Antibodies aggravate the development of ischemic heart failure

Heart-specific antibodies have been widely associated with myocardial infarction (MI). However, it remains unclear whether autoantibodies mediate disease progression or are a byproduct of cardiac injury. To disambiguate the role of immunoglobulins in MI, we characterized the development of ischemic heart failure in agammaglobulinemic mice (AID-/-μS-/-). Although these animals can produce functional B cells, they cannot synthesize secretory IgM (μS-/-) or perform Ig class switching (AID-/-), leading to complete antibody deficiency. Agammaglobulinemia did not affect overall post-MI survival but resulted in a significant reduction in infarct size. Echocardiographic analyses showed that, compared with wild-type infarcted control mice, AID-/-μS-/- mice exhibited improved cardiac function and reduced remodeling on day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AID-/-μS-/- mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as matrix metalloproteinase-9, collagen type I a1, collagen type III a1, and IL-6. An unbiased screening of the heart reactivity potential in the plasma of wild-type MI animals revealed the presence of antibodies that target the myocardial scar and collagenase-sensitive epitopes. Moreover, we found that IgG accumulated within the scar tissues of infarcted mice and remained in close proximity with cells expressing Fcγ receptors (CD16/32), suggesting the existence of an in situ IgG-Fcγ receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic heart failure progression and provide novel insights into the mechanisms underlying this phenomenon. NEW & NOTEWORTHY Our study sheds some light on the long-standing debate over the relevance of autoantibodies in heart failure and might stimulate future research in the field. The observation of extracellular matrix-specific antibodies and the detection of Fcγ receptor-expressing cells within the scar provide novel insights into the mechanisms by which antibodies may contribute to adverse remodeling.info:eu-repo/semantics/publishedVersio

Revisiting the Past: Replicability of a Historic Long-Term Vegetation Dynamics Assessment in the Era of Big Data Analytics

Open and analysis-ready data, as well as methodological and technical advancements have resulted in an unprecedented capability for observing the Earth’s land surfaces. Over 10 years ago, Landsat time series analyses were inevitably limited to a few expensive images from carefully selected acquisition dates. Yet, such a static selection may have introduced uncertainties when spatial or inter-annual variability in seasonal vegetation growth were large. As seminal pre-open-data-era papers are still heavily cited, variations of their workflows are still widely used, too. Thus, here we quantitatively assessed the level of agreement between an approach using carefully selected images and a state-of-the-art analysis that uses all available images. We reproduced a representative case study from the year 2003 that for the first time used annual Landsat time series to assess long-term vegetation dynamics in a semi-arid Mediterranean ecosystem in Crete, Greece. We replicated this assessment using all available data paired with a time series method based on land surface phenology metrics. Results differed fundamentally because the volatile timing of statically selected images relative to the phenological cycle introduced systematic uncertainty. We further applied lessons learned to arrive at a more nuanced and information-enriched vegetation dynamics description by decomposing vegetation cover into woody and herbaceous components, followed by a syndrome-based classification of change and trend parameters. This allowed for a more reliable interpretation of vegetation changes and even permitted us to disentangle certain land-use change processes with opposite trajectories in the vegetation components that were not observable when solely analyzing total vegetation cover. The long-term budget of net cover change revealed that vegetation cover of both components has increased at large and that this process was mainly driven by gradual processes. We conclude that study designs based on static image selection strategies should be critically evaluated in the light of current data availability, analytical capabilities, and with regards to the ecosystem under investigation. We recommend using all available data and taking advantage of phenology-based approaches that remove the selection bias and hence reduce uncertainties in results.Peer Reviewe

Myocardial aging as a T-cell–mediated phenomenon

In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissue-resident leukocytes and with an accumulation of activated CD4+ Foxp3- (forkhead box P3) IFN-γ+ T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.info:eu-repo/semantics/publishedVersio

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities

心房ナトリウム利尿ペプチドは、ミネラルコルチコイド受容体活性を抑制して心筋リモデリングを予防する

BACKGROUND:The endocrine balance between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone system is critical for the maintenance of arterial blood pressure and volume homeostasis. This study investigated whether a cardiac imbalance between ANP and aldosterone, toward increased mineralocorticoid receptor (MR) signaling, contributes to adverse left ventricular remodeling in response to pressure overload.METHODS AND RESULTS:We used the MR-selective antagonist eplerenone to test the role of MRs in mediating pressure overload-induced dilatative cardiomyopathy of mice with abolished local, cardiac ANP activity. In response to 21 days of transverse aortic constriction, mice with cardiomyocyte-restricted inactivation (knockout) of the ANP receptor (guanylyl cyclase [GC]-A) or the downstream cGMP-dependent protein kinase I developed enhanced left ventricular hypertrophy and fibrosis together with contractile dysfunction. Treatment with eplerenone (100 mg/kg/d) attenuated left ventricular hypertrophy and fully prevented fibrosis, dilatation, and failure. Transverse aortic constriction induced the cardiac expression of profibrotic connective tissue growth factor and attenuated the expression of SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) in knockout mice, but not in controls. These genotype-dependent molecular changes were similarly prevented by eplerenone. ANP attenuated the aldosterone-induced nuclear translocation of MRs via GC-A/cGMP-dependent protein kinase I in transfected HEK 293 (human embryonic kidney) cells. Coimmunoprecipitation and fluorescence resonance energy transfer experiments demonstrated that a population of MRs were membrane associated in close interaction with GC-A and cGMP-dependent protein kinase I and, moreover, that aldosterone caused a conformational change of this membrane MR/GC-A protein complex which was prevented by ANP.CONCLUSIONS:ANP counter-regulates cardiac MR activation in hypertensive heart disease. An imbalance in cardiac ANP/GC-A (inhibition) and aldosterone/MR signaling (augmentation) favors adverse cardiac remodeling in chronic pressure overload.博士（医学）・甲第630号・平成27年3月16日© 2014 American Heart Association, Inc

Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach

BackgroundCognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits.MethodsThe prospective cohort study “Cognition.Matters-HF” recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing.ResultsDendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the “global deficits” cluster and the “no deficits” group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048).ConclusionApart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition

Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction

Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI

Inflammation in acute myocardial infarction: the good, the bad and the ugly.

Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and -6 pathways. Taking lessons from such past research may inform an optimized approach to target post-AMI inflammation, tailored to spare 'The Good' (repair and defence) while treating 'The Bad' (smouldering RIR) and capturing 'The Ugly' (flaming early burst of excess inflammation in the acute phase). Key constituents of such a strategy may read as follows: select patients with large pro-inflammatory burden (i.e. large AMI); initiate treatment early (e.g. ≤12 h post-AMI); implement a precisely targeted anti-inflammatory agent; follow through with a tapering treatment regimen. This approach warrants testing in rigorous clinical trials

The relationship between mental health, sleep quality and the immunogenicity of COVID-19 vaccinations.

Sleep modulates the immune response, and sleep loss can reduce vaccine immunogenicity; vice versa, immune responses impact sleep. We aimed to investigate the influence of mental health and sleep quality on the immunogenicity of COVID-19 vaccinations and, conversely, of COVID-19 vaccinations on sleep quality. The prospective CoVacSer study monitored mental health, sleep quality and Anti-SARS-CoV-2-Spike IgG titres in a cohort of 1082 healthcare workers from 29 September 2021 to 19 December 2022. Questionnaires and blood samples were collected before, 14 days, and 3 months after the third COVID-19 vaccination, as well as in 154 participants before and 14 days after the fourth COVID-19 vaccination. Healthcare workers with psychiatric disorders had slightly lower Anti-SARS-CoV-2-Spike IgG levels before the third COVID-19 vaccination. However, this effect was mediated by higher median age and body mass index in this subgroup. Antibody titres following the third and fourth COVID-19 vaccinations ("booster vaccinations") were not significantly different between subgroups with and without psychiatric disorders. Sleep quality did not affect the humoral immunogenicity of the COVID-19 vaccinations. Moreover, the COVID-19 vaccinations did not impact self-reported sleep quality. Our data suggest that in a working population neither mental health nor sleep quality relevantly impact the immunogenicity of COVID-19 vaccinations, and that COVID-19 vaccinations do not cause a sustained deterioration of sleep, suggesting that they are not a precipitating factor for insomnia. The findings from this large-scale real-life cohort study will inform clinical practice regarding the recommendation of COVID-19 booster vaccinations for individuals with mental health and sleep problems