Conduction recovery following pacemaker implantation after transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is increasingly used to treat severe aortic stenosis. A frequent complication of TAVR is high-grade or complete atrioventricular (AV) block requiring a permanent pacemaker (PPM). There are little data on the long-term dependency on pacing after TAVR. The objective of this study was to determine the proportion of patients receiving a PPM for high-grade or complete AV block after TAVR who remain dependent on the PPM in follow-up and to determine any risk factors for, particularly the effect of postballoon dilation (PBD) on, pacemaker dependency. METHODS: Of 594 consecutive patients without prior PPM undergoing TAVR (81.9% balloon-expandable, 18.1% self-expandable valve), 67 (13.1%) received a PPM after TAVR. PPM dependency was defined as AV block with a ventricular escape rate of ≤ 40 beats/min. Patient and procedural characteristics were examined according to PPM dependency status. RESULTS: Of the 67 patients who received a PPM within 10 days after TAVR, 27/67 (40.3%) were dependent at first follow-up and only 9/41 (21.9%) at 1 year. PPM dependency was more common after a self-expanding valve (76.9% vs 31.5%, P < 0.01), in those who underwent PBD (66.7% vs 24.4%, P < 0.01), and in patients in persistent complete AV block at PPM implantation (62.5% vs 7.4%, P < 0.01). CONCLUSIONS: Fewer than half of patients who receive a new PPM following TAVR are pacemaker dependent at early follow-up (< 30 days). The use of self-expanding valves and PBD are associated with a markedly increased risk of PPM dependency.

Coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction.

There are multiple proposed mechanisms for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). We hypothesized that coronary microvascular dysfunction is common in these patients. In a prospective, observational study, patients undergoing cardiac catheterization with HFpEF [left ventricular (LV) ejection fraction ≥ 50% and with clinical HF] were compared with similar patients without HFpEF. Patients with ≥50% stenosis were excluded, and coronary flow reserve (CFR) and the index of microvascular resistance (IMR) were measured after adenosine administration using a guidewire, with CFR ≤ 2 and IMR ≥ 23 being abnormal. Baseline characteristics and CFR and IMR were compared in 30 HFpEF patients and 14 control subjects. Compared with control subjects, HFpEF patients were older (65.4 ± 9.6 vs. 55.1 ± 3.1 yr, P < 0.01), had higher numbers of comorbidities (4.4 ± 1.5 vs. 2.6 ± 1.9, P = 0.002), had higher median B-type natriuretic peptide [161 (interquartile range: 75-511) pg/dl vs. 37 (interquartile range: 18.5-111) pg/dl, P < 0.01], and had higher LV end-diastolic pressure (17.8 ± 4.2 vs. 8.4 ± 4.2, P < 0.01). HFpEF patients had lower CFR (2.55 ± 1.60 vs. 3.84 ± 1.89, P = 0.024) and higher IMR (26.7 ± 10.3 vs. 19.7 ± 9.7 units, P = 0.037) than control subjects. Most (71.4%) control subjects had normal coronary physiology, whereas 36.7% of HFpEF patients had both abnormal CFR and IMR and another 36.7% had either abnormal CFR or IMR. In conclusion, this is the first study that has reported invasively determined CFR and IMR in HFpEF patients. We demonstrated the presence of four distinct coronary physiology groups in HFpEF patients. Investigation into the potential mechanisms for these findings is needed. NEW & NOTEWORTHY In this prospective observational study of patients with heart failure with preserved ejection fraction (HFpEF), we found that patients with HFpEF had more abnormalities of coronary flow and resistance than asymptomatic control patients, indicating that coronary microvascular dysfunction may play a role in the HFpEF disease process.

Global longitudinal strain from resting echocardiogram is associated with long-term adverse cardiac outcomes in patients with suspected coronary artery disease.

PURPOSE: Measuring myocardial strain using two-dimensional speckle tracking echocardiography has emerged as a new tool to identify subclinical ventricular dysfunction. Abnormal strain has been shown to have superior sensitivity compared with dobutamine stress echocardiography for viability assessment; however, there is a paucity of data regarding the prediction of long-term major adverse cardiac events. We compared the prognostic ability of both global longitudinal strain (GLS) from resting echocardiograms to regional wall motion score index (WMSI) from stress echocardiograms in their ability to predict long-term major adverse cardiac events. METHODS: Patients referred for stress echocardiography, who also underwent coronary angiography within 3 months of stress echo (n=122), were enrolled. Patients with reduced ejection fractions (<40%) were excluded. Patients were followed for a median of 3.4 years for major adverse cardiac events, readmissions and repeat cardiac testing. RESULTS: Patients with abnormal GLS (GLS <16.8%) from the resting echocardiogram obtained as part of the exercise echocardiogram experienced a significantly shorter time to major adverse cardiac events (p=0.026), first cardiovascular hospitalization and repeat cardiac testing (p=0.0011) compared to those with normal GLS. Abnormal GLS appears to be a better predictor than abnormal WMSI in predicting major adverse cardiac events (p=0.174) and time to first cardiovascular hospitalization or repeat cardiac testing (p=0.0093). CONCLUSION: GLS may be a better predictor of long-term major adverse cardiac events, readmissions and repeat cardiac testing than WMSI in patients undergoing stress echocardiography.

Contemporary management of ST-segment elevation myocardial infarction.

ST-elevation myocardial infarction (STEMI), which constitutes nearly 25-40 % of current acute myocardial infarction (AMI) cases, is a medical emergency that requires prompt recognition and treatment. Since the 2013 STEMI practice guidelines, a wealth of additional data that may further advance optimal STEMI practices has emerged. These data highlight the importance of improving patient treatment and transport algorithms for STEMI from non-primary percutaneous coronary intervention (PCI) centers. In addition, a focus on the reduction of total pain-to-balloon (P2B) times rather than simply door-to-balloon (D2B) times may further improve outcomes after primary PCI for STEMI. The early administration of newer oral P2Y12 inhibitors, including crushed forms of these agents for faster absorption, represents another treatment advancement. Recent data also suggest avoiding concurrent morphine use due to interactions with P2Y12 inhibitors. Furthermore, new technological advancements and investigational therapies, including Bioresorbable Vascular Scaffolds and the use of pre-intervention intravenous microbubbles with transthoracic ultrasound, hold promise to play a useful role in future STEMI care. Despite these advancements, the prompt recognition of STEMI, at both the patient and health care system level, remains the cornerstone of optimal treatment.

Efficacy and safety of novel oral anticoagulants in patients with bioprosthetic valves.

PURPOSE: Prosthetic valve replacement is performed in several hundred thousand patients worldwide annually, and many of these patients have or will ultimately develop atrial fibrillation or flutter (AF). Novel oral anticoagulants (NOACs) are not recommended in patients with AF and mechanical valves but have not been evaluated in patients with bioprosthetic valves. This study sought to evaluate the efficacy and safety of NOACs in patients with AF and bioprosthetic valves. METHODS: A retrospective single-center cohort study was performed on all patients with bioprosthetic valve implantation, for whom a NOAC was prescribed for the indication of AF. Patients were evaluated for thromboembolic events including imaging confirmed ischemic stroke, clinically suspected transient ischemic attack, and major bleeding events (according to International Society on Thrombosis and Hemostasis definition). RESULTS: In total, 73 patients (26 female, 35.6 %) were identified. NOAC therapy began, on average, 990.0 ± 1029.1 days after bioprosthetic valve implantation for an average duration of 511.8 ± 400.8 days. Aspirin was used concomitantly in a majority of patients (72.6 %). There were no ischemic strokes identified (0.0 %) and one possible TIA (1.4 %). There were 6 (8.2 %) minor and 5 (6.9 %) major bleeding events. CONCLUSION: The use of NOAC therapy for AF in patients with bioprosthetic valves appears safe and effective in the occurrence of thromboembolic events, however, at the expense of increased bleeding. Larger studies are necessary to confirm these findings.

Architecture of a serine recombinase-DNA regulatory complex.

An essential feature of many site-specific recombination systems is their ability to regulate the direction and topology of recombination. Resolvases from the serine recombinase family assemble an interwound synaptic complex that harnesses negative supercoiling to drive the forward reaction and promote recombination between properly oriented sites. To better understand the interplay of catalytic and regulatory functions within these synaptic complexes, we have solved the structure of the regulatory site synapse in the Sin resolvase system. It reveals an unexpected synaptic interface between helix-turn-helix DNA-binding domains that is also highlighted in a screen for synapsis mutants. The tetramer defined by this interface provides the foundation for a robust model of the synaptic complex, assembled entirely from available crystal structures, that gives insight into how the catalytic activity of Sin and other serine recombinases may be regulated.

Metal ion-mediated reduction in surface entropy improves diffraction quality of crystals of the IRAK-4 death domain.

Interleukin-1 receptor-associated kinase-4 (IRAK-4) is an essential component of innate immunity in mice and humans. IRAK-4 is a bipartite protein composed of a death domain (DD) that mediates molecular recognition, and a catalytic kinase domain. Structure determination of the proteolytically stable, soluble IRAK-4 DD was hampered by poor diffraction quality. Addition of manganese (II) chloride to the crystallization solution produced significant improvements in diffraction, and the structure has been determined to 1.7-Angstrom resolution. Examination of the IRAK-4 DD crystal structure reveals a single manganese ion coordinated to surface residues lysine-21 and aspartate-24. Coordination of the manganese ion resulted in a reduction in the surface entropy at this region of the molecule, by generating a contact-forming and conformationally homogenous surface patch. Prior studies have shown that surface entropy reduction by mutation of surface residues with large flexible side chains (i.e., Lys and Glu) to smaller side chains results in the production of diffraction-quality crystals. The intrinsic high surface entropy of Lys residues can also be decreased by reductive methylation. Our results suggest that screening of manganese ions as a crystallization additive may also facilitate ordered crystallization by reduction of surface entropy. Given the quick and inexpensive nature of screening, this technique is likely to be amenable to high-throughput methods such as those employed by Protein Structure Initiatives.

Cutting edge: molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling.

IL-1R-associated kinase (IRAK) 4 is an essential component of innate immunity. IRAK-4 deficiency in mice and humans results in severe impairment of IL-1 and TLR signaling. We have solved the crystal structure for the death domain of Mus musculus IRAK-4 to 1.7 A resolution. This is the first glimpse of the structural details of a mammalian IRAK family member. The crystal structure reveals a six-helical bundle with a prominent loop, which among IRAKs and Pelle, a Drosophila homologue, is unique to IRAK-4. This highly structured loop contained between helices two and three, comprises an 11-aa stretch. Although innate immune domain recognition is thought to be very similar between Drosophila and mammals, this structural component points to a drastic difference. This structure can be used as a framework for future mutation and deletion studies and potential drug design.