Initial experience of a large, self-expanding, and fully recapturable transcatheter aortic valve: The UK & Ireland Implanters' registry.

OBJECTIVES: The UK & Ireland Implanters' registry is a multicenter registry which reports on real-world experience with novel transcatheter heart valves. BACKGROUND: The 34 mm Evolut R transcatheter aortic valve is a self-expanding and fully recapturable transcatheter aortic valve, designed to treat patients with a large aortic annulus. METHODS: Between January 2017 and April 2018, clinical, procedural and 30-day outcome data were prospectively collected from all patients receiving the 34 mm Evolut R valve across 17 participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2(VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. RESULTS: A total of 217 patients underwent attempted implant. Mean age was 79.5 ± 8.8 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.2% ± 3.4%. Iliofemoral access was used in 91.2% of patients. Device success was 79.7%. Mean gradient was 7.0 ± 4.6 mmHg and effective orifice area 2.0 ± 0.6 cm2 . Paravalvular regurgitation was more than mild in 7.2%. A new permanent pacemaker was implanted in 15.7%. Early safety was demonstrated in 91.2%. At 30 days, all-cause mortality was 3.2%, stroke 3.7%, and major vascular complication 2.3%. CONCLUSIONS: Real-world experience of the 34 mm Evolut R transcatheter aortic valve demonstrated acceptable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation.

Gene and microRNA transcriptional signatures of angiotensin II in endothelial cells.

Growth of atherosclerotic plaque requires neovascularization (angiogenesis). To elucidate the involvement of angiotensin II (Ang II) in angiogenesis, we performed gene microarray and microRNA (miRNA) polymerase chain reaction array analyses on human coronary artery endothelial cells exposed to moderate concentration of Ang II for 2 and 12 hours. At 12, but not 2, hours, cultures treated with Ang II exhibited shifts in transcriptional activity involving 267 genes (>1.5-fold difference; P < 0.05). Resulting transcriptome was most significantly enriched for genes associated with blood vessel development, angiogenesis, and regulation of proliferation. Majority of upregulated genes implicated in angiogenesis shared a commonality of being either regulators (HES1, IL-18, and CXCR4) or targets (ADM, ANPEP, HES1, KIT, NOTCH4, PGF, and SOX18) of STAT3. In line with these findings, STAT3 inhibition attenuated Ang II-dependent stimulation of tube formation in Matrigel assay. Expression analysis of miRNAs transcripts revealed that the pattern of differential expression for miRNAs was largely consistent with proangiogenic response with a prominent theme of upregulation of miRs targeting PTEN (miR-19b-3p, miR-21-5p, 23b-3p, and 24-3p), many of which are directly or indirectly STAT3 dependent. We conclude that STAT3 signaling may be an intrinsic part of Ang II-mediated proangiogenic response in human endothelial cells.

P-wave duration in lead aVR and the risk of atrial fibrillation in hypertension.

BACKGROUND: Hypertension entails atrial remodeling that affect P-wave (PW) duration on electrocardiogram (ECG). PW indices (e.g., variance, dispersion, and terminal force) are associated with a higher risk for atrial fibrillation (AF), but their calculation requires multiple measurements of PW duration, limiting their use in clinical practice. We evaluated whether PW duration in specific ECG leads may identify patients with increased susceptibility to AF in a population of hypertensive patients. METHODS: In a case-control study, AF and control subjects were matched for age, sex, and left atrial (LA) dimensions. PW duration was measured from digitally stored ECGs. Logistic regression was used to assess the association of PW duration and indices with AF. RESULTS: We enrolled 44 hypertensive AF patients (16 paroxysmal and 28 persistent) and 44 hypertensive controls. AF and control subjects were matched for sex (males, n = 27), age (67 ± 8 years), LA diameter (40 ± 5 mm), and were comparable for left ventricular mass (45 ± 11 g/m(2.7) vs 48 ± 12 g/m(2.7) , P = 0.19), ejection fraction (58 ± 7% in both groups), and prevalence of mild valvular heart disease (7% vs 5%; P = 0.64). PW duration in lead aVR was significantly higher in AF patients as compared with controls (115 ± 18 ms vs 101 ± 14 ms; P < 0.0001) and was the best independent predictor of AF in multivariable logistic regression (PW ≥ 100 ms: RR = 3.7; 95% CI: 1.3-10.3; P = 0.02). CONCLUSIONS: Simple measurement of PW duration in lead aVR allows effective identification of AF patients in a population of hypertensives. Confirmation of this finding in a larger population would provide a simple and effective risk marker of AF in hypertensive patients.

Prevention of export of anoxia/reoxygenation injury from ischemic to nonischemic cardiomyocytes via inhibition of endocytosis.

Myocardial infarct size is determined by the death of nonischemic border zone cardiomyocytes caused by export of injury signals from the infarct zone. The countermeasures to limit infarct size, therefore, should be aimed at nonselective blockade of most, if not all, injury signals from entering nonischemic cells. To test whether inhibition of endocytosis might limit infarct size, HL-1 cardiomyocytes were subjected to anoxia (6 h) and reoxygenation (1 h). Anoxic and reoxygenated cells showed a multifold increase in mitochondrial ROS production accompanied with upregulation of scavenger receptors lectin-like oxidized low-density lipoprotein receptor-1 and CD36 and stimulation of stress signals, including NADPH oxidase subunit p22(phox), SOD2, and beclin-1. Incubation of healthy cardiomyocytes in media from anoxic and reoxygenated cells (conditioned media) resulted in qualitatively similar responses, including increase in the generation of mitochondrial ROS, p22(phox), SOD2, and beclin-1. Anoxia and reoxygenation caused collapse of clathrin-mediated endocytosis and stimulation of macropinocytosis, whereas in cultures exposed to conditioned media, the activity of endocytosis was uniformly higher. Conditioned media also significantly aggravated cytotoxic effects of TNF-α and angiotensin II, and suppression of endocytosis reversed these trends, resulting in an overall increase of metabolic activity. Moreover, inhibition of endocytosis prevented binding of oxidized cellular fragments with greater efficiency than targeted neutralization of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1. Many of the observations in HL-1 cardiomyocytes were confirmed in primary cardiomyocyte cultures. Our data suggest that endocytosis is upregulated in border zone cardiomyocytes, and inhibition of endocytosis may be an effective approach to prevent export of injury signals from the infarct zone.

High fat diet causes renal fibrosis in LDLr-null mice through MAPK-NF-κB pathway mediated by Ox-LDL.

BACKGROUND: Dyslipidemia, particularly increased LDL-cholesterol level in serum, is associated with atherosclerosis and fibrosis in different organs. This study was designed to investigate the effects of increase in LDL-cholesterol on renal fibrosis. METHODS: Wild-type (WT) and LDLr knockout (KO) mice were fed standard or high fat diet (HFD), and their kidneys were collected after 26 weeks of dietary intervention for identification of fibrosis and study of potential mechanisms. Additional studies were performed in cultured renal fibroblasts. RESULTS: We observed extensive and diffuse fibrosis in the kidneys of mice given HFD (P < 0.05 vs. standard chow). Fibrosis was associated with enhanced expression of fibronectin, nicotinamide adenine dinucleotide phosphate oxidases and activated p38 and p44/42 mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). There was evidence for accumulation of 4-hydroxynonenal, a lipid peroxidation product, in the kidneys and of ox-LDL in the arteries of LDLr KO mice given HFD. The expression of ox-LDL receptor LOX-1 and of transforming growth factor beta 1 (TGFß1) was increased in these kidneys. All these changes were more pronounced in LDLr KO mice than in the WT mice. In in vitro studies, treatment of fibroblasts from kidneys of LDLr KO mice with ox-LDL showed intense proliferation and collagen formation (all P < 0.05, fibroblasts from WT mice kidneys). Blockade of p38 MAPK, p44/42 MAPK, or NF-κB significantly attenuated expression of profibrotic signals, collagen formation, and proliferation of fibroblasts. CONCLUSIONS: HFD induces renal fibrosis in LDLr-null mice primarily through activation of the nicotinamide adenine dinucleotide phosphate oxidase MAPK-NF-κB pathway by ox-LDL.

LOX-1 in the maintenance of cytoskeleton and proliferation in senescent cardiac fibroblasts.

Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for binding and uptake of ox-LDL in endothelial cells, vascular smooth muscle cells and cardiomyocytes. In this study in cultured mice heart fibroblasts, we describe a decrease in LOX-1 expression as these cells go through successive passages. Further, fibroblast aging is associated with significant changes in morphology and proliferation ability. The same phenomena were observed in primary cardiac fibroblasts isolated from the aged mice (130-week). We also noted that the senescent fibroblasts have increased susceptibility to apoptosis and have a disorganized cytoskeleton. To ascertain the contribution of LOX-1 in the decline in proliferative ability and morphological changes in the aged cells, senescent fibroblasts were transfected with h-LOX-1. Transfection with h-LOX-1 resulted in cytoskeleton reorganization and partial restoration of the expression of related proteins, CDC42 and p70 S6 kinase. Upregulation of LOX-1 also significantly enhanced their proliferation potential and restored the expression of related genes Mdm2 and phos-Akt, and modestly reduced the expression of aging markers 4-HNE and ß-catenin. These findings suggest that LOX-1 contributes, at least in part, to the process of fibroblast senescence and may be viewed as a new aging maker.

Regulation of MSR-1 and CD36 in macrophages by LOX-1 mediated through PPAR-γ.

We observed uniform sustained Dil-ox-LDL uptake in macrophages in the presence or absence of ox-LDL receptor-1 (LOX-1). We wondered if the deficiency of LOX-1 modulates the expression of two other scavenger receptors, macrophage scavenger receptor-1 (MSR1) and CD36, on macrophages to account for the unaltered ox-LDL uptake. Macrophages were isolated from wild-type (WT) and LOX-1 knockout (KO) mice and stimulated with ox-LDL. Dil-ox-LDL uptake and expression of MSR1 and CD36 examined. Abrogation of LOX-1 did not significantly change Dil-ox-LDL uptake by macrophages. LOX-1 KO macrophages showed a significant decrease in CD36 at baseline as well as after ox-LDL stimulation and a marked almost 100% increase in the expression of MSR1, both at mRNA and protein levels (all p<0.05 vs. WT macrophages). Further, we observed a reduction in the expression of PPAR-γ in LOX-1 KO macrophages. To ascertain the role of PPAR-γ in the altered expression of MSR1 and CD36, LOX-1 KO macrophages were treated with troglitazone, a PPAR-γ agonist. Activation of PPAR-γ by troglitazone reversed the increased expression of MSR1 as well as the decreased expression of CD36 in LOX-1 KO macrophages. LOX-1 abrogation induces MSR1 and inhibits CD36 expression. The increase in MSR1 most likely accounts for sustained Dil-ox-LDL uptake despite LOX-1 abrogation. The alterations in CD36 and MSR1 occur through a decrease in PPAR-γ.

Regulation of autophagy and apoptosis in response to angiotensin II in HL-1 cardiomyocytes.

BACKGROUND: Autophagy and apoptosis are two important regulators of cell survival, and are often observed simultaneously in response to noxious stimuli. Anoxia is a known stimulus for autophagy and apoptosis, and angiotensin (Ang) II is a major mediator of anoxic injury. However, specific responses to anoxia and Ang II in terms of occurrence of autophagy and apoptosis have still not been delineated. METHODS AND RESULTS: We observed that autophagy (measured as LC3 staining, and Beclin-1 and p62 Western blotting) was an early response and apoptosis (measured as TUNEL staining, and Annexin V and Smac/Diablo Western blotting) became dominant as the duration of anoxia was prolonged. Autophagy also occurred quickly in response to low concentrations of Ang II. When exposed to high concentrations of Ang II, a significant number of cells developed apoptosis, while autophagy response decreased. Ang II-mediated apoptosis was blocked by Ang II type 1 receptor (AT1R) blocker losartan as well as by the AT2R blocker PD123319. Ang II-induced autophagy was blocked by losartan, but not by PD123319. CONCLUSION: Exposure to Ang II, a mediator of anoxic injury, initiates a rapid autophagy response, perhaps in an attempt to protect tissues from the impending noxious effects. However, when anoxia (and thereby release of Ang II) is prolonged, the process of apoptosis dominates. These processes will determine the outcome of cardiomyocyte well-being in states of hypoxia.

LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells.

A growing body of evidence indicates that glucagon-like peptide-1 (GLP-1) agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors play an important role in modulating oxidant stress in vascular beds. However, the underlying mechanism of this process remains unclear. In recent studies, we observed an increase in GLP-1 receptor (GLP-1R) expression in the aorta of LOX-1 knock-out mice. Since LOX-1 is a pivotal regulator of reactive oxygen species (ROS), we conducted studies to identify relationship between LOX-1, ROS and GLP-1 agonism or DPP-4 antagonism. We observed a sustained decrease in GLP-1R expression in human vascular smooth muscle cells (VSMCs) treated with ox-LDL. When VSMCs were treated with different concentration of liraglutide (a GLP-1 agonist) or NVPDPP728 (a DPP-4 inhibitor), expression of ROS decreased compared with ox-LDL alone treatment. To further prove that LOX-1 plays a pivotal role in ROS and GLP-1R expression, we treated VSMCs with LOX-1 antibody or transfected cells with human LOX-1 cDNA. The inhibitory effect of ox-LDL on GLP-1R expression was reversed with anti-LOX-1 antibody treatment, while the inhibitory effect of liraglutide and NVPDPP728 on ROS generation was attenuated when cells were transfected with LOX-1 cDNA. Our results suggest that LOX-1 may play a bridging role in GLP-1 activation and ROS interaction.

Clinical Predictors for Procedural Stroke and Implications for Embolic Protection Devices during TAVR: Results from the Multicenter Transcatheter Aortic Valve Replacement In-Hospital Stroke (TASK) Study.

Background: Data to support the routine use of embolic protection devices for stroke prevention during transcatheter aortic valve replacement (TAVR) are controversial. Identifying patients at high risk for peri-procedural cerebrovascular events may facilitate effective patient selection for embolic protection devices during TAVR. Aim: To generate a risk score model for stratifying TAVR patients according to peri-procedural cerebrovascular events risk. Methods and results: A total of 8779 TAVR patients from 12 centers worldwide were included. Peri-procedural cerebrovascular events were defined as an ischemic stroke or a transient ischemic attack occurring ≤24 h from TAVR. The peri-procedural cerebrovascular events rate was 1.4% (n = 127), which was independently associated with 1-year mortality (hazards ratio (HR) 1.78, 95% confidence interval (CI) 1.06−2.98, p < 0.028). The TASK risk score parameters were history of stroke, use of a non-balloon expandable valve, chronic kidney disease, and peripheral vascular disease, and each parameter was assigned one point. Each one-point increment was associated with a significant increase in peri-procedural cerebrovascular events risk (OR 1.96, 95% CI 1.56−2.45, p < 0.001). The TASK score was dichotomized into very-low, low, intermediate, and high (0, 1, 2, 3−4 points, respectively). The high-risk TASK score group (OR 5.4, 95% CI 2.06−14.16, p = 0.001) was associated with a significantly higher risk of peri-procedural cerebrovascular events compared with the low TASK score group. Conclusions: The proposed novel TASK risk score may assist in the pre-procedural risk stratification of TAVR patients for peri-procedural cerebrovascular events.

Chimney Stenting for Coronary Occlusion During TAVR: Insights From the Chimney Registry.

OBJECTIVES: The aim of this study was to determine the safety and efficacy of chimney stenting, a bailout technique to treat coronary artery occlusion (CAO). BACKGROUND: CAO during transcatheter aortic valve replacement (TAVR) is a rare but often fatal complication. METHODS: In the international Chimney Registry, patient and procedural characteristics and data on outcomes are retrospectively collected from patients who underwent chimney stenting during TAVR. RESULTS: To date, 16 centers have contributed 60 cases among 12,800 TAVR procedures (0.5%). Chimney stenting was performed for 2 reasons: 1) due to the development of an established CAO (n = 25 [41.6%]); or 2) due to an impending CAO (n = 35 [58.3%]). The majority of cases (92.9%) had 1 or more classical risk factors for CAO. Upfront coronary protection was performed in 44 patients (73.3%). Procedural and in-hospital mortality occurred in 1 and 2 patients, respectively. Myocardial infarction (52.0% vs. 0.0%; p < 0.01), cardiogenic shock (52.0% vs. 2.9%; p < 0.01), and resuscitation (44.0% vs. 2.9%; p < 0.01) all occurred more frequently in patients with established CAO compared with those with impending CAO. The absence of upfront coronary protection was the sole independent risk factor for the combined endpoint of death, cardiogenic shock, or myocardial infarction. During a median follow-up time of 612 days (interquartile range: 405 to 842 days), 2 cases of stent failure were reported (1 in-stent restenosis, 1 possible late stent thrombosis) after 157 and 374 days. CONCLUSIONS: Chimney stenting appears to be an acceptable bailout technique for CAO, with higher event rates among those with established CAO and among those without upfront coronary protection.

Transcatheter aortic valve implantation: status update.

Transcatheter aortic valve implantation (TAVI) has emerged as the gold standard technique for all patients with symptomatic severe aortic stenosis at elevated surgical risk. Much progress has been made to reduce procedural complications and improve patient outcomes. The impressive results of contemporary TAVI can be attributed to a variety of factors, including improving operator experience, pre-operative patient screening, and developments in transcatheter heart valve and delivery system technology. Despite these advances, serious procedural complications continue to occur and there remain some anatomical subsets and patient groups to whom TAVI technology has not been expanded. Herein we discuss these unmet needs in TAVI.

Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles.

Neurodegenerative diseases are largely defined by protein aggregates in affected tissues. Aggregates contain some shared components as well as proteins thought to be specific for each disease. Aggregation has not previously been reported in the normal, aging heart or the hypertensive heart. Detergent-insoluble protein aggregates were isolated from mouse heart and characterized on 2-dimensional gels. Their levels increased markedly and significantly with aging and after sustained angiotensin II-induced hypertension. Of the aggregate components identified by high-resolution proteomics, half changed in abundance with age (392/787) or with sustained hypertension (459/824), whereas 30% (273/901) changed concordantly in both, each P<0.05. One fifth of these proteins were previously associated with age-progressive neurodegenerative or cardiovascular diseases, or both (eg, ApoE, ApoJ, ApoAIV, clusterin, complement C3, and others involved in stress-response and protein-homeostasis pathways). Because fibrosis is a characteristic of both aged and hypertensive hearts, we posited that aging of fibroblasts may contribute to the aggregates observed in cardiac tissue. Indeed, as cardiac myofibroblasts "senesced" (approached their replicative limit) in vitro, they accrued aggregates with many of the same constituent proteins observed in vivo during natural aging or sustained hypertension. In summary, we have shown for the first time that compact (detergent-insoluble) protein aggregates accumulate during natural aging, chronic hypertension, and in vitro myofibroblast senescence, sharing many common proteins. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual.

Dipeptidyl peptidase-4 inhibitors in cardioprotection: a promising therapeutic approach.

Cardiovascular diseases are major killers in all developed societies and rapidly becoming the leading cause of morbidity and mortality in the developing world. Patients with diabetes mellitus are at particular risk of developing cardiovascular diseases. The present treatment options for management of diabetes have expanded since the development of glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. There is a growing body of evidence that these agents may have cardioprotective effects even in patients who do not have diabetes. Here, we discuss this evidence as well as pathways that DPP-4 inhibitors target in the cardiovascular system. These agents over time will find an appropriate place in the management of cardiovascular diseases.

Atrial natriuretic Peptide single nucleotide polymorphisms in patients with nonfamilial structural atrial fibrillation.

BACKGROUND: Atrial natriuretic peptide (ANP) has antihypertrophic and antifibrotic properties that are relevant to AF substrates. The -G664C and rs5065 ANP single nucleotide polymorphisms (SNP) have been described in association with clinical phenotypes, including hypertension and left ventricular hypertrophy. A recent study assessed the association of early AF and rs5065 SNPs in low-risk subjects. In a Caucasian population with moderate-to-high cardiovascular risk profile and structural AF, we conducted a case-control study to assess whether the ANP -G664C and rs5065 SNP associate with nonfamilial structural AF. METHODS: 168 patients with nonfamilial structural AF and 168 age- and sex-matched controls were recruited. The rs5065 and -G664C ANP SNPs were genotyped. RESULTS: The study population had a moderate-to-high cardiovascular risk profile with 86% having hypertension, 23% diabetes, 26% previous myocardial infarction, and 23% left ventricular systolic dysfunction. Patients with AF had greater left atrial diameter (44 ± 7 vs. 39 ± 5 mm; P < 0.001) and higher plasma NTproANP levels (6240 ± 5317 vs. 3649 ± 2946 pmol/mL; P < 0.01). Odds ratios (ORs) for rs5065 and -G664C gene variants were 1.1 (95% confidence interval [CI], 0.7-1.8; P = 0.71) and 1.2 (95% CI, 0.3-3.2; P = 0.79), respectively, indicating no association with AF. There were no differences in baseline clinical characteristics among carriers and noncarriers of the -664C and rs5065 minor allele variants. CONCLUSIONS: We report lack of association between the rs5065 and -G664C ANP gene SNPs and AF in a Caucasian population of patients with structural AF. Further studies will clarify whether these or other ANP gene variants affect the risk of different subphenotypes of AF driven by distinct pathophysiological mechanisms.