Decreased Heart Rate Variability in Children with Acute Decompensated Heart Failure is Associated with Poor Outcomes.

Heart rate variability (HRV) is a noninvasive indicator of the health of neurocardiac interactions of the autonomic nervous system. In adults, decreased HRV correlates with increased cardiovascular mortality. However, the relationship between HRV and outcomes in children with acute decompensated heart failure (ADHF) has not been described. Patients < 21 years old hospitalized with ADHF from 2013 to 2019 were included (N = 79). Primary outcome was defined as death, heart transplant, or mechanical circulatory support (MCS). The median standard deviation of the R-to-R interval in 5-min intervals (SDNN) was calculated from telemetry data obtained across the first 24 h of admission. Patients who met the primary outcome had significantly lower median SDNN (13.8 [7.8, 29.1]) compared to those who did not (24.6 [15.3, 84.4]; p = 0.004). A median SDNN of 20 ms resulted in a sensitivity of 68% and specificity of 69%. Median SDNN < 20 ms represented decreased freedom from primary outcome (p = 0.043) and a hazard ratio of 2.2 in multivariate analysis (p = 0.016). Pediatric patients with ADHF who died, underwent heart transplant, or required MCS had significantly decreased HRV at presentation compared to those that did not. This supports HRV as a noninvasive tool to improve prognostication in children in ADHF.

Abnormal Left Ventricular Strain Correlates with Left Ventricular Dysfunction but not Aortic Pathology in Marfan Syndrome in Children.

Cardiomyopathy is a complication in adults with Marfan syndrome (MFS). Early recognition of MFS patients at high risk of cardiomyopathy could impact monitoring and treatment. Abnormal ventricular strain has been associated with impaired ventricular function among adults with MFS but remains understudied in children. We retrospectively analyzed a cohort of patients with MFS undergoing cardiac magnetic resonance imaging (CMR) performed in 2003-2018 at age < 19 years. Correlations were evaluated between initial global circumferential strain (GCS) and global longitudinal strain (GLS) and the outcomes of left ventricular ejection fraction (LVEF), aortic root z-score, and vertebral artery tortuosity index corrected for height (VTI-h), all measured from CMR, using Spearman correlation. In those with serial CMR, the ability of ventricular strain to predict development of abnormal LVEF within a 5-year period was assessed. A total of 31 subjects were included (median age at initial CMR 13.5 years, Q1Q3 10.7-16.2 years), with 48% (n = 15) having LVEF < 55%. Worse GCS and worse GLS were associated with lower LVEF (ρ = - 0.629, p < 0.001 and ρ = - 0.411, p = 0.030, respectively). A clinical cutoff of GCS = - 34% predicted LVEF < 55% with sensitivity = 80% and specificity = 50%. Neither GCS nor GLS was associated with aortic root z-score (GCS: p = 0.524; GLS: p = 0.624) nor VTI-h (GCS: p = 0.949; GLS: p = 0.593). Of those with LVEF ≥ 55%, initial GCS and GLS did not differ between those with later normal versus abnormal LVEF (GCS: p = 0.505; GLS: p = 0.232). In this cohort, abnormal LV strain was associated with abnormal LVEF, but not with aortic dilation or low LVEF within the 5 years post-CMR.

Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.

BACKGROUND: TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing. METHODS: Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed. RESULTS: Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance. CONCLUSIONS: Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.

A 14-year-old in heart failure with multiple cardiomyopathy variants illustrates a role for signal-to-noise analysis in gene test re-interpretation.

Variants of unknown significance in cardiomyopathic disease should be analyzed systematically based on the prevalence of the variant in the population compared to prevalence of disease, evidence that other variants in the gene are pathologic, consistency of prediction software on pathogenicity, and the current clinical consensus.

Eliminating Regurgitation Reduces Fibrotic Remodeling of Functional Mitral Regurgitation Conditioned Valves.

Functional mitral regurgitation (FMR) is an insidious and poorly understood condition affecting patients with myocardial disease. While current treatments reduce regurgitation, their ability to reverse mitral valve pathology is unclear. We utilized a pseudo-physiological flow loop to study how repair impacted valve composition. Porcine mitral valves were cultured in control geometry (native papillary muscle position and annular area) or high-tension FMR geometry (5 mm apical and 5 mm lateral displacement of papillary muscles, 65% increased annular area) for 2 weeks. To mimic repair, a reversal condition was created by returning one-week FMR conditioned valves to a non-regurgitant geometry and culturing for 1 week. Valve composition and material properties were analyzed. After two-week culture, FMR conditioned tissues were stiffer and stronger than control and underwent extensive fibrotic remodeling, with increased prolyl-4-hydroxylase, lysyl oxidase, matrix metalloproteinase-1, and decorin. The reversal condition displayed a heterogeneous, leaflet- and orientation-dependent response. Reversal-conditioned anterior leaflets and circumferential tissue sections continued to have significant fibrotic remodeling compared to control, whereas reversal-conditioned posterior leaflets, chordae tendineae, and radial tissue sections had significantly decreased remodeling compared to FMR-conditioned tissues. These findings suggest current repairs only partially reverse pathology, underscoring the need for innovation in the treatment of FMR.

Regurgitation Hemodynamics Alone Cause Mitral Valve Remodeling Characteristic of Clinical Disease States In Vitro.

Mitral valve regurgitation is a challenging clinical condition that is frequent, highly varied, and poorly understood. While the causes of mitral regurgitation are multifactorial, how the hemodynamics of regurgitation impact valve tissue remodeling is an understudied phenomenon. We employed a pseudo-physiological flow loop capable of long-term organ culture to investigate the early progression of remodeling in living mitral valves placed in conditions resembling mitral valve prolapse (MVP) and functional mitral regurgitation (FMR). Valve geometry was altered to mimic the hemodynamics of controls (no changes from native geometry), MVP (5 mm displacement of papillary muscles towards the annulus), and FMR (5 mm apical, 5 mm lateral papillary muscle displacement, 65% larger annular area). Flow measurements ensured moderate regurgitant fraction for regurgitation groups. After 1-week culture, valve tissues underwent mechanical and compositional analysis. MVP conditioned tissues were less stiff, weaker, and had elevated collagen III and glycosaminoglycans. FMR conditioned tissues were stiffer, more brittle, less extensible, and had more collagen synthesis, remodeling, and crosslinking related enzymes and proteoglycans, including decorin, matrix metalloproteinase-1, and lysyl oxidase. These models replicate clinical findings of MVP (myxomatous remodeling) and FMR (fibrotic remodeling), indicating that valve cells remodel extracellular matrix in response to altered mechanical homeostasis resulting from disease hemodynamics.

Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain.

To determine how extracellular matrix and contractile valvular cells contribute to the heterogeneous motion and strain across the mitral valve (MV) during the cardiac cycle, regional MV material properties, matrix composition, matrix turnover, and cell phenotype were related to regional leaflet strain. Radiopaque markers were implanted into 14 sheep to delineate the septal (SEPT), lateral (LAT), and anterior and posterior commissural leaflets (ANT-C, POST-C). Videofluoroscopy imaging was used to calculate radial and circumferential strains. Mechanical properties were assessed using uniaxial tensile testing and micropipette aspiration. Matrix composition and cell phenotypes were immunohistochemically evaluated within each leaflet region [basal leaflet (BL), mid-leaflet (ML), and free edge]. SEPT-BL segments were stiffer and stronger than other valve tissues, while LAT segments demonstrated more extensibility and strain. Collagens I and III in SEPT were greater than in LAT, although LAT showed greater collagen turnover [matrix metalloprotease (MMP)-13, lysyl oxidase] and cell activation [smooth muscle alpha-actin (SMaA), and non-muscle myosin (NMM)]. MMP13, NMM, and SMaA were strongly correlated with each other, as well as with radial and circumferential strains in both SEPT and LAT. SMaA and MMP13 in POST-C ML was greater than ANT-C, corresponding to greater radial strains in POST-C. This work directly relates leaflet strain, material properties, and matrix turnover, and suggests a role for myofibroblasts in the heterogeneity of leaflet composition and strain. New approaches to MV repair techniques and ring design should preserve this normal coupling between leaflet composition and motion.

Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction.

PURPOSE: Regional heterogeneity in mitral annular contraction, which is generally ascribed to the fibrous vs. muscular annular composition, ensures proper leaflet motion and timing of coaptation. It is unknown whether the fibroblast-like cells in the annulus modulate this heterogeneity, even though valvular interstitial cells (VICs) can be mechanically "activated." METHODS: Fourteen sheep underwent implantation of radiopaque markers around the mitral annulus defining four segments: septal (SEPT), lateral (LAT), and anterior (ANT-C) and posterior (POST-C) commissures. Segmental annular contraction was calculated using biplane videofluoroscopy. Immunohistochemistry of annular cross sections assessed regional matrix content, matrix turnover, and cell phenotype. Micropipette aspiration measured the Young's modulus of the leaflets adjacent to the myocardial border. RESULTS: Whereas SEPT contained more collagen I and III, LAT demonstrated more collagen and elastin turnover as shown by greater decorin, lysyl oxidase, and matrix metalloprotease (MMP)-13 and smooth muscle alpha-actin (SMaA). This greater matrix turnover paralleled greater annular contraction in LAT vs. SEPT (22.5% vs. 4.1%). Similarly, POST-C had more SMaA and MMP13 than ANT-C, consistent with greater annular contraction in POST-C (18.8% vs. 11.1%). Interestingly, POST-C had the greatest effective modulus, significantly higher than LAT. CONCLUSIONS: These data suggest that matrix turnover by activated VICs relates to annular motion heterogeneity, maintains steady-state mechanical properties in the annulus, and could be a therapeutic target when annular motion is impaired. Conversely, alterations in this heterogeneous annular contraction, whether through disease or secondary to ring annuloplasty, could disrupt this normal pattern of cell-mediated matrix remodeling and further adversely impact mitral valve function.

The tensile and viscoelastic properties of aortic valve leaflets treated with a hyaluronidase gradient.

Purpose: When diseased, aortic valves are typically replaced with bioprosthetic heart valves (BPHVs), porcine valves or bovine pericardium that are fixed in glutaraldehyde. These replacements fail within 10-15 years due to calcification and fatigue, and their failure coincides with a loss of glycosaminoglycans (GAGs). This study investigates this relationship between GAG concentration and the tensile and viscoelastic properties of aortic valve leaflets. Methods: Aortic valve leaflets were dissected from porcine hearts and digested in hyaluronidase in concentrations ranging from 0-5 U/mL for 0-24 hours, yielding a spectrum of GAG concentrations that was measured using the uronic acid assay and confirmed by Alcian Blue staining. Digested leaflets with varying GAG concentrations were then tested in tension in the circumferential and radial directions with varying strain rate, as well as in stress relaxation. Results: The GAG concentration of the leaflets was successfully reduced using hyaluronidase, although water content was not affected. Elastic modulus, the maximum stress, and hysteresis significantly increased with decreasing GAG concentration. Extensibility and the radius of transition curvature did not change with GAG concentration. The stress relaxation behavior and strain-rate independent nature of the leaflet did not change with GAG concentration. Conclusions: These results suggest that GAGs in the spongiosa lubricate tissue motion and reduce stresses experienced by the leaflet. This study forms the basis for predictive models of BPHV mechanics based on GAG concentration, and guides the rational design of future heart valve replacements.

Differentiating the aging of the mitral valve from human and canine myxomatous degeneration.

During the course of both canine and human aging, the mitral valve remodels in generally predictable ways. The connection between these aging changes and the morbidity and mortality that accompany pathologic conditions has not been made clear. By exploring work that has investigated the specific valvular changes in both age and disease, with respect to the cells and the extracellular matrix found within the mitral valve, heretofore unexplored connections between age and myxomatous valve disease can be found. This review addresses several studies that have been conducted to explore such age and disease related changes in extracellular matrix, valvular endothelial and interstitial cells, and valve innervation, and also reviews attempts to correlate aging and myxomatous disease. Such connections can highlight avenues for future research and help provide insight as to when an individual diverts from an aging pattern into a diseased pathway. Recognizing these patterns and opportunities could result in earlier intervention and the hope of reduced morbidity and mortality for patients.