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European Heart Journal. Cardiovascular... Dec 2023The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected... (Observational Study)
Observational Study
AIMS
The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected patients increases. However, studies on ECV progression over time are lacking. We aimed to investigate the progression of ECV and its prognostic impact in CA patients.
METHODS AND RESULTS
Serial cardiac magnetic resonance (CMR) examinations, including ECV quantification, were performed in consecutive CA patients. Between 2012 and 2021, 103 CA patients underwent baseline and follow-up CMR, including ECV quantification. Median ECVs at baseline of the total (n = 103), transthyretin [(ATTR) n = 80], and [light chain (AL) n = 23] CA cohorts were 48.0%, 49.0%, and 42.6%, respectively. During a median period of 12 months, ECV increased significantly in all cohorts [change (Δ) +3.5% interquartile range (IQR): -1.9 to +6.9, P < 0.001; Δ +3.5%, IQR: -2.0 to +6.7, P < 0.001; and Δ +3.5%, IQR: -1.6 to +9.1, P = 0.026]. Separate analyses for treatment-naïve (n = 21) and treated (n = 59) ATTR patients revealed that the median change of ECV from baseline to follow-up was significantly higher among untreated patients (+5.7% vs. +2.3%, P = 0.004). Survival analyses demonstrated that median change of ECV was a predictor of outcome [total: hazard ratio (HR): 1.095, 95% confidence interval (CI): 1.047-1.0145, P < 0.001; ATTR: HR: 1.073, 95% CI: 1.015-1.134, P = 0.013; and AL: HR: 1.131, 95% CI: 1.041-1.228, P = 0.003].
CONCLUSION
The present study supports the use of serial ECV quantification in CA patients, as change of ECV was a predictor of outcome and could provide information in the evaluation of amyloid-specific treatments.
Topics: Humans; Amyloidosis; Cardiomyopathies; Contrast Media; Magnetic Resonance Imaging, Cine; Myocardium; Predictive Value of Tests; Registries; Prospective Studies
PubMed: 37549339
DOI: 10.1093/ehjci/jead188 -
Canadian Journal of Physiology and... Dec 2023The purpose of this study was to characterize the role of β-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac... (Review)
Review
The purpose of this study was to characterize the role of β-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac hypertrophy. T was administered at 0.5 mg·kg·day for 10 days in β1-KO and WT groups, while control groups received vehicle alone. Echocardiography and myocardial histology was performed; cardiac and serum ANGI/ANGII and ANP and cardiac levels of p-PKA, p-ERK1/2, p-p38-MAPK, p-AKT, p-4EBP1, and ACE were measured. WT showed decreased IVST and increased LVEDD versus WT ( < 0.05). β1-KO exhibited lower LVEDD and higher relative IVST versus β1-KO, the lowest levels of ejection fraction, and the highest levels of cardiomyocyte diameter ( < 0.05). Cardiac ANP levels decreased in WT versus β1-KO ( < 0.05). Cardiac ACE expression was increased in T-treated groups ( < 0.05). Phosphorylated-p38 MAPK levels were higher in WT versus WT or β1-KO p-4EBP1 was elevated in β1-KO animals, and p-ERK1/2 was up-regulated in β1-KO. These findings suggest that β-AR signaling is crucial for TiCH.
Topics: Mice; Animals; Cardiomyopathy, Restrictive; Mice, Knockout; Myocardium; Thyroid Hormones; Receptors, Adrenergic; Angiotensin II
PubMed: 37747059
DOI: 10.1139/cjpp-2023-0153 -
Perfusion Nov 2023A basic prerequisite for a good surgical outcome in heart surgery is optimal myocardial protection. However, cardioplegia strategies used in adult cardiac surgery are...
INTRODUCTION
A basic prerequisite for a good surgical outcome in heart surgery is optimal myocardial protection. However, cardioplegia strategies used in adult cardiac surgery are not directly transferable to infant hearts. Paediatric microplegia, analogous to Calafiore cardioplegia used in adult cardiac surgery, offers the advantage of safe myocardial protection without haemodilution. The use of concentration-dependent paediatric microplegia is new in clinical implementation.
MATERIAL AND METHODS
Paediatric microplegia has been in clinical use in our institution since late 2014. It is applied via an 1/8 inch tube of a S5-HLM roller pump (LivaNova, Italy). As cardioplegic additive, a mixture of potassium (K) 20 mL (2 mmol/mL potassium chloride 14.9% Braun) and magnesium (Mg) 10 mL (4 mmol/mL Mg-sulphate Verla® i. v. 50%) is fixed into a syringe-pump (B. Braun, Germany). This additive is mixed with arterial patient blood from the oxygenator in different flowdependent ratios to form an effective cardioplegia.
TECHNIQUE
After microplegia application of initially 25 mmol/L K with 11 mmol/L Mg for 2 min, a safe cardioplegic cardiac arrest is achieved, which after release of the coronary circulation, immediately returns to a spontaneous cardiac-rhythm. In the case of prolonged aortic clamping, microplegia is repeated every 20 min with a reduction of the application dose of K by 20% and Mg by 30% (20 mmol/L K; 8.5 mmol/L Mg) and a further reduction down to a maintenance dose (15 mmol/L K; 6 mmol/L Mg) after additional 20 min.
SUMMARY
The microplegia adapted to the needs of paediatric myocardium is convincing due to its simple technical implementation for the perfusionist while avoiding haemodilution. However, the required intraoperative interval of microplegia of approx. 20 min demands adapted intraoperative management from the surgeon.
Topics: Adult; Humans; Child; Heart Arrest, Induced; Cardiac Surgical Procedures; Myocardium; Italy; Cardioplegic Solutions
PubMed: 36121780
DOI: 10.1177/02676591221127926 -
Nature Communications Dec 2023Therapeutic angiogenesis represents a promising avenue to revascularize the ischemic heart. Its limited success is partly due to our poor understanding of the cardiac...
Therapeutic angiogenesis represents a promising avenue to revascularize the ischemic heart. Its limited success is partly due to our poor understanding of the cardiac stroma, specifically mural cells, and their response to ischemic injury. Here, we combine single-cell and positional transcriptomics to assess the behavior of mural cells within the healing heart. In response to myocardial infarction, mural cells adopt an altered state closely associated with the infarct and retain a distinct lineage from fibroblasts. This response is concurrent with vascular rarefaction and reduced vascular coverage by mural cells. Positional transcriptomics reveals that the infarcted heart is governed by regional-dependent and temporally regulated programs. While the remote zone acts as an important source of pro-angiogenic signals, the infarct zone is accentuated by chronic activation of anti-angiogenic, pro-fibrotic, and inflammatory cues. Together, our work unveils the spatiotemporal programs underlying cardiac repair and establishes an association between vascular deterioration and mural cell dysfunction.
Topics: Humans; Microvascular Rarefaction; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Signal Transduction
PubMed: 38129410
DOI: 10.1038/s41467-023-44227-6 -
Signal Transduction and Targeted Therapy Apr 2024Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation...
Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors. In this study, we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors. With this unbiased protocol, we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes. Particularly in fibroblasts, a novel regulator, PKNOX2, was identified as being associated with physiological fibroblast activation in healthy hearts. To validate the roles of these transcription factors in maintaining homeostasis, we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling. The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation. Both gain- and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling. Moreover, fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis, respectively. In summary, this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle. With this optimized protocol, we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.
Topics: Animals; Humans; Male; Mice; Disease Models, Animal; Fibroblasts; Fibrosis; Heart Failure; Homeodomain Proteins; Mice, Knockout; Myocardium; Myofibroblasts
PubMed: 38644381
DOI: 10.1038/s41392-024-01804-5 -
International Journal of Molecular... Jul 2023The intercalated disk is a cardiac specific structure composed of three main protein complexes-adherens junctions, desmosomes, and gap junctions-that work in concert to... (Review)
Review
The intercalated disk is a cardiac specific structure composed of three main protein complexes-adherens junctions, desmosomes, and gap junctions-that work in concert to provide mechanical stability and electrical synchronization to the heart. Each substructure is regulated through a variety of mechanisms including proteolysis. Calpain proteases, a class of cysteine proteases dependent on calcium for activation, have recently emerged as important regulators of individual intercalated disk components. In this review, we will examine how calcium homeostasis regulates normal calpain function. We will also explore how calpains modulate gap junctions, desmosomes, and adherens junctions activity by targeting specific proteins, and describe the molecular mechanisms of how calpain dysregulation leads to structural and signaling defects within the heart. We will then examine how changes in calpain activity affects cardiomyocytes, and how such changes underlie various heart diseases.
Topics: Calpain; Calcium; Myocardium; Myocytes, Cardiac; Adherens Junctions
PubMed: 37511485
DOI: 10.3390/ijms241411726 -
Experimental Physiology Feb 2024Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial... (Review)
Review
Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial injury and functional disability. Studies have shown that the development of diabetic cardiomyopathy is related to disorders in mitochondrial metabolic substrates, changes in mitochondrial dynamics, an imbalance in mitochondrial Ca regulation, defects in the regulation of microRNAs, and mitochondrial oxidative stress. Physical activity may play a role in resistance to the development of diabetic cardiomyopathy by improving myocardial mitochondrial biogenesis, the level of autophagy and dynamic changes in fusion and division; enhancing the ability to cope with oxidative stress; and optimising the metabolic substrates of the myocardium. This paper puts forward a new idea for further understanding the specific mitochondrial mechanism of the occurrence and development of diabetic cardiomyopathy and clarifying the role of exercise-mediated myocardial mitochondrial changes in the prevention and treatment of diabetic cardiomyopathy. This is expected to provide a new theoretical basis for exercise to reduce diabetic cardiomyopathy symptoms.
Topics: Humans; Diabetic Cardiomyopathies; Mitochondria, Heart; Myocardium; Exercise; Oxidative Stress; Diabetes Mellitus
PubMed: 37845840
DOI: 10.1113/EP091309 -
Circulation Research Aug 2023Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that...
BACKGROUND
Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking.
METHODS
Permeabilized porcine cardiac tissue and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse model of genetic dilated cardiomyopathy was used to evaluate the ability of danicamtiv to correct the contractile deficit.
RESULTS
Danicamtiv increased force and calcium sensitivity via increasing the number of myosins in the ON state and slowing cross-bridge turnover. Our detailed analysis showed that inhibition of ADP release results in decreased cross-bridge turnover with cross bridges staying attached longer and prolonging myofibril relaxation. Danicamtiv corrected decreased calcium sensitivity in demembranated tissue, abnormal twitch magnitude and kinetics in intact cardiac tissue, and reduced ejection fraction in the whole organ.
CONCLUSIONS
As demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering cross-bridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopathy.
Topics: Mice; Animals; Swine; Cardiomyopathy, Dilated; Calcium; Myocardium; Myosins; Myocytes, Cardiac; Cardiotonic Agents
PubMed: 37470183
DOI: 10.1161/CIRCRESAHA.123.322629 -
Cell Death & Disease Jul 2023MicroRNA-150 (miR-150) is conserved between rodents and humans, is significantly downregulated during heart failure (HF), and correlates with patient outcomes. We...
MicroRNA-150 (miR-150) is conserved between rodents and humans, is significantly downregulated during heart failure (HF), and correlates with patient outcomes. We previously reported that miR-150 is protective during myocardial infarction (MI) in part by decreasing cardiomyocyte (CM) apoptosis and that proapoptotic small proline-rich protein 1a (Sprr1a) is a direct CM target of miR-150. We also showed that Sprr1a knockdown in mice improves cardiac dysfunction and fibrosis post-MI and that Sprr1a is upregulated in pathological mouse cardiac fibroblasts (CFs) from ischemic myocardium. However, the direct functional relationship between miR-150 and SPRR1A during both post-MI remodeling in mice and human CF (HCF) activation was not established. Here, using a novel miR-150 knockout;Sprr1a-hypomorphic (Sprr1a) mouse model, we demonstrate that Sprr1a knockdown blunts adverse post-MI effects caused by miR-150 loss. Moreover, HCF studies reveal that SPRR1A is upregulated in hypoxia/reoxygenation-treated HCFs and is downregulated in HCFs exposed to the cardioprotective β-blocker carvedilol, which is inversely associated with miR-150 expression. Significantly, we show that the protective roles of miR-150 in HCFs are directly mediated by functional repression of profibrotic SPRR1A. These findings delineate a pivotal functional interaction between miR-150 and SPRR1A as a novel regulatory mechanism pertinent to CF activation and ischemic HF.
Topics: Animals; Humans; Mice; Disease Models, Animal; Fibroblasts; Fibrosis; MicroRNAs; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Ventricular Remodeling
PubMed: 37468478
DOI: 10.1038/s41419-023-05982-y -
Pharmacological Research Dec 2023The cardio-protective and immuno-regulatory properties of RTP-026, a synthetic peptide that spans the Annexin-A1 (AnxA1) N-terminal region, were tested in rat acute...
AIMS
The cardio-protective and immuno-regulatory properties of RTP-026, a synthetic peptide that spans the Annexin-A1 (AnxA1) N-terminal region, were tested in rat acute myocardial infarction.
METHODS AND RESULTS
In vitro, selective activation of formyl-peptide receptor type 2 (FPR2) by RTP-026 occurred with apparent EC in the 10-30 nM range. With human primary cells, RTP-026 counteracted extension of neutrophil life-span and augmented phagocytosis of fluorescent E.coli by blood myeloid cells. An in vivo model of rat acute infarction was used to quantify tissue injury and phenotype immune cells in myocardium and blood. The rat left anterior descending coronary artery was occluded and then reopened for 2-hour or 24-hour reperfusion. For the 2-hour reperfusion protocol, RTP-026 (25-500 µg/kg; given i.v. at the start of reperfusion) significantly reduced infarct size by ∼50 %, with maximal efficacy at 50 µg/kg. Analyses of cardiac immune cells showed that RTP-026 reduced neutrophil and classical monocyte recruitment to the damaged heart. In the blood, RTP-026 (50 µg/kg) attenuated activation of neutrophils and monocytes monitored through CD62L and CD54 expression. Modulation of vascular inflammation by RTP-026 was demonstrated by reduction in plasma levels of mediators like TNF-α, IL-1β, KC, PGE and PGF For the 24-hour reperfusion protocol, RTP-026 (30 µg/kg given i.v. at 0, 3 and 6 h reperfusion) reduced necrotic myocardium by ∼40 %.
CONCLUSIONS
RTP-026 modulate immune cell responses and decreases infarct size of the heart in preclinical settings. Tempering over-exuberant immune cell activation by RTP-026 is a suitable approach to translate the biology of AnxA1 for therapeutic purposes.
Topics: Rats; Animals; Humans; Annexin A1; Peptides; Myocardial Infarction; Myocardium; Heart; Neutrophils
PubMed: 37992916
DOI: 10.1016/j.phrs.2023.107005