Abstract
BACKGROUND. Idiopathic pulmonary arterial hypertension (IPAH) alters right ventricular size and function, curtailing life-expectancy. Patients may experience angina and myocardial ischemia. However, the mechanisms underlying these changes are poorly understood. METHODS. A cross-sectional, case-control design of coronary pathophysiology (in vivo and ex vivo) in IPAH. Patients with IPAH (Group-1.1) undergoing clinically indicated right heart catheterization were prospectively enrolled. Participants underwent functional testing during coronary angiography using a dual pressure/temperature-sensitive guidewire. Cardiovascular magnetic resonance measured left and right ventricular mass and function. Autopsy cardiac tissues from end-stage PAH (Group-1) and control individuals were analyzed for right ventricular pathophysiology. RESULTS. Eleven participants with IPAH and 15 control participants completed the protocol (IPAH: 45±15 years, 73% female; controls: 58.3±9.1 years, 73% female). 73% (n=8) of IPAH patients had an elevated index of microcirculatory resistance (IMR >25) and 55% (n=6) had reduced coronary flow reserve (CRF <2.0). The mean IMR was significantly higher in IPAH participants (39.2±27.0 vs. 15.3±5.0, p=0.002) whereas mean CFR was lower (2.8±2.1 vs. 4.0±1.4; p=0.077). Paired right coronary artery/ventricular measurements (n=6) revealed IMR positively correlated with right ventricular mass (r=0.91, p=0.12), and negatively with CFR (r=-0.82, p=0.046). Compared to controls (n=5), PAH participants (n=4) had reduced right ventricular capillary density (111±18 vs. 167±20, p=0.032), increased cardiomyocyte area (383±118μm2 vs. 231±61μm2, p=0.0390), and increased mural area in small pre-capillary arterioles (127±10μm2 vs. 107±20μm2, p=0.041). CONCLUSIONS. Coronary microvascular dysfunction is prevalent in IPAH and correlates with increased right ventricular mass. Histopathology revealed vascular rarefaction and remodeling of pre-capillary arterioles. The clinical significance merits prospective evaluation. Invasive coronary function testing was feasible and safe in IPAH, providing a platform to assess therapeutic impacts on cardiac microvascular function.
Authors
Erin Boland, Michael G. Freeman, David S. Corcoran, Thomas J. Ford, Barry Hennigan, Damien Collison, Aida Llucià-Valldeperas, Frances S. de Man, Kanarath P. Balachandran, Martin Johnson, Colin Church, Colin Berry
Abstract
Cardiomyocyte growth is tightly controlled by multiple signaling pathways. Identification of master kinases in this process is essential in exploring potential targets for the treatment of pathological cardiac hypertrophy and heart failure. Here we identified the mTOR-independent activation of ribosomal protein S6 kinase b1 (Rps6kb1/S6K1) during cardiomyocyte growth. By utilizing phosphoproteomics in primary neonatal rat ventricular myocytes (NRVMs), we revealed Rps6kb1 as one of most activated kinases under growth stimulation. We further demonstrated the role of Rps6kb1 phosphorylation in pathological cardiac hypertrophy and heart failure. We showed that the phosphorylation of multiple sites at Rps6kb1, including T367 in the kinase domain and S418/T421/S424 in the C-terminal domain, is not directly regulated by the activity of mTOR, rather coupled with the activation of the MEK1-ERK axis. In mice, cardiomyocyte-specific deletion of Rps6kb1 significantly inhibited both constitutively active ERK- and pressure overload-induced cardiac hypertrophy. In contrast, cardiomyocyte-specific overexpression of wild-type Rps6kb1, rather than the phosphorylation-defective mutant, elevated cardiac hypertrophy and augmented pressure overload-induced heart failure. In conclusion, our findings reveal that the MEK-ERK axis primes Rps6kb1 activation through phosphorylation of two separate domains of Rps6kb1, which may play an essential role in cardiac hypertrophy and heart failure under hemodynamic stress.
Authors
Chao Li, Pengfei Zhang, Kai Zhang, Jane A. Cook, Weidan Song, Megan Virostek, Lily A. Slotabec, Nadiyeh Rouhi, Mohammed Hazari, Michael I. Adenawoola, Xiaofei Liu, Hao Zhang, Guangyu Zhang, Erica L Niewold, Qinfeng Li, Yong Fang, Waleed M. Elhelaly, Xue-Nan Sun, Xuejiang Guo, Andrew Lemoff, Yingfeng Deng, Thomas G. Gillette, Ji Li, Philipp E. Scherer, Zhao V. Wang
Abstract
Congenital long QT syndrome (LQTS) promotes risk for life-threatening cardiac arrhythmia and sudden death in children and young adults. Pathogenic variants in the voltage-gated potassium channel KCNQ1 are the most frequently discovered genetic cause. Most LQTS-associated KCNQ1 variants cause loss-of-function secondary to impaired trafficking of the channel to the plasma membrane. There are currently no therapeutic approaches that address this underlying molecular defect. Using a high-throughput screening paradigm, we identified VU0494372, a small molecule that increases total and cell surface levels and trafficking efficiency of WT KCNQ1 as well as three LQTS-associated variants. Additionally, 16-hour treatment of cells with VU0494372 increased IKs (KCNQ1-KCNE1 current) for WT KCNQ1 and the LQTS-associated variant V207M in cells co-expressing KCNE1. VU0494372 had no impact on KCNQ1 transcription, degradation, or thermal stability, and increased the rate of KCNQ1 reaching the cell surface. We identified a potential direct interaction site with KCNQ1 at or near the binding site of the KCNQ1 potentiator ML277. Together, these findings demonstrate that small molecules can increase the expression levels and cell surface trafficking efficiency of KCNQ1 and introduce a potential new pharmacological approach for treating LQTS.
Authors
Katherine R. Clowes Moster, Carlos G. Vanoye, Ana C. Chang-Gonzalez, Ian M. Romaine, Katherine M. Stefanski, Mason C. Wilkinson, Joshua A. Bauer, Thomas P. Hasaka, Emily L. Days, Reshma R. Desai, Kathryn R. Butcher, Gary A. Sulikowski, Alex G. Waterson, Jens Meiler, Kaitlyn V. Ledwitch, Alfred L. George, Jr., Charles R. Sanders
Abstract
Cardiac arrhythmias increase during acute SARS-CoV-2 infection and in long COVID syndrome, by unknown mechanisms. This study explored the acute and long-term effects of COVID-19 on cardiac electrophysiology and the cardiac conduction system (CCS) in a hamster model. Electrocardiograms and subpleural pressures were recorded by telemetry for 4 weeks after SARS-CoV-2 infection, and interferon-stimulated gene expression and macrophage infiltration of the CCS were assessed at 4 days and 4 weeks postinfection. COVID-19 induced pronounced tachypnea and cardiac arrhythmias, including bradycardia and persistent atrioventricular block, though no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped, indicating persistent CCS injury. COVID-19 induced cardiac cytokine expression, connexin mislocalization, and CCS macrophage remodeling. Interestingly, sterile innate immune activation by direct cardiac injection of polyinosinic:polycytidylic acid (PIC) induced arrhythmias similar to those of COVID-19. PIC strongly induced cytokine secretion and interferon signaling in hearts, human induced pluripotent stem cell–derived cardiomyocytes, and engineered heart tissues, accompanied by alterations in excitation-contraction coupling. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by JAK/STAT inhibition or a mitochondrially targeted antioxidant, indicating that SARS-CoV-2 infection indirectly leads to arrhythmias by innate immune activation and redox stress, which could have implications for long COVID syndrome.
Authors
Deepthi Ashok, Ting Liu, Misato Nakanishi-Koakutsu, Joseph Criscione, Meghana Prakash, Alexis Tensfeldt, Byunggik Kim, Bryan Ho, Julian Chow, Morgan Craney, Mark J. Ranek, Brian L. Lin, Kyriakos Papanicolaou, Agnieszka Sidor, D. Brian Foster, Hee Cheol Cho, Andrew Pekosz, Jason Villano, Deok-Ho Kim, Brian O’Rourke
Abstract
BACKGROUND Platelets are increasingly recognized as active participants in immune signaling and systemic inflammation. Upon activation, platelets form monocyte platelet aggregates (MPA) representing the crossroads of thrombosis and inflammation. We hypothesized that platelet transcriptomics could capture this thromboinflammatory axis and identify individuals at elevated cardiovascular risk.METHODS: MPA levels, defined as CD14+CD61+ cells, were measured using flow cytometry at 2 time points, 4 weeks apart, in healthy individuals Platelets were isolated and sequenced. Individuals were categorized as MPAhi or MPAlo based on consistently high or low MPA levels across time points.RESULTS Among 149 participants (median age 52 years, 57% female, 50% non-White), MPAhi individuals exhibited increased expression of platelet activation markers P-selectin (P < 0.001), PAC-1 (P = 0.021), and CD40L (P < 0.001) and enriched immune signaling pathways. Informed by MPA levels and derived from the platelet transcriptome, we developed a 42-gene thromboinflammation platelet signature (TIPS), which correlated with MPA levels in multiple cohorts and was reproducible over time. TIPS was elevated in patients with COVID-19 (P = 0.0002) and myocardial infarction (Padj = 0.008), and as in predicted future cardiovascular events in patients who underwent lower extremity revascularization after a median follow-up of 18 months (adjusted for age, sex, race, and ethnicity [adjHR] 1.55, P = 0.006). Notably, TIPS was modifiable by ticagrelor (P = 0.002) but not aspirin.CONCLUSION These findings establish MPA as a biomarker of thromboinflammation and introduce TIPS, a platelet RNA signature, that captures thromboinflammation and provides a promising tool for cardiovascular risk stratification and a potential therapeutic target.TRIAL REGISTRATION NCT04369664FUNDING NIH R35HL144993, NIH R01HL139909, and AHA 16SFRN2873002 to JSB, DFG Walter-Benjamin-Programme 537070747 to AB.
Authors
Antonia Beitzen-Heineke, Matthew A. Muller, Yuhe Xia, Elliot Luttrell-Williams, Florencia Schlamp, Deepak Voora, Kelly V. Ruggles, Michael S. Garshick, Tessa J. Barrett, Jeffrey S. Berger
Abstract
BACKGROUND Suboptimal fetal growth (SFG), being born small for gestational age (SGA), and catch-up (CU) growth are, individually and together, linked to cardiometabolic risks. However, not all develop adverse outcomes. This study aimed to validate a transcriptomic signature to identify individuals at greatest cardiometabolic risk.METHODS Using National Heart, Lung and Blood Institute (NHLBI) criteria to define cardiometabolic risk, healthy and prehypertensive 17-year-olds were identified in the Avon Longitudinal Study of Parents and Children (ALSPAC) (UK) childhood cohort. Epigenomic and transcriptomic differences were analyzed. A hypergraph identified functionally related genes, which were used in random forest classification to predict prehypertensive phenotypes. The BabyGRO (UK) cohort included 80 children aged 3–7 years, born at term following pregnancies with SFG risks. Anthropometric and cardiometabolic markers and transcriptomic profiles were collected, fetal and childhood weight trajectories and their relationship to cardiometabolic markers were assessed, and transcriptome was used for prediction.RESULTS Individuals with CU-SGA in ALSPAC were 1.6 times more likely than all others to be prehypertensive at 17 years (P < 1 × 10–5). A 42-gene hypergraph cluster was highly predictive of prehypertension (AUC 0.984, error rate 5.4%). In BabyGRO, 20 of these genes accurately predicted higher systolic blood pressure (AUC 0.971, error rate 3.6%). This transcriptomic signature could help identify children with adverse pre- and postnatal growth who may develop prehypertension.CONCLUSION A blood transcriptomic signature exists in childhood which distinguishes those at risk of adult cardiometabolic disease among children with adverse pre- and postnatal growth.TRIAL REGISTRATION Regional ethics committee reference 17/NW/0153, IRAS project ID 187679.FUNDING Centre grant to the Maternal and Fetal Health Research Centre by Tommy’s The Pregnancy and Baby Charity, Child Growth Foundation, European Research Council funding as part of the Health and Environment-wide Associations based on Large Population Surveys (HEALS) study
Authors
Reena Perchard, Terence Garner, Philip G. Murray, Amirul Roslan, Lucy E. Higgins, Edward D. Johnstone, Adam Stevens, Peter E. Clayton
Abstract
The biological age of organs may better quantify risk for health deterioration compared with chronological age. We investigated organ-specific aging patterns in a community-based cohort and assessed the associations with adverse health outcomes. Biological ages of 11 organs were estimated for 11,757 participants of the Atherosclerosis Risk in Communities (ARIC) study (55.6% women, mean age, 57.1 years) using a circulating protein–based model. Older organ ages were significantly associated with related adverse outcomes, even after accounting for chronological age; for example, older arteries and hearts were associated with an increased risk for coronary heart disease (CHD; hazard ratio [HR] per 5-year-higher age gap, 1.22; 95% CI [1.13–1.31] and 1.16 [1.07–1.26], respectively, and older lungs with lung cancer (HR 1.12 [1.09–1.16]). Hierarchical agglomerative clustering based on organ ages revealed 3 patient phenotypes: those with older organs, normal/slightly older organs, and younger organs. The patients with older organs were at higher risk for cancer (HR 1.19; 95% CI [1.08–1.31]), death (HR 1.75 [1.64–1.86]), end-stage kidney disease (HR 6.12 [4.65–8.06]), CHD (HR 1.21 [1.06–1.38]), heart failure (HR 1.92 [1.73–2.13]), infection (HR 1.56 [1.44–1.68]), and stroke (HR 1.36 [1.16–1.61]). Proteomic organ aging signatures demonstrated significant associations with multiple adverse health outcomes and may be useful for health risk identification.
Authors
Celina S. Liu, Wan-Jin Yeo, Aditya Surapaneni, B. Gwen Windham, Hamilton S.-H. Oh, Anna Prizment, Sanaz Sedaghat, Pascal Schlosser, Eugene P. Rhee, Sushrut S. Waikar, Josef Coresh, Keenan A. Walker, Morgan E. Grams
Abstract
Acute rheumatic fever (ARF) and associated rheumatic heart disease are serious sequelae of a Group A Streptococcus (GAS/Strep A) infection. Autoantibodies are thought to contribute to pathogenesis, with deeper exploration of the autoantibody repertoire needed to improve mechanistic understanding and identify new biomarkers. Phage immunoprecipitation and Sequencing (PhIP-Seq) with the HuScan library (>250,000 overlapping 90-mer peptides spanning the human proteome) was utilised to analyse autoreactivity in sera from children with ARF, uncomplicated Strep A pharyngitis and matched healthy controls. A global proteome-wide increase in autoantigen reactivity was observed in ARF, as was marked heterogeneity between patients. Public epitopes, common between individuals with ARF were rare, and comprised < 1% of all enriched peptides. Differential analysis identified both novel and previously identified ARF autoantigens, including PPP1R12B, a myosin phosphatase complex regulatory subunit expressed in cardiac muscle, and members of the collagen-protein family, respectively. Pathway analysis found antigens from the disease-relevant processes encompassing sarcomere and heart-morphogenesis were targeted. In sum, PhIP-Seq has substantially expanded the spectrum of autoantigens in ARF, and reveals the rarity of public epitopes in the disease. It provides further support for the role of epitope spreading in pathogenesis and has identified PPP1R12B as a novel, enriched autoantigen.
Authors
Reuben McGregor, Lauren H. Carlton, Timothy J. O'Donnell, Elliot Merritt, Campbell R. Sheen, Florina Chan Mow, William John Martin, Michael G. Baker, Nigel Wilson, Uri Laserson, Nicole J. Moreland
Abstract
Impaired cardiac lipid metabolism has been reported to cause heart failure. Lipin1, a multifunctional protein, is a phosphatidate phosphatase that generates diacylglycerol from phosphatidic acid and a transcriptional cofactor that regulates lipid metabolism-related gene expression. Here, we investigated the roles of lipin1 in cardiac remodeling after myocardial infarction (MI). The expression levels of lipin1 significantly decreased in cardiomyocytes of the human failing heart and murine ischemic myocardium. Cardiomyocyte-specific Lpin1 knockout (cKO) mice showed left ventricle enlargement and reduced fractional shortening after MI, compared to control mice. This was accompanied by elevated cardiac fibrosis, accumulation of reactive oxygen species, and increased expression of inflammatory cytokines. In contrast, cardiomyocyte-specific Lpin1 overexpression (cOE) mice showed reduced fibrosis and inflammation and improved cardiac function compared to control mice. Cardiac lipid droplets (LDs) were reduced after MI in wild-type (WT) mice hearts and were further downregulated in the hearts of cKO mice with a decrease in triglyceride and free fatty acid content, while cOE mice hearts exhibited increased LDs and lipid content. Expression levels of genes involved in fatty acid oxidation, such as Ppargc1a (PGC1A) and Acaa2, were decreased and increased in the MI hearts of cKO mice and cOE mice, respectively. These results suggest the protective role of lipin1 against ischemic injury by maintaining lipid metabolism in ischemic cardiomyocytes.
Authors
Jiaxi Guo, Kohei Karasaki, Kazutaka Ueda, Manami Katoh, Masaki Hashimoto, Toshiyuki Ko, Masato Ishizuka, Satoshi Bujo, Chunxia Zhao, Risa Kishikawa, Haruka Yanagisawa-Murakami, Hiroyuki Sowa, Bowen Zhai, Mutsuo Harada, Seitaro Nomura, Norihiko Takeda, Brian N. Finck, Haruhiro Toko, Issei Komuro
Abstract
Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well-suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein alpha (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18-kDa (TSPO) and the norepinephrine transporter (NET), respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.
Authors
Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John W. Babich, Annarita Di Lorenzo, James M. Kelly
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