperative surgical complication). RESULTS: Three hundred thirty-four patients were transferred from 70 hospitals. Transfer reasons varied with the majority due to the need for specialized services (44.3%) or a surgeon (26.6%). Imaging was performed in 95.8% and 35.3% had surgeon contact before transfer. The percentage of patients who underwent procedures at referring facilities was 7.5% (n = 25), while 60.6% (n = 83) underwent procedures following transfer. Mean time between transfer request and arrival at the accepting hospital was lower for patients who subsequently underwent a procedure at the accepting hospital compared to those who did not for patients originating in emergency departments (2.6 versus 3.4 h, P < 0.05) and inpatient units (6.9 versus 14.3 h, P < 0.05). CONCLUSIONS: Interhospital transfers for EGS conditions are frequently motivated by a need for a higher level of care or specialized services as well as a need for a general surgeon. Understanding reasons for transfers can inform decisions regarding the allocation and provision of care for this vulnerable population.

Right Ventricular-Pulmonary Vascular Interactions.

Accurate and comprehensive evaluation of right ventricular (RV)-pulmonary vascular (PV) interactions is critical to the assessment of cardiopulmonary function, dysfunction, and failure. Here, we review methods of quantifying RV-PV interactions and experimental results from clinical trials as well as large- and small-animal models based on pressure-volume analysis. We conclude by outlining critical gaps in knowledge that should drive future studies.

Multiscale structure-function relationships in right ventricular failure due to pressure overload.

Right ventricular (RV) failure (RVF) is the major cause of death in pulmonary hypertension. Recent studies have characterized changes in RV structure in RVF, including hypertrophy, fibrosis, and abnormalities in mitochondria. Few, if any, studies have explored the relationships between these multiscale structural changes and functional changes in RVF. Pulmonary artery banding (PAB) was used to induce RVF due to pressure overload in male rats. Eight weeks postsurgery, terminal invasive measurements demonstrated RVF with decreased ejection fraction (70 ± 10 vs. 45 ± 15%, sham vs. PAB, P < 0.005) and cardiac output (126 ± 40 vs. 67 ± 32 ml/min, sham vs. PAB, P < 0.05). At the organ level, RV hypertrophy was directly correlated with increased contractility, which was insufficient to maintain ventricular-vascular coupling. At the tissue level, there was a 90% increase in fibrosis that had a direct correlation with diastolic dysfunction measured by reduced chamber compliance ( r2 = 0.43, P = 0.008). At the organelle level, transmission electron microscopy demonstrated an abundance of small-sized mitochondria. Increased mitochondria was associated with increased ventricular oxygen consumption and reduced mechanical efficiency ( P < 0.05). These results demonstrate an association between alterations in mitochondria and RV oxygen consumption and mechanical inefficiency in RVF and a link between fibrosis and in vivo diastolic dysfunction. Overall, this work provides key insights into multiscale RV remodeling in RVF due to pressure overload. NEW & NOTEWORTHY This study explores the functional impact of multiscale ventricular remodeling in right ventricular failure (RVF). It demonstrates correlations between hypertrophy and increased contractility as well as fibrosis and diastolic function. This work quantifies mitochondrial ultrastructural remodeling in RVF and demonstrates increased oxygen consumption and mechanical inefficiency as features of RVF. Direct correlation between mitochondrial changes and ventricular energetics provides insight into the impact of organelle remodeling on organ level function.

Natural history of the proximal aorta in patients with descending thoracic aortic disease.

OBJECTIVE: This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease. METHODS: We examined 200 patients with descending thoracic aortic disease including acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow-up (n = 108). Survival data were derived from all 200 patients in this study. RESULTS: Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 ± 0.51 cm in the root, 3.67 ± 0.48 cm in the ascending aorta, and 3.50 ± 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 ± 0.64 mm/y, 0.26 ± 0.44 mm/y, and 0.25 ± 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter ≥4.1 cm grew faster than those <4.1 cm at the ascending aorta (P = .028) and proximal arch (P = .019). There was no difference in aortic growth rates at the aortic root (P = .887). After the index scan, five patients underwent six ascending aortic replacement procedures, leading to a 3% ascending aortic intervention rate. Overall median life expectancy was 86.15 years. CONCLUSIONS: Native ascending aortic growth in patients with descending thoracic aortic disease is slow. We suggest regular follow-up for index ascending aorta ≥4.1 cm because of its larger initial size and more rapid growth.

Multiscale Computational Analysis of Right Ventricular Mechanoenergetics.

Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO.

Acute retrograde type A aortic dissection: morphologic analysis and clinical implications.

BACKGROUND: This study compares the morphology and outcomes of acute retrograde type A dissections (RTADs) with acute antegrade type A dissections (ATADs), and acute type B dissections. MATERIALS AND METHODS: From 2000 to 2016, there were 12 acute RTADs, 96 ATADs, and 92 type B dissections with available imaging. Dissections were characterized using computerized tomography angiography images. We examined clinical features, tear characteristics, and various morphologic measurements. RESULTS: Compared with acute type B dissections, RTAD primary tears were more common in the distal arch (75% versus 43%, P = 0.04), and the false-to-true lumen contrast intensity ratio at the mid-descending thoracic aorta was lower (0.46 versus 0.71, P = 0.020). RTAD had less false lumen decompression because there were fewer aortic branch vessels distal to the subclavian that were perfused through the false lumen (0.40 versus 2.19, P < 0.001). Compared with ATAD, RTAD had less root involvement where root true-to-total lumen area ratio was higher (0.88 versus 0.76, P = 0.081). Furthermore, RTAD had a lower false-to-true lumen contrast intensity ratio at the root (0.25 versus 0.57, P < 0.05), ascending aorta (0.25 versus 0.72, P < 0.001), and proximal arch (0.39 versus 0.67, P < 0.05). RTAD were more likely to undergo aortic valve resuspension (100% versus 74%, P = 0.044). CONCLUSIONS: RTAD tends to occur when primary tears occur in close proximity to the aortic arch and when false lumen decompression through the distal aortic branches are less effective. Compared with ATAD, RTAD has less root involvement, and successful aortic valve resuspension is more likely.

ß-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.

Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). ß-Arrestins are important signaling molecules involved in ß-adrenergic receptor (ß-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that ß-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased collagen synthesis, and myocardial fibrosis which are important in the development of HF. ß-Arrestin1 & 2 expression is significantly upregulated in adult human CF isolated from failing left ventricles and ß-AR signaling is uncoupled with loss of ß-agonist-mediated inhibition of collagen synthesis versus normal control CF. Knockdown of either ß-arrestin1 or 2 restored ß-AR signaling and ß-agonist mediated inhibition of collagen synthesis. Overexpression of ß-arrestins in normal CF led to a failing phenotype with increased baseline collagen synthesis, impaired ß-AR signaling, and loss of ß-agonist-mediated inhibition of collagen synthesis. ß-Arrestin knockdown in failing CF diminished TGF-ß stimulated collagen synthesis and also inhibited ERK phosphorylation. Overexpression of ß-arrestins in normal CF increased basal ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-ß-stimulated collagen synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Enhanced ß-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic phenotype via uncoupling of ß-AR signaling as well as potentiating ERK and Smad signaling. Targeted inhibition of ß-arrestins in CF may represent a therapeutic strategy to prevent maladaptive myocardial fibrosis.

Biomechanical and Mechanobiological Drivers of the Transition From PostCapillary Pulmonary Hypertension to Combined Pre-/PostCapillary Pulmonary Hypertension.

Combined pre-/postcapillary pulmonary hypertension (Cpc-PH), a complication of left heart failure, is associated with higher mortality rates than isolated postcapillary pulmonary hypertension alone. Currently, knowledge gaps persist on the mechanisms responsible for the progression of isolated postcapillary pulmonary hypertension (Ipc-PH) to Cpc-PH. Here, we review the biomechanical and mechanobiological impact of left heart failure on pulmonary circulation, including mechanotransduction of these pathological forces, which lead to altered biological signaling and detrimental remodeling, driving the progression to Cpc-PH. We focus on pathologically increased cyclic stretch and decreased wall shear stress; mechanotransduction by endothelial cells, smooth muscle cells, and pulmonary arterial fibroblasts; and signaling-stimulated remodeling of the pulmonary veins, capillaries, and arteries that propel the transition from Ipc-PH to Cpc-PH. Identifying biomechanical and mechanobiological mechanisms of Cpc-PH progression may highlight potential pharmacologic avenues to prevent right heart failure and subsequent mortality.

G protein-coupled receptor kinase-2 is a novel regulator of collagen synthesis in adult human cardiac fibroblasts.

Cardiac fibroblasts (CF) make up 60-70% of the total cell number in the heart and play a critical role in regulating normal myocardial function and in adverse remodeling following myocardial infarction and the transition to heart failure. Recent studies have shown that increased intracellular cAMP can inhibit CF transformation and collagen synthesis in adult rat CF; however, mechanisms by which cAMP production is regulated in CF have not been elucidated. We investigated the potential role of G protein-coupled receptor kinase-2 (GRK2) in modulating collagen synthesis by adult human CF isolated from normal and failing left ventricles. Baseline collagen synthesis was elevated in failing CF and was not inhibited by ß-agonist stimulation in contrast to normal controls. ß-adrenergic receptor (ß-AR) signaling was markedly uncoupled in the failing CF, and expression and activity of GRK2 were increased 3-fold. Overexpression of GRK2 in normal CF recapitulated a heart failure phenotype with minimal inhibition of collagen synthesis following ß-agonist stimulation. In contrast, knockdown of GRK2 expression in normal CF enhanced cAMP production and led to greater ß-agonist-mediated inhibition of basal and TGFß-stimulated collagen synthesis versus control. Inhibition of GRK2 activity in failing CF by expression of the GRK2 inhibitor, GRK2ct, or siRNA-mediated knockdown restored ß-agonist-stimulated inhibition of collagen synthesis and decreased collagen synthesis in response to TGFß stimulation. GRK2 appears to play a significant role in regulating collagen synthesis in adult human CF, and increased activity of this kinase may be an important mechanism of maladaptive ventricular remodeling as mediated by cardiac fibroblasts.

Effect of Transfer Status on Outcomes of Emergency General Surgery Patients.

INTRODUCTION: Transferred emergency general surgery (EGS) patients are a vulnerable, high acuity population. The outcomes of and health care utilization among transferred (TRAN) as compared to directly admitted (DA) patients have been studied primarily using single institution or hospital system data which limits generalizability. We evaluated these outcomes among EGS patients using a national database. METHODS: We identified encounters of patients aged ≥18 years with a diagnosis of EGS as defined by the American Association for the Surgery of Trauma in the 2008-2011 Nationwide Inpatient Sample (NIS). Multivariable regression analyses determined if transfer status independently predicted in-hospital mortality (logistic regression) and morbidity (presence of any complication among those who survived to discharge; logistic regression), cost (log-linear regression), and duration of stay (among those who survived to discharge; log-linear regression) accounting for the NIS sampling design. RESULTS: We identified 274,145 TRAN (57,885 unweighted) and 10,456,100 DA (2,187,132 unweighted) encounters. On univariate analysis, TRAN patients were more likely to have greater comorbidity scores, have Medicare insurance, and reside in an area with a lesser median household income compared to DA patients (p<0.0001). Mortality was greater in the TRAN vs DA groups (4.4% vs 1.6%; p<0.0001). Morbidity (presence of any complication) was also greater among TRAN patients (38.8% vs 26.1%; p<0.0001). Morbidity among TRAN patients was primarily due to urinary- (13.7%), gastrointestinal- (12.9%), and pulmonary-related (13.3%) complications. Median duration of hospital stay was 4.3 days for TRAN vs 3.0 days for DA (p<0.0001) patients. Median cost was greater for TRAN patients ($8,935 vs $7,167; p<0.0001). Regression analyses determined that after adjustment, TRAN patients had statistically significantly greater mortality, morbidity, and cost as well as longer durations of stay. CONCLUSIONS: EGS patients who are transferred experience increased in-hospital morbidity and mortality as well as increased durations of stay and cost. As the population and age of patients diagnosed with EGS conditions increase while the EGS workforce decreases, the need for inter-hospital transfers will increase. Identifying risk factors associated with worse outcomes among transferred patients can inform the design of initiatives in performance improvement and direct the finite resources available to this vulnerable patient population.

Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by ß-arrestins.

Cardiac fibroblasts (CF) play a critical role in post-infarction remodeling which can ultimately lead to pathological fibrosis and heart failure. Recent evidence demonstrates that remote (non-infarct) territory fibrosis is a major mechanism for ventricular dysfunction and arrhythmogenesis. ß-arrestins are important signaling molecules involved in ß-adrenergic receptor (ß-AR) desensitization and can also mediate signaling in a G protein independent fashion. Recent work has provided evidence that ß-arrestin signaling in the heart may be beneficial, however, these studies have primarily focused on cardiac myocytes and their role in adult CF biology has not been well studied. In this study, we show that ß-arrestins can regulate CF biology and contribute to pathological fibrosis. Adult male rats underwent LAD ligation to induce infarction and were studied by echocardiography. There was a significant decline in LV function at 2-12 weeks post-MI with increased infarct and remote territory fibrosis by histology consistent with maladaptive remodeling. Collagen synthesis was upregulated 2.9-fold in CF isolated at 8 and 12 weeks post-MI and ß-arrestin expression was significantly increased. ß-adrenergic signaling was uncoupled in the post-MI CF and ß-agonist-mediated inhibition of collagen synthesis was lost. Knockdown of ß-arrestin1 or 2 in the post-MI CF inhibited transformation to myofibroblasts as well as basal and TGF-ß-stimulated collagen synthesis. These data suggest that ß-arrestins can regulate CF biology and that targeted inhibition of these signaling molecules may represent a novel approach to prevent post-infarction pathological fibrosis and the transition to HF.

Outcomes of surgical aortic valve replacement for mixed aortic valve disease.

BACKGROUND: Mixed aortic valve disease (MAVD) is associated with a poorer natural history compared with isolated lesions. However, clinical and echocardiographic outcomes for aortic valve replacement (AVR) in mixed disease are less well understood. METHODS: Retrospective review of AVRs (n=1,011) from 2000-2016. Isolated AVR, AVR + coronary bypass, and AVR + limited ascending aortic replacement were included. Predominant aortic stenosis (AS) group was stratified into group 1 (n=660) with concomitant mild or less aortic insufficiency (AI), and group 2 (n=197) with accompanying moderate or greater AI. Predominant AI group was stratified using the same schema for concomitant AS into groups 3 (n=143) and 4 (n=53). Median follow-up was 3.1 and 4.4 years respectively for AS and AI groups. RESULTS: For the predominant AS group (n=857) preoperatively, group 2 had a larger preoperative left ventricular end diastolic diameter (LVESD) (51.0±8.4 vs. 48.6±7.2, P=0.02) and lower preoperative left ventricular ejection fraction (LVEF) (57.6% vs. 60.2%, P=0.043). No differences in left ventricular (LV) dimensions, LV or right ventricular (RV) function was evident at follow up (P>0.05). After propensity matching for age, operation, and comorbidities, there was no difference in survival (P=0.19). After propensity matching for the predominant AI group (n=196), survival was lower for group 4 compared to 3 (P=0.02). There were no differences in LV dimensions, LV or RV function preoperatively or on follow-up (P>0.05). CONCLUSIONS: Predominant AS associated with higher AI grades had larger LV dimensions and worse LV function preoperatively. These differences resolve after AVR with equivalent survival. However, predominant AI with more severe AS had reduced survival despite AVR.

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions.

Introduction: Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy. Methods: A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α1A-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH. Results: Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload. Conclusion: Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure.

Cluster analysis of acute ascending aortic dissection provides novel insight into mechanisms of distal progression.

BACKGROUND: Whether primary tear size impacts extent of type A dissection is unclear. Using statistical groupings based on dissection morphology, we examined its relationship to primary tear area. METHODS: We retrospectively reviewed 108 patients who underwent acute ascending dissection repair from 2000-2016. Dissection morphology was characterized using 3-dimensional (3D) reconstructions of computed tomography (CT) scan images. Two-step cluster analysis was performed to group the dissections by examining the true lumen area as a fraction of the total aortic area at various levels. RESULTS: Cluster analysis defined two distinct categories. This first grouping corresponds to DeBakey type I (n=71, 65.7%) with a dissection extending from the ascending aorta to the aortic bifurcation. The second grouping conforms more closely to DeBakey type II dissection (n=37, 34.3%). It differs however from the classic type II definition as the dissection may extend up to the distal arch from the ascending aorta. Compared to type I, this "extended" DeBakey type II had no malperfusion (P<0.05), a larger primary tear area (6.6 vs. 3.7 cm2, P=0.009), and a greater burden of atherosclerotic coronary artery disease (P<0.05). A smaller aortic valve annulus (P=0.025) and a smaller root false lumen area (P=0.017) may explain less aortic valve insufficiency (P<0.05) in extended type II dissections. No differences in complications or survival were seen. CONCLUSIONS: In this series, limited distal extension of DeBakey type II dissections appears to be related to a larger primary tear area and greater atherosclerotic disease burden. It is also associated with less malperfusion and aortic valve insufficiency.

Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4.

Cardiac myocyte oxidative stress and apoptosis are considered important mechanisms for the development of heart failure (HF). Chronic HF is characterized by increased circulating catecholamines to augment cardiac output. Long-term stimulation of myocardial ß-adrenergic receptors (ß-ARs) is deleterious in cardiac myocytes, however, the potential mechanisms underlying increased cell death are unclear. We hypothesize that GRK2, a critical regulator of myocardial ß-AR signaling, plays an important role in mediating cellular oxidative stress and apoptotic cell death in response to ß-agonist stimulation. Stimulation of H9c2 cells with a non-selective ß-agonist, isoproterenol (Iso) caused increased oxidative stress and apoptosis. There was also increased Nox4 expression, but no change in Nox2, the primary NADPH isoforms and major sources of ROS generation in cardiac myocytes. Adenoviral-mediated overexpression of GRK2 led to similar increases in ROS production and apoptosis as seen with Iso stimulation. These increases in oxidative stress were abolished by pre-treatment with the non-specific Nox inhibitor, apocynin, or siRNA knockdown of Nox4. Adenoviral-mediated expression of a GRK2 inhibitor prevented ROS production and apoptosis in response to Iso stimulation. ß-Arrestins are signaling proteins that function downstream of GRK2 in ß-AR uncoupling. Adenoviral-mediated overexpression of ß-arrestins increased ROS production and Nox4 expression. Chronic ß-agonist stimulation in mice increased Nox4 expression and apoptosis compared to PBS or AngII treatment. These data demonstrate that GRK2 may play an important role in regulating oxidative stress and apoptosis in cardiac myocytes and provides an additional novel mechanism for the beneficial effects of cardiac-targeted GRK2 inhibition to prevent the development of HF.