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The MacNew questionnaire is a disease-specific quality of life measure that has been used in patients with myocardial infarction and heart failure. We aimed to investigate the impact of transcatheter aortic valve implantation (TAVI) on health-related quality of life (HRQoL) using MacNew Questionnaire and identify predictors associated with a change in its score. This was a prospective multi-center study performed across 5 National Health Service hospitals in the United Kingdom performing TAVI between 2016 and 2018. HRQoL was assessed using MacNew Questionnaire, Euro Quality of Life-5D-5L, and Short Form 36 questionnaires collected at baseline, 3-, 6- and 12 months after the procedure. Out of 225 recruited patients, 19 did not have TAVI and 4 withdrew their consent, and hence 202 patients were included. HRQoL was assessed in 181, 161, and 147 patients at 3, 6, and 12 months, respectively. Using MacNew, there was a significant improvement in all domains of HRQoL as early as 3 months after TAVI which was sustained up to 12 months with improved discrimination of change in HRQoL compared with other scales. Poor mobility at baseline and history of myocardial infarction were independent predictors of reduced improvement in HRQoL at 3 months. HRQoL increased in all subgroups of patients including frail ones. In conclusion, the MacNew assessment tool performed well in a representative TAVI cohort and could be used as an alternative disease-specific method for assessing HRQoL change after TAVI.

Service Specification for TAVI: Recommendations of the British Cardiovascular Intervention Society – Updated July 2019 Severe AS (sAS) is the most common primary valve disease leading to surgery or catheter intervention in Europe and North America, with a growing prevalence due to the ageing population.[3] It is a degenerative condition in which the outflow of blood from the heart is restricted by progressive narrowing of the aortic valve. This leads to symptoms of breathlessness, exertional chest pain or blackouts. Untreated, the condition causes left ventricular failure and death, with up to 40% of patients dying within 1 year of symptom onset. No medical therapy can improve outcome for this condition and therefore valve intervention is the only treatment option that alters prognosis. The standard of care for this condition has historically been surgical aortic valve replacement (sAVR), but around one-third of patients are ineligible for sAVR due to a combination of age and comorbidities. TAVI is a transformational technology; it is a much less invasive approach than sAVR and involves implantation of a new valve without the need for complex surgery or the use of a heart–lung bypass machine. This is most commonly done via the femoral arteries (transfemoral or TF approach), but it may also be accomplished via the subclavian arteries or via minimally invasive access using the cardiac apex between the ribs, directly into the aorta through a small incision. Less common approaches via the carotid arteries, axillary artery and the femoral veins or abdominal aorta have also been described. Therefore, for most patients undergoing TAVI, the procedure is performed via the femoral artery, under local anaesthesia or conscious sedation in a catheter laboratory. This results in quicker patient recovery, a shorter hospital stay and reduced use of expensive and limited resources such as cardiac operating theatres and intensive care unit beds, as well as postoperative nursing care. A number of different valve designs are available, including balloon-expandable and self-expandable devices. Each has different performance characteristics, which may be tailored to specific anatomical or patient-specific features. TAVI has been proven to be superior to medical therapy for inoperable patients and superior to sAVR in patients who are high risk for sAVR (Society of Thoracic Surgeons [STS] or Euroscore II >8%).[4–6] Trials have also shown that patients with intermediate surgical risk (STS or Euroscore II >4%) who are eligible for a TF approach have superior outcomes with TAVI.[7–9] Moreover, randomised trials have shown TAVI to be superior to sAVR in patients classified as low risk (STS

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.

OBJECTIVES The United Kingdom and Ireland Implanters' registry is a multicenter registry which reports on real-world experience with new transcatheter heart valves. BACKGROUND The Evolut PRO (Medtronic, Minneapolis, MN) transcatheter aortic valve is a self-expanding transcatheter aortic valve with an outer pericardial wrap, designed to minimize paravalvular regurgitation. METHODS Between July 2017 and December 2018, clinical, procedural, and 30-day outcome data were prospectively collected from all patients receiving the Evolut PRO valve across nine 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 317 patients underwent implantation. Mean age was 81.8 ± 6.4 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.5 ± 1.8%. Iliofemoral access was used in 99.1% of patients. Device success was 91.2%. Mean gradient was 7.6 ± 4.7 mmHg and effective orifice area 1.9 ± 0.7 cm2 . The incidence of moderate paravalvular regurgitation was 1.7% and there was no severe paravalvular regurgitation. A new permanent pacemaker was implanted in 17.8% of patients without a pacemaker at baseline. Early safety was demonstrated in 92.7%. At 30 days, all-cause mortality was 0.6%, stroke 3.8%, and major vascular complication 2.8%. CONCLUSIONS Real-world experience of the Evolut PRO transcatheter aortic valve demonstrated favorable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation.

A meta-analysis of published studies was conducted to evaluate the incidence, predictors, and clinical outcomes of stent fractures. Eight studies with 108 stent fractures in 5,321 patients were analyzed using the Bayesian method. Study end points included in-stent restenosis (ISR) and target lesion revascularization (TLR). The mean incidence of stent fracture per patient was 4.0% (95% confidence interval 0.4% to 16.3%). All cases, except 1, were reported with sirolimus-eluting stents. The incidence of stent fracture was 30.4% in the left anterior descending coronary artery, 10.9% in the left circumflex coronary artery, 56.4% in the right coronary artery,0.01% in the left main coronary artery, and 1.7% in saphenous vein grafts. The probability of stent fracture was significantly higher in the right coronary artery than in the left anterior descending and left circumflex lesions (p0.01). Left main stents were less likely to fracture compared to those in all other vessels (p0.01). The probability of stent fracture was significantly increased in overlapping stents (7.5% vs 2.1%, p = 0.01) and long stents (46 vs 32.5 mm, p0.01). Lesions with stent fractures had higher rates of ISR (38% vs 8.2%, p0.01) and TLR (17% vs 5.6%, p0.01). Conversely, the probability of stent fractures was higher in patients with ISR (12.8% vs 2.1%, p0.01) and TLR (8.8% vs 2.7%, p0.01). In conclusion, although not always associated with clinical sequelae, the probability of ISR and TLR is increased with stent fracture. Conversely, the probability of stent fractures is increased in lesions with ISR or TLR, thus raising the need for surveillance and management guidelines for at-risk patients.

Atherosclerosis is a diffuse, systemic disorder of the large and medium-sized arterial vessels, affecting the coronary, cerebral and peripheral circulation. Chronic inflammatory processes are the central pathophysiological mechanism largely driven by lipid accumulation, and provide the substrate for occlusive thrombus formation. The clinical sequelae of acute arterial thrombosis, heart attack and stroke, are the most common causes of morbidity and mortality in the industrialized world. Such acute events are characterized by rupture or erosion of the atherosclerotic plaque leading to acute thrombosis. The atherosclerotic process and associated thrombotic complications are collectively termed atherothrombosis. The platelet is a pivotal mediator of various endothelial, immune, thrombotic and inflammatory responses and therefore a key player in the initiation and progression of atherothrombosis. A robust evidence base supports the clear clinical benefits of antiplatelet agents in the primary and secondary therapy of atherothrombotic disorders. Percutaneous coronary and peripheral interventions have an established central role in the management of atherothrombotic disease and demand a greater understanding of platelet biology. In this article, we provide a clinically orientated overview of the pathophysiology of arterial thrombosis and the evidence supporting the use of the various established antiplatelet therapies, and discuss new and future agents.

There is intense interest in the identification of novel biomarkers which improve the diagnosis of heart failure. Serum samples from 52 patients with systolic heart failure (EF

Purpose of review The rapid advancement in transcatheter therapies seeks to provide less invasive options compared with conventional surgery in the treatment of acquired valvular heart disease. A number of transcatheter mitral valve devices using a variety of approaches for the treatment of mitral regurgitation are under development or in early clinical application. Although yet to be clearly defined, there is no doubt that transcatheter mitral valve procedures will have a significant role alongside conventional surgery. The question is: will surgeons, who have led the treatment of mitral valve disease for the past 30 years, have a role in these procedures? Recent findings In order to answer this question, this review discusses key understanding of mitral valve anatomy, function and disorder required to perform transcatheter mitral valve interventions. It assesses the potential role of transcatheter therapies with particular reference to percutaneous edge-to-edge repair using the Mitraclip system (Abbott Vascular Devices, California, USA). The new era in collaboration between surgeons and cardiologists is discussed and the potential role of the surgeon in percutaneous mitral valve procedures is examined. Summary Transcatheter mitral valve procedures demand increasing collaboration between cardiologists and surgeons in order to achieve optimal outcomes. Interventional cardiologists will require dedicated training in the specialized field of transcatheter interventions in acquired structural heart diseases. As the delivery of such therapies brings the interface between interventional cardiology and cardiac surgery ever closer, there is the potential for a niche area in cardiac surgery to develop comprising minimally invasive surgical and transcatheter skills.

The time that transcription factors remain nuclear is a major determinant for transcriptional activity. It has recently been demonstrated that the phosphatase calcineurin is translocated to the nucleus with the transcription factor nuclear factor of activated T cells (NF-AT). This study identifies a nuclear localization sequence (NLS) and a nuclear export signal (NES) in the sequence of calcineurin. Furthermore we identified the nuclear cargo protein importinβ1to be responsible for nuclear translocation of calcineurin. Inhibition of the calcineurin/importin interaction by a competitive peptide (KQECKIKYSERV), which mimicked the calcineurin NLS, prevented nuclear entry of calcineurin. A noninhibitory control peptide did not interfere with the calcineurin/importin binding. Using this approach, we were able to prevent the development of myocardial hypertrophy. In angiotensin II-stimulated cardiomyocytes, [3H]-leucine incorporation (159%±9 versus 111%±11;PPP=NS). We conclude that calcineurin is not only capable of dephosphorylating NF-AT, thus enabling its nuclear import, but the presence of calcineurin in the nucleus is also important for full NF-AT transcriptional activity.

The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and alpha-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, alpha-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399-447 of alpha-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin.dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality.

The plasma membrane calcium/calmodulin dependent ATPase (PMCA) is a calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. PMCA is the only system for calcium extrusion in the majority of cells. In excitable cells such as cardiomyocytes however, PMCA has been shown to play only a minor role in calcium homeostasis. In these cells the main mechanism of calcium extrusion is the sodium calcium exchanger. However, increasing evidence points to an important role for PMCA in signal transduction; in particular in the nitric oxide signalling pathway. In this review we will discuss recent advances that support a key role for PMCA in signal transduction and the potential for therapeutic targeting of this molecule in the treatment of cardiac diseases.

The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma membrane calcium/calmodulin ATPase pump (PMCA), as a potential modulator of signal transduction pathways. We demonstrate a novel interaction between PMCA and the calcium/calmodulin-dependent phosphatase, calcineurin, in mammalian cells. The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. This inhibition was notably reversed by the co-expression of the PMCA4b interaction domain, demonstrating the functional significance of this interaction. PMCA4b was, however, unable to confer its inhibitory effect in the presence of a calcium/calmodulin-independent constitutively active mutant calcineurin A suggesting a calcium/calmodulin-dependent mechanism. The modulatory function of PMCA4b is further supported by the observation that endogenous calcineurin moves from the cytoplasm to the plasma membrane when PMCA4b is overexpressed. We suggest recruitment by PMCA4b of calcineurin to a low calcium environment as a possible explanation for these findings. In summary, our results offer strong evidence for a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. This study reinforces the emerging role of PMCA as a molecular organizer and regulator of signaling transduction pathways.

Plasma membrane calmodulin-dependent calcium ATPases (PMCAs) are enzymatic systems implicated in the extrusion of calcium from the cell. We and others have previously identified molecular interactions between the cytoplasmic COOH-terminal end of PMCA and PDZ domain-containing proteins. These interactions suggested a new role for PMCA as a modulator of signal transduction pathways. The existence of other intracellular regions in the PMCA molecule prompted us to investigate the possible participation of other domains in interactions with different partner proteins. A two-hybrid screen of a human fetal heart cDNA library, using the region 652-840 of human PMCA4b (located in the catalytic, second intracellular loop) as bait, revealed a novel interaction between PMCA4b and the tumor suppressor RASSF1, a Ras effector protein involved in H-Ras-mediated apoptosis. Immunofluorescence co-localization, immunoprecipitation, and glutathione S-transferase pull-down experiments performed in mammalian cells provided further confirmation of the physical interaction between the two proteins. The interaction domain has been narrowed down to region 74-123 of RASSF1C (144-193 in RASSF1A) and 652-748 of human PMCA4b. The functionality of this interaction was demonstrated by the inhibition of the epidermal growth factor-dependent activation of the Erk pathway when PMCA4b and RASSF1 were co-expressed. This inhibition was abolished by blocking PMCA/RASSSF1 association with an excess of a green fluorescent protein fusion protein containing the region 50-123 of RASSF1C. This work describes a novel protein-protein interaction involving a domain of PMCA other than the COOH terminus. It suggests a function for PMCA4b as an organizer of macromolecular protein complexes, where PMCA4b could recruit diverse proteins through interaction with different domains. Furthermore, the functional association with RASSF1 indicates a role for PMCA4b in the modulation of Ras-mediated signaling.

Transcatheter aortic valve implantation (TAVI) is considered in patients with severe aortic stenosis who are not suitable or high risk for open surgery. Access via the femoral approach is not feasible in people with extensive iliac and femoral vascular disease and in these patients alternative