miR-467 regulates inflammation and blood insulin and glucose.

Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.

Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart.

BACKGROUND: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado). METHODS: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). RESULTS: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10-100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P<0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P<0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10-100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P<0.01) and GIRK4 (1.7±0.8-fold; P<0.05) protein expression than lateral/posterior LA. CONCLUSIONS: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.

Race, Genotype, and Prognosis in Black Patients With Transthyretin Cardiac Amyloidosis.

Previous studies suggest worse outcomes in patients with variant transthyretin cardiac amyloidosis (ATTR-CA) because of valine-to-isoleucine substitution at Position 122 (V122I) (ATTRv-CA) compared with patients with wild-type (WT) disease (ATTRwt-CA). Given V122I is almost exclusively found in Black patients, it is unclear if this is attributable to the biology of genotype or racial differences. Patients with ATTR-CA diagnosed between January 2001 and August 2021 were characterized into 3 categories: (1) White with ATTRwt-CA (White-WT); (2) Black with V122I ATTRv-CA (Black-V122I), and (3) Black with ATTRwt-CA (Black-WT). Event-free survival (composite of death, left ventricular assist device, or cardiac transplant) was evaluated using univariable and multivariable analyses over a median follow-up of 1.6 (0.7 to 2.90) years. Of 694 ATTR-CA patients, 502 (72%) were White-WT, 139 Black-V122I (20%), and 53 Black-WT (8%). Notably, 28% of Black patients with ATTR-CA had WT disease and not the V122I variant. Using multivariable modeling to adjust for several prognostic features, Black-V122I had higher risk of the composite adverse outcome compared with a grouped cohort of patients with WT disease (White-WT and Black-WT) (hazard ratio [HR] 1.82, confidence interval [CI] 1.30-2.56, p < 0.001). Furthermore, the Black cohort as a whole (Black-V122I and Black-WT) demonstrated greater risk of adverse outcomes compared with White-WT (HR 1.63, CI 1.19-2.24, p = 0.002). Black-V122I had greater risk of the primary end point compared with White-WT (HR 1.80, CI 1.27-2.56, p = 0.001). Black patients with ATTR-CA have worse event-free survival than White-WT despite risk adjustment. However, it remains unclear whether this is driven by differences in race or genotype given the smaller number of Black-WT patients. Approximately one-quarter of Black patients had WT, of which a greater proportion were female compared with White-WT.

Pericardial Disease in Cardiac Amyloidosis: A Comprehensive Review.

In patients with cardiac amyloidosis, pericardial involvement is common, with up to half of patients presenting with pericardial effusions. The pathophysiological mechanisms of pericardial pathology in cardiac amyloidosis include chronic elevations in right-sided filling pressures, myocardial and pericardial inflammation due to cytotoxic effects of amyloid deposits, and renal involvement with subsequent uremia and hypoalbuminemia. The pericardial effusions are typically small; however, several cases of life-threatening cardiac tamponade with hemorrhagic effusions have been described as a presenting clinical scenario. Constrictive pericarditis can also occur due to amyloidosis and its identification presents a clinical challenge in patients with cardiac amyloidosis who concurrently manifest signs of restrictive cardiomyopathy. Multimodality imaging, including echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging, is useful in the evaluation and management of this patient population. The recognition of pericardial effusion is important in the risk stratification of patients with cardiac amyloidosis as its presence confers a poor prognosis. However, specific treatment aimed at the effusions themselves is seldom indicated. Cardiac tamponade and constrictive pericarditis may necessitate pericardiocentesis and pericardiectomy, respectively.

Dobutamine-Induced Takotsubo Cardiomyopathy With Severe Left Ventricular Dysfunction.

Takotsubo cardiomyopathy (TCM) is characterized by severe left ventricular dysfunction. It presents as an acute coronary syndrome; however, the difference lies in the lack of coronary artery obstruction during a coronary angiogram. The left ventricular dysfunction extends beyond the area supplied with concordant coronary arteries. We describe a case of a 41-year-old female evaluated for acute coronary syndrome, later diagnosed with a unique reverse subtype of TCM.

Novel application of 3D contrast-enhanced CMR to define fibrotic structure of the human sinoatrial node in vivo.

AIMS: The adult human sinoatrial node (SAN) has a specialized fibrotic intramural structure (35-55% fibrotic tissue) that provides mechanical and electrical protection from the surrounding atria. We hypothesize that late gadolinium-enhanced cardiovascular magnetic resonance (LGE-CMR) can be applied to define the fibrotic human SAN structure in vivo. METHODS AND RESULTS: LGE-CMR atrial scans of healthy volunteers (n olu, 23-52 y.o.) using a 3 Tesla magnetic resonance imaging system with a spatial resolution of 1.0 mm3 or 0.625 × 0.625 × 1.25 mm3 were obtained and analysed. Percent fibrosis of total connective and cardiomyocyte tissue area in segmented atrial regions were measured based on signal intensity differences of fibrotic vs. non-fibrotic cardiomyocyte tissue. A distinct ellipsoidal fibrotic region (length: 23.6 ± 1.9 mm; width: 7.2 ± 0.9 mm; depth: 2.9 ± 0.4 mm) in all hearts was observed along the posterior junction of the crista terminalis and superior vena cava extending towards the interatrial septum, corresponding to the anatomical location of the human SAN. The SAN fibrotic region consisted of 41.9 ± 5.4% of LGE voxels above an average threshold of 2.7 SD (range 2-3 SD) from the non-fibrotic right atrial free wall tissue. Fibrosis quantification and SAN identification by in vivo LGE-CMR were validated in optically mapped explanted donor hearts ex vivo (n ivo, 19-65 y.o.) by contrast-enhanced CMR (9.4 Tesla; up to 90 µm3 resolution) correlated with serial histological sections of the SAN. CONCLUSION: This is the first study to visualize the 3D human SAN fibrotic structure in vivo using LGE-CMR. Identification of the 3D SAN location and its high fibrotic content by LGE-CMR may provide a new tool to avoid or target SAN structure during ablation.

Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure.

The human sinoatrial node (SAN) efficiently maintains heart rhythm even under adverse conditions. However, the specific mechanisms involved in the human SAN's ability to prevent rhythm failure, also referred to as its robustness, are unknown. Challenges exist because the three-dimensional (3D) intramural structure of the human SAN differs from well-studied animal models, and clinical electrode recordings are limited to only surface atrial activation. Hence, to innovate the translational study of human SAN structural and functional robustness, we integrated intramural optical mapping, 3D histology reconstruction, and molecular mapping of the ex vivo human heart. When challenged with adenosine or atrial pacing, redundant intranodal pacemakers within the human SAN maintained automaticity and delivered electrical impulses to the atria through sinoatrial conduction pathways (SACPs), thereby ensuring a fail-safe mechanism for robust maintenance of sinus rhythm. During adenosine perturbation, the primary central SAN pacemaker was suppressed, whereas previously inactive superior or inferior intranodal pacemakers took over automaticity maintenance. Sinus rhythm was also rescued by activation of another SACP when the preferential SACP was suppressed, suggesting two independent fail-safe mechanisms for automaticity and conduction. The fail-safe mechanism in response to adenosine challenge is orchestrated by heterogeneous differences in adenosine A1 receptors and downstream GIRK4 channel protein expressions across the SAN complex. Only failure of all pacemakers and/or SACPs resulted in SAN arrest or conduction block. Our results unmasked reserve mechanisms that protect the human SAN pacemaker and conduction complex from rhythm failure, which may contribute to treatment of SAN arrhythmias.

Three-dimensional Integrated Functional, Structural, and Computational Mapping to Define the Structural "Fingerprints" of Heart-Specific Atrial Fibrillation Drivers in Human Heart Ex Vivo.

BACKGROUND: Structural remodeling of human atria plays a key role in sustaining atrial fibrillation (AF), but insufficient quantitative analysis of human atrial structure impedes the treatment of AF. We aimed to develop a novel 3-dimensional (3D) structural and computational simulation analysis tool that could reveal the structural contributors to human reentrant AF drivers. METHODS AND RESULTS: High-resolution panoramic epicardial optical mapping of the coronary-perfused explanted intact human atria (63-year-old woman, chronic hypertension, heart weight 608 g) was conducted during sinus rhythm and sustained AF maintained by spatially stable reentrant AF drivers in the left and right atrium. The whole atria (107×61×85 mm3) were then imaged with contrast-enhancement MRI (9.4 T, 180×180×360-µm3 resolution). The entire 3D human atria were analyzed for wall thickness (0.4-11.7 mm), myofiber orientations, and transmural fibrosis (36.9% subendocardium; 14.2% midwall; 3.4% subepicardium). The 3D computational analysis revealed that a specific combination of wall thickness and fibrosis ranges were primarily present in the optically defined AF driver regions versus nondriver tissue. Finally, a 3D human heart-specific atrial computer model was developed by integrating 3D structural and functional mapping data to test AF induction, maintenance, and ablation strategies. This 3D model reproduced the optically defined reentrant AF drivers, which were uninducible when fibrosis and myofiber anisotropy were removed from the model. CONCLUSIONS: Our novel 3D computational high-resolution framework may be used to quantitatively analyze structural substrates, such as wall thickness, myofiber orientation, and fibrosis, underlying localized AF drivers, and aid the development of new patient-specific treatments.

Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways.

INTRODUCTION: Despite a century of extensive study on the human sinoatrial node (SAN), the structure-to-function features of specialized SAN conduction pathways (SACP) are still unknown and debated. We report a new method for direct analysis of the SAN microstructure in optically-mapped human hearts with and without clinical history of SAN dysfunction. METHODS: Two explanted donor human hearts were coronary-perfused and optically-mapped. Structural analyses of histological sections parallel to epicardium (∼13-21 µm intervals) were integrated with optical maps to create 3D computational reconstructions of the SAN complex. High-resolution fiber fields were obtained using 3D Eigen-analysis of the structure tensor, and used to analyze SACP microstructure with a fiber-tracking approach. RESULTS: Optical mapping revealed normal SAN activation of the atria through a lateral SACP proximal to the crista terminalis in Heart #1 but persistent SAN exit block in diseased Heart #2. 3D structural analysis displayed a functionally-observed SAN border composed of fibrosis, fat, and/or discontinuous fibers between SAN and atria, which was only crossed by several branching myofiber tracts in SACP regions. Computational 3D fiber-tracking revealed that myofiber tracts of SACPs created continuous connections between SAN #1 and atria, but in SAN #2, SACP region myofiber tracts were discontinuous due to fibrosis and fat. CONCLUSIONS: We developed a new integrative functional, structural and computational approach that allowed for the resolution of the specialized 3D microstructure of human SACPs for the first time. Application of this integrated approach will shed new light on the role of the specialized SAN microanatomy in maintaining sinus rhythm.