Hybrid Closure of Postinfarction Apical Ventricular Septal Defect Using Septal Occluder Device and Right Ventricular Free Wall: The Apical BASSINET Concept.

BACKGROUND: Postinfarction ventricular septal defect (VSD) is a catastrophic complication of myocardial infarction. Surgical repair still has poor outcomes. This report describes clinical outcomes after a novel hybrid transcatheter/surgical repair in patients with apical VSD. METHODS: Seven patients with postmyocardial infarction apical VSD underwent hybrid transcatheter repair via subxiphoid surgical access. A transcatheter occluder (Amplatzer Septal Occluder) with a trailing premounted suture was deployed through the right ventricular wall and through the ventricular septum into the left ventricular apex. The trailing suture was used to connect an anchor external to the right ventricular wall. Tension on the suture then collapses the right ventricular free wall against the septum and left ventricular occluder, thereby obliterating the VSD. Outcomes were compared with 9 patients who underwent surgical repair using either patch or primary suture closure. RESULTS: All patients had significant left-to-right shunt (Qp:Qs 2.5:1; interquartile range [IQR, 2.1-2.6] hybrid repair versus 2.0:1 [IQR, 2.0-2.5] surgical repair), and elevated right ventricular systolic pressure (62 [IQR, 46-71] versus 49 [IQR, 43-54] mm Hg, respectively). All had severely depressed stroke volume index (22 versus 21 mL/m2) with ≈45% in each group requiring mechanical support preprocedurally. The procedure was done 15 (IQR, 10-50) versus 24 (IQR, 10-134) days postmyocardial infarction, respectively. Both groups of patients underwent repair with technical success and without intraprocedural death. One patient in the hybrid group and 4 in the surgical group developed multiorgan failure. The hybrid group had a higher survival at discharge (86% versus 56%) and at 30 days (71% versus 56%), but similar at 1 year (57% versus 56%). During follow-up, 1 patient in each group required reintervention for residual VSD (hybrid: 9 months versus surgical: 5 days). CONCLUSIONS: Early intervention with a hybrid transcatheter/surgical repair may be a viable alternative to traditional surgery for postinfarction apical VSD.

A Comparison of Thirty-Day Clinical and Echocardiographic Outcomes of Patients Undergoing Transcatheter vs. Surgical Aortic Valve Replacement for Native Aortic Insufficiency.

OBJECTIVES: We aim to compare in-hospital and 30-day outcomes of transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) for native aortic insufficiency (AI). BACKGROUND: TAVR is increasingly used off-label in patients with AI deemed high risk for SAVR. There is a paucity of data comparing TAVR and SAVR with current commercially available TAVR devices. METHODS: A single-center, retrospective cohort study of patients undergoing TAVR or SAVR for native AI between 2014 and 2020 was performed. Data were obtained from the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database, Transcatheter Valve Therapy (TVT) registry, and chart review. In-hospital and 30-day outcomes are reported. RESULTS: Of 125 total patients, 91 underwent SAVR and 34 underwent TAVR. The TAVR group had a higher STS predictive risk of mortality (PROM) (TAVR = 3.96 %, SAVR = 1.25 %, p < 0.0001). In the postoperative period, the SAVR group had higher rates of new-onset atrial fibrillation (20.9 % vs. 0 %, p < 0.001), while the TAVR group had higher rates of complete heart block requiring permanent pacemaker implantation (20.6 % vs. 2.2 %, p < 0.001). There was no difference in in-hospital or 30-day mortality, stroke, myocardial infarction, residual AI, or repeat valve intervention. CONCLUSIONS: Despite higher STS PROM and more comorbidities, patients who underwent TAVR for AI had similar in-hospital and 30-day outcomes as patients who underwent SAVR for AI. These results support TAVR in selected high-risk patients with AI, with the knowledge that pacemaker needs may be higher than patients undergoing SAVR.

Evolving computed tomography angiography for aortic valve replacement: Optimizing transcatheter and surgical therapies.

Transcatheter aortic valve replacement (TAVR) has transformed the treatment of aortic stenosis and pre-procedure planning relies heavily on advanced imaging. Multidetector computed tomography angiography, the "TAVR CT," facilitates essential planning steps of measuring the aortic root for valve sizing and feasibility and assessment of potential access vessels, making it the guideline gold standard in preprocedural TAVR work up. This Impact of Advanced Imaging Techniques on Cardiac Surgery article will examine the development of TAVR CT, illustrate the current impact and utility, and highlight potential areas of future growth. Clinicians who keep informed of these changes and can become proficient with TAVR CT analyses will offer patients the most optimal results and fuel future therapeutic growth.

Use of transesophageal echocardiography for transcatheter valve-in-valve implantation for patients with prior bioprosthetic surgical aortic, mitral, tricuspid, and pulmonic valves.

Valve-in-valve (ViV) transcatheter procedures are the preferred option for redo valve replacement in patients who otherwise would be high risk for surgery. Transesophageal echocardiography (TEE) is an integral imaging modality for both peri-procedural and intra-procedural guidance during transcatheter ViV replacement. When intentional leaflet laceration is needed, such as with the BASILICA (Bioprosthetic or native Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstructions during TAVR) or LAMPOON (Laceration of the Anterior Mitral valve leaflet to Prevent left ventricular Outlet ObstructioN) procedures, TEE is critical to proper guidewire positioning and achieving a successful laceration. In this paper we detail the role of TEE in ViV transcatheter valve replacement in patients with prior surgical aortic, mitral, tricuspid, and pulmonic valves.

Medical Therapy Utilization and Long-Term Outcomes Following Percutaneous Coronary Intervention: Five-Year Results From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System Program.

BACKGROUND: Optimal medical therapy is endorsed by national guidelines in the management of ischemic heart disease; however, few studies have examined its long-term utilization following percutaneous coronary intervention (PCI) and association with clinical outcomes. We sought to assess longitudinal trends in medical therapy use after PCI and its prognostic significance. METHODS AND RESULTS: From the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we retrospectively identified 57 900 Veteran's Affairs patients undergoing PCI from January 2005 to May 2014. Using prescription fill dates, the utilization of 4 classes of medical therapy including statins, ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, P2Y12 inhibitors, and their composites were assessed at discharge, 6 months, 1, 3, and 5 years post-PCI. Multivariable Cox regression models were developed to assess the association between medical therapy status and major adverse cardiovascular events, defined as all-cause mortality, rehospitalization for myocardial infarction, rehospitalization for stroke, or repeat revascularization. At discharge following PCI, 58.3% of patients received all 4 classes of medical therapy. Utilization of statins, ß-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased from 89%, 84.9%, and 72.2% on discharge, respectively, to 72.7%, 67.9%, and 57.9% at 5 years. Prescription refills of P2Y12 inhibitors declined from 96.5% on discharge to 28.3% at 5 years, driven by a large decline in P2Y12 inhibitor use after 1 year. Use of each class of medical therapy, and its composite use, was associated with a significant reduction in major adverse cardiovascular events at 5 years, with the largest effect size seen by the use of statins (HR, 0.77; 95% CI, 0.75-0.79; P<0.0001) and P2Y12 inhibitors (HR, 0.82; 95% CI, 0.79-0.85; P<0.0001). CONCLUSIONS: Consistent declines in medical therapy use following PCI were observed over time, which is associated with worse outcomes. Further efforts are needed to promote long-term adherence to secondary prevention therapies after revascularization.

10-Year Resource Utilization and Costs for Cardiovascular Care.

BACKGROUND: Cardiovascular disease (CVD) imparts a heavy economic burden on the U.S. health care system. Evidence regarding the long-term costs after comprehensive CVD screening is limited. OBJECTIVES: This study calculated 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a registry sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health. METHODS: Cumulative 10-year costs for CVD medications, office visits, diagnostic procedures, coronary revascularization, and hospitalizations were calculated from detailed follow-up data. Costs were derived by using Medicare nationwide and zip code-specific costs, inflation corrected, discounted at 3% per year, and presented in 2014 U.S. dollars. RESULTS: Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one-third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78%). Approximately $2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level >3 mg/l, or coronary artery calcium score (CACS) ≥400. Costs varied widely from <$7,700 for low-risk (Framingham risk score <6%, 0 CACS, and normal glucose measurements at baseline) to >$35,800 for high-risk (persons with diabetes, Framingham risk score ≥20%, or CACS ≥400) subgroups. Among high-risk enrollees, CVD costs accounted for $74 million of the $155 million consumed by MESA participants. CONCLUSIONS: Longitudinal patterns of health care resource use after screening revealed new evidence on the economic burden of treatment and testing patterns not previously reported. Maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals.

Heterogeneity of signal transduction by Na-K-ATPase α-isoforms: role of Src interaction.

Of the four Na-K-ATPase α-isoforms, the ubiquitous α1 Na-K-ATPase possesses both ion transport and Src-dependent signaling functions. Mechanistically, we have identified two putative pairs of domain interactions between α1 Na-K-ATPase and Src that are critical for α1 signaling function. Our subsequent report that α2 Na-K-ATPase lacks these putative Src-binding sites and fails to carry on Src-dependent signaling further supported our proposed model of direct interaction between α1 Na-K-ATPase and Src but fell short of providing evidence for a causative role. This hypothesis was specifically tested here by introducing key residues of the two putative Src-interacting domains present on α1 but not α2 sequence into the α2 polypeptide, generating stable cell lines expressing this mutant, and comparing its signaling properties to those of α2-expressing cells. The mutant α2 was fully functional as a Na-K-ATPase. In contrast to wild-type α2, the mutant gained α1-like signaling function, capable of Src interaction and regulation. Consistently, the expression of mutant α2 redistributed Src into caveolin-1-enriched fractions and allowed ouabain to activate Src-mediated signaling cascades, unlike wild-type α2 cells. Finally, mutant α2 cells exhibited a growth phenotype similar to that of the α1 cells and proliferated much faster than wild-type α2 cells. These findings reveal the structural requirements for the Na-K-ATPase to function as a Src-dependent receptor and provide strong evidence of isoform-specific Src interaction involving the identified key amino acids. The sequences surrounding the putative Src-binding sites in α2 are highly conserved across species, suggesting that the lack of Src binding may play a physiologically important and isoform-specific role.

Effect of Chronic Kidney Disease on Mortality in Patients Who Underwent Lower Extremity Peripheral Vascular Intervention.

It is known that chronic kidney disease (CKD) is associated with increased postoperative morbidity and mortality in patients with peripheral artery disease who underwent lower extremity surgical revascularization; however, outcomes after peripheral vascular intervention (PVI) are less well established. This study sought to determine the impact of CKD on adverse outcomes in patients with peripheral artery disease who underwent PVI. Using data from the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we identified a cohort of 755 patients who underwent lower extremity PVI from June 2005 to August 2010 at 33 sites. The outcomes of interest were mortality, progression to dialysis, myocardial infarction, limb amputation, and stroke. Kaplan-Meier survival analysis and Cox proportional hazard frailty models assessed the association between CKD and adverse outcomes. Of the patients who underwent lower extremity PVI, 201 patients (27%) had CKD. The presence of CKD was associated with decreased survival (5-year survival probability of CKD compared with non-CKD: 49.9% [41.6% to 59.9%] vs 80.1% [76.2% to 84.1]), which persisted after risk adjustment (HR 1.57; 95% confidence interval 1.13 to 2.19). In addition, there was a significant association between CKD and progression to dialysis (HR 6.62; 95% confidence interval 2.25 to 19.43). In contrast, there was no association between CKD and re-hospitalization for myocardial infarction, limb amputation, or stroke. In conclusion, CKD is present in 1 of 4 patients who underwent PVI and is associated with increased risk of mortality and progression to dialysis.

Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.

BACKGROUND: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K-ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K-ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway. METHODS AND RESULTS: Biosynthesis of MBG by cultured human JEG-3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 µmol/L of rapamycin inhibited production of MBG in human JEG-2 cells. Male Sprague-Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; P<0.01), systolic blood pressure (169±1 vs 111±1 mm Hg; P<0.01), and cardiac fibrosis compared to controls. Plasma MBG levels were significantly decreased in PNx-rapamycin animals compared to PNx (373±46 vs 1025±60 pmol/L; P<0.01), and cardiac fibrosis was substantially attenuated by rapamycin treatment. CONCLUSIONS: Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG-mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy.

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells.

Na-K-ATPase is a fundamental component of ion transport. Four α isoforms of the Na-K-ATPase catalytic α subunit are expressed in human cells. The ubiquitous Na-K-ATPase α1 was recently discovered to also mediate signal transduction through Src kinase. In contrast, α2 expression is limited to a few cell types including myocytes, where it is coupled to the Na(+)/Ca(2+) exchanger. To test whether rat Na-K-ATPase α2 is capable of cellular signaling like its α1 counterpart in a recipient mammalian system, we used an α1 knockdown pig renal epithelial cell (PY-17) to create an α2-expressing cell line with no detectable level of α1 expression. These cells exhibited normal ouabain-sensitive ATPase, but failed to effectively regulate Src. In contrast to α1-expressing cells, ouabain did not stimulate Src kinase or downstream effectors such as ERK and Akt in α2 cells, although their signaling apparatus was intact as evidenced by EGF-mediated signal transduction. Additionally, α2 cells were unable to rescue caveolin-1. Unlike the NaKtide sequence derived from Na-K-ATPase α1, which downregulates basal Src activity, the corresponding α2 NaKtide was unable to inhibit Src in vitro. Finally, coimmunoprecipitation of cellular Src was diminished in α2 cells. These findings indicate that Na-K-ATPase α2 does not regulate Src and, therefore, may not serve the same role in signal transduction as α1. This further implies that the signaling mechanism of Na-K-ATPase is isoform specific, thereby supporting a model where α1 and α2 isoforms play distinct roles in mediating contraction and signaling in myocytes.

Na/K-ATPase mimetic pNaKtide peptide inhibits the growth of human cancer cells.

Cells contain a large pool of nonpumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of α1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/K-ATPase to regulate Src-related signaling processes. A supplement of pNaKtide, a peptide derived from α1 Na/K-ATPase, reduces the activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness of pNaKtide and suggest that the defect in Na/K-ATPase-mediated signal transduction may be targeted for developing new anticancer therapeutics.

NaKtide, a Na/K-ATPase-derived peptide Src inhibitor, antagonizes ouabain-activated signal transduction in cultured cells.

We have previously shown that the Na/K-ATPase binds and inhibits Src. Here, we report the molecular mechanism of Na/K-ATPase-mediated Src regulation and the generation of a novel peptide Src inhibitor that targets the Na/K-ATPase/Src receptor complex and antagonizes ouabain-induced protein kinase cascades. First, the Na/K-ATPase inhibits Src kinase through the N terminus of the nucleotide-binding domain of the alpha1 subunit. Second, detailed mapping leads to the identification of a 20-amino acid peptide (NaKtide) that inhibits Src (IC50 = 70 nm) in an ATP concentration-independent manner. Moreover, NaKtide does not directly affect the ERK and protein kinase C family of kinases. It inhibits Lyn with a much lower potency (IC50 = 2.5 microm). Third, highly positively charged leader peptide conjugates including HIV-Tat-NaKtide (pNaKtide) readily enter cultured cells. Finally, the following functional studies of pNaKtide demonstrate that this conjugate can specifically target the Na/K-ATPase-interacting pool of Src and act as a potent ouabain antagonist in cultured cells: 1) pNaKtide, unlike PP2, resides in the membranes. Consistently, it affects the basal Src activity much less than that of PP2. 2) pNaKtide is effective in disrupting the formation of the Na/K-ATPase/Src receptor complex in a dose-dependent manner. Consequently, it blocks ouabain-induced activation of Src, ERK, and hypertrophic growth in cardiac myocytes. 3) Unlike PP2, pNaKtide does not affect IGF-induced ERK activation in cardiac myocytes. Taken together, we suggest that pNaKtide may be used as a novel antagonist of ouabain for probing the physiological and pathological significance of the newly appreciated signaling function of Na/K-ATPase and cardiotonic steroids.

Changes in sodium pump expression dictate the effects of ouabain on cell growth.

Here we show that ouabain-induced cell growth regulation is intrinsically coupled to changes in the cellular amount of Na/K-ATPase via the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Ouabain increases the endocytosis and degradation of Na/K-ATPase in LLC-PK1, human breast (BT20), and prostate (DU145) cancer cells. However, ouabain stimulates the PI3K/Akt/mTOR pathway and consequently up-regulates the expression of Na/K-ATPase in LLC-PK1 but not BT20 and DU145 cells. This up-regulation is sufficient to replete the plasma membrane pool of Na/K-ATPase and to stimulate cell proliferation in LLC-PK1 cells. On the other hand, ouabain causes a gradual depletion of Na/K-ATPase and an increased expression of cell cycle inhibitor p21(cip), which consequently inhibits cell proliferation in BT20 and DU145 cells. Consistently, we observe that small interfering RNA-mediated knockdown of Na/K-ATPase is sufficient to induce the expression of p21(cip) and slow the proliferation of LLC-PK1 cells. Moreover, this knockdown converts the growth stimulatory effect of ouabain to growth inhibition in LLC-PK1 cells. Mechanistically, both Src and caveolin-1 are required for ouabain-induced activation of Akt and up-regulation of Na/K-ATPase. Furthermore, inhibition of the PI3K/Akt/mTOR pathway by rapamycin completely blocks ouabain-induced expression of Na/K-ATPase and converts ouabain-induced growth stimulation to growth inhibition in LLC-PK1 cells. Taken together, we conclude that changes in the expression of Na/K-ATPase dictate the growth regulatory effects of ouabain on cells.

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.

The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

The Na/K-ATPase-mediated signal transduction as a target for new drug development.

The Na/K-ATPase, or Na+ pump, is a member of the P-type ATPase superfamily. In addition to pumping ions, the Na/K-ATPase is a receptor that not only regulates the function of protein kinases, but also acts as a scaffold, capable of tethering different proteins into a signalplex. The signaling Na/K-ATPase resides in caveolae and forms a "binary receptor" with the tyrosine kinase Src. Endogenous cardiotonic steroids and digitalis drugs such as ouabain act as agonists and provoke this binary receptor, resulting in tyrosine phosphorylation of the proteins that are either associated with, or in close proximity to, the signaling Na/K-ATPase. Subsequently, this initiates protein kinase cascades including ERKs and PKC isozymes. It also increases mitochondrial production of reactive oxygen species (ROS) and regulates intracellular calcium concentration. Like other receptors, activation of the Na/K-ATPase/Src by ouabain induces the endocytosis of the plasma membrane Na/K-ATPase. Significantly, this newly appreciated signaling function of the Na/K-ATPase appears to play an important role in the pathogenesis of many cardiovascular diseases, therefore serving as an important target for development of novel therapeutic agents.