Influenza and sudden unexpected death: the possible role of peptide cross-reactivity

This study investigates the hypothesis that cross-reactions may occur between human cardiac proteins and influenza antigens, thus possibly representing the molecular mechanism underlying influenzaassociated sudden unexpected death (SUD). Using titin protein as a research model, data were obtained on (1) the occurrence of the titin octapeptide AELLVLLE or its mimic AELLVALE in influenza A virus hemagglutinin (HA) sequences; (2) the immunological potential of AELLVLLE and its mimic AELLVALE; (3) the possible role of the flanking amino acid aa) context of the two octapeptide determinants in eliciting cross-reactivity between the human cardiac titin protein and HA antigens.

Abstract 11217: A New Treatment for Diastolic Heart Failure: Trabecular Cutting

Background: Heart failure with preserved ejection fraction remains a leading cause of hospitalization, without development of new medications and operative procedures to treat these patients. We hypothesize that trabeculae carneae serve an important role in modulating LV diastolic compliance, and during hypertrophy of the myocardium, trabeculae contribute to abnormal compliance. Methods and Results: Eight ex vivo human hearts from patients with LV diastolic dysfunction were perfused at 37[[Unable to Display Character: &#8304;]]C and had a balloon inserted into the LV through the mitral annulus. Diastolic LV pressure-volume compliance curves were measured at baseline and following trabecular cutting. LV compliance improved significantly (n=6, p<0.001), but not in the control hearts without trabecular cutting (n=2, p=0.85). The figure shows aggregate data from the six hearts before and after trabecular cutting. To determine if trabeculae serve a similar role in all mammals, 28 hearts from 10 species were obtained. We demonstrate significant relationships between circumferential wall stress and the number of trabeculae in these species, particularly trabeculae which attach nets of trabeculae to the ventricle walls (p=0.02, n=733) and trabeculae located at the apex and free wall (p=0.02, n=602). The percent of LV cardiac titin of the stiff isoform (%N2B), a determinate of LV diastolic compliance, also demonstrated a significant relationship with the number of trabeculae with the same anatomic subsets (p=0.04, n=597; and p=0.02, n=488, respectively). Conclusions: We demonstrate for the first time that rather than being an embryologic remnant, trabeculae carneae serve an important role in the maintenance of passive LV diastolic compliance, and can contribute to LV diastolic dysfunction. A new procedure, cutting trabeculae, is proposed to improve LV diastolic compliance.

Abstract 279: A Deletion In The N2A Region Of Titin Carried By Muscular Dystrophy With Myositis (mdm) Mice Severely Affects Skeletal Muscle, But Not The Heart

20% of dilated cardiomyopathy patients carry mutations in the giant protein titin. Mutations are predominant in A band but also occur in I band, a domain that regulates passive tension and myocyte signaling. A recessive mouse mutation in titin I band N2A region (mdm) causes early onset muscular dystrophy with myositis and death. We assessed cardiac morphology, function, and transcriptional profiles (RNAseq) in mdm mice. Young homozygous mdm mice (n>6) have reduced body weight (7gms) vs. heterozygous (20gm) or WT (17gm) littermates, with severe skeletal muscle dystrophy. Four-week old homozygous mdm mice have higher left ventricular (LV): body weight ratios. Echocardiography revealed thinner LV posterior wall and septum (LVPWd and IVSd) and normal LV diameter (LVDd); when normalized for body weight, cardiac dimensions were increased compared to WT or heterozygous mdm mice. Fractional shortening was reduced in homozygous Mdm mice (35%) vs. WT (40-41%, p<0.01); histology showed neither overt pathology nor fibrosis. Titin gels showed lack of difference in cardiac titin isoform pattern, consistent with RNAseq, which showed the mdm titin transcript excluded exons 107 and 108, deleting in frame 48 amino acids. 240 transcripts (0.8%) were differentially expressed (fold change >1.5 and <0.75, p<0.001) in homozygous vs. heterozygous mdm hearts; ANP and BNP were mildly upregulated (2- and 1.2-fold). Altered transcripts participated in extracellular and immune signaling pathways. Among titin binding partners, only calpain-3 that interacts with N2A was changed (0.6-fold), consistent with previous reports in skeletal muscle. As humans have heterozygous mutations, we stressed adult heterozygous mdm and WT mice (2 weeks of angiotensin II infusion): both had comparable hypertrophic responses (increased LVPWd and IVSd). Aged (89 week old) unstressed heterozygous mdm mice had normal cardiac dimensions and function. The N2A region, I-band titin mdm mutation causes minimal cardiac dysfunction in mice, unlike the severe skeletal muscle phenotype. Human I-band mutations are unlikely to cause dilated cardiomyopathy.