Research

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17 pages, 3103 KiB

Open AccessArticle

Identification of Serum Interleukin-22 as Novel Biomarker in Pulmonary Hypertension: A Translational Study

by Friederike Klein, Sandesh Dinesh, Desiree Fiedler, Katja Grün, Andrea Schrepper, Jürgen Bogoviku, Laura Bäz, Alexander Pfeil, Daniel Kretzschmar, P. Christian Schulze, Sven Möbius-Winkler and Marcus Franz

Int. J. Mol. Sci. 2024, 25(7), 3985; https://doi.org/10.3390/ijms25073985 - 03 Apr 2024

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Abstract

Growing evidence suggests the crucial involvement of inflammation in the pathogenesis of pulmonary hypertension (PH). The current study analyzed the expression of interleukin (IL)-17a and IL-22 as potential biomarkers for PH in a preclinical rat model of PH as well as the serum [...] Read more.

Growing evidence suggests the crucial involvement of inflammation in the pathogenesis of pulmonary hypertension (PH). The current study analyzed the expression of interleukin (IL)-17a and IL-22 as potential biomarkers for PH in a preclinical rat model of PH as well as the serum levels in a PH patient collective. PH was induced by monocrotalin (60 mg/kg body weight s.c.) in 10 Sprague Dawley rats (PH) and compared to 6 sham-treated controls (CON) as well as 10 monocrotalin-induced, macitentan-treated rats (PH_MAC). Lung and cardiac tissues were subjected to histological and immunohistochemical analysis for the ILs, and their serum levels were quantified using ELISA. Serum IL levels were also measured in a PH patient cohort. IL-22 expression was significantly increased in the lungs of the PH and PH_MAC groups (p = 0.002), whereas increased IL17a expression was demonstrated only in the lungs and RV of the PH (p < 0.05) but not the PH_MAC group (p = n.s.). The PH group showed elevated serum concentrations for IL-22 (p = 0.04) and IL-17a (p = 0.008). Compared to the PH group, the PH_MAC group demonstrated a decrease in IL-22 (p = 0.021) but not IL17a (p = n.s.). In the PH patient collective (n = 92), increased serum levels of IL-22 but not IL-17a could be shown (p < 0.0001). This elevation remained significant across the different etiological groups (p < 0.05). Correlation analysis revealed multiple significant relations between IL-22 and various clinical, laboratory, functional and hemodynamic parameters. IL-22 could serve as a promising inflammatory biomarker of PH with potential value for initial diagnosis, functional classification or even prognosis estimation. Its validation in larger patients’ cohorts regarding outcome and survival data, as well as the probability of promising therapeutic target structures, remains the object of further studies. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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14 pages, 2548 KiB

Open AccessArticle

Prognostic Value of Galectin-3 after Left Atrial Appendage Occlusion for Predicting Peri-Device Leakage

by Franz Haertel, Paul Lustermann, Ali Hamadanchi, Katja Gruen, Jurgen Bogoviku, Pawel Aftanski, Julian Westphal, Laura Baez, Marcus Franz, P. Christian Schulze and Sven Moebius-Winkler

Int. J. Mol. Sci. 2023, 24(23), 16802; https://doi.org/10.3390/ijms242316802 - 27 Nov 2023

Viewed by 668

Abstract

Echocardiographic detection of residual peri-device leakage (PDL) after percutaneous left atrial appendage occlusion (LAAO) is crucial for managing anticoagulation. Galectin-3, a protein involved in tissue–foreign body interactions, may hold significance in understanding PDL and cardiac tissue remodeling after LAAO. This study aimed to [...] Read more.

Echocardiographic detection of residual peri-device leakage (PDL) after percutaneous left atrial appendage occlusion (LAAO) is crucial for managing anticoagulation. Galectin-3, a protein involved in tissue–foreign body interactions, may hold significance in understanding PDL and cardiac tissue remodeling after LAAO. This study aimed to analyze galectin-3 serum levels in relation to PDL using a novel echo-morphological classification. LAAO eligible patients were included in the study. Galectin-3 serum levels were measured before LAAO, at 45 days (45D), and at 6 months (6M) after the procedure. Transesophageal echocardiography was used to assess LAAO success. A new echo-morphological classification categorized the degree of LAAO into three different types (A: homogenous echodensity, indicating completely thrombosed device; B: inhomogeneous echolucencies (<50% of device); and C: partially thrombosed device with echolucencies > 50%). Among 47 patients, complete LAAO was achieved in 60% after 45D and in 74% after 6M. We observed a significant increase and distribution of serum levels of galectin-3 [ng/mL] after 45D among the three types (baseline: 13.1 ± 5.8 ng/mL; 45D: 16.3 ± 7.2 ng/mL (Type A) vs. 19.2 ± 8.6 ng/mL (Type B) vs. 25.8 ± 9.4 ng/mL (Type C); p = 0.031), followed by a drop in galectin-3 for Types A and B after 6M toward and below the baseline levels (6M: 8.9 ± 3.1 ng/mL (Type A) vs. 12.4 ± 5.5 ng/mL (Type B)), whereas Type C persisted in showing elevated galectin-3 levels compared to all other types (6M: 17.5 ± 4.5 ng/mL (Type C); p < 0.01). Increased galectin-3 serum levels after LAAO likely reflect the transition from thrombus formation to fibrotic scar development in the LAA lumen. Successful occlusion is associated with a time-restricted decrease in galectin-3 levels after 6 months, while relevant PDL leads to persistently elevated levels, making galectin-3 a potential predictor of occlusion success. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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12 pages, 5040 KiB

Open AccessArticle

Aging Model for Analyzing Drug-Induced Proarrhythmia Risks Using Cardiomyocytes Differentiated from Progeria-Patient-Derived Induced Pluripotent Stem Cells

by Neil Daily, Julian Elson and Tetsuro Wakatsuki

Int. J. Mol. Sci. 2023, 24(15), 11959; https://doi.org/10.3390/ijms241511959 - 26 Jul 2023

Viewed by 802

Abstract

Among various cardiac safety concerns, proarrhythmia risks, including QT prolongation leading to Torsade de Pointes, is one of major cause for drugs being withdrawn (~45% 1975–2007). Preclinical study requires the evaluation of proarrhythmia using in silico, in vitro, and/or animal models. Considering that [...] Read more.

Among various cardiac safety concerns, proarrhythmia risks, including QT prolongation leading to Torsade de Pointes, is one of major cause for drugs being withdrawn (~45% 1975–2007). Preclinical study requires the evaluation of proarrhythmia using in silico, in vitro, and/or animal models. Considering that the primary consumers of prescription drugs are elderly patients, applications of “aging-in-a-dish” models would be appropriate for screening proarrhythmia risks. However, acquiring such models, including cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPSCs), presents extensive challenges. We proposed the hypothesis that CMs differentiated from iPSCs derived from Hutchinson–Gilford progeria syndrome (HGPS, progeria) patients, an ultra-rare premature aging syndrome, can mimic the phenotypes of aging CMs. Our objective, therefore, was to examine this hypothesis by analyzing the response of 11 reference compounds utilized by the Food and Drug Administration (FDA)’s Comprehensive in vitro Proarrhythmia Assay (CiPA) using progeria and control CMs. As a sensitive surrogate marker of modulating cardiac excitation–contraction coupling, we evaluated drug-induced changes in calcium transient (CaT). We observed that the 80% CaT peak duration in the progeria CMs (0.98 ± 0.04 s) was significantly longer than that of control CMs (0.70 ± 0.05 s). Furthermore, when the progeria CMs were subjected to four doses of 11 compounds from low-, intermediate-, and high-risk categories, they demonstrated greater arrhythmia susceptibility than control cells, as shown through six-parameter CaT profile analyses. We also employed the regression analysis established by CiPA to classify the 11 reference compounds and compared proarrhythmia susceptibilities between the progeria and control CMs. This analysis revealed a greater proarrhythmia susceptibility in the progeria CMs compared to the control CMs. Interestingly, in both CMs, the compounds categorized as low risk did not exceed the safety risk threshold of 0.8. In conclusion, our study demonstrates increased proarrhythmia sensitivity in progeria CMs when tested with reference compounds. Future studies are needed to analyze underlying mechanisms and further validate our findings using a larger array of reference compounds. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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14 pages, 1394 KiB

Open AccessArticle

Fluoxetine Treatment Decreases Cardiac Vagal Input and Alters the Serotonergic Modulation of the Parasympathetic Outflow in Diabetic Rats

by Mónica García-Domingo, José Ángel García-Pedraza, Juan Francisco Fernández-González, Cristina López, María Luisa Martín and Asunción Morán

Int. J. Mol. Sci. 2022, 23(10), 5736; https://doi.org/10.3390/ijms23105736 - 20 May 2022

Cited by 1 | Viewed by 1689

Abstract

Comorbid diabetes and depression constitutes a major health problem, worsening associated cardiovascular diseases. Fluoxetine’s (antidepressant) role on cardiac diabetic complications remains unknown. We determined whether fluoxetine modifies cardiac vagal input and its serotonergic modulation in male Wistar diabetic rats. Diabetes was induced by [...] Read more.

Comorbid diabetes and depression constitutes a major health problem, worsening associated cardiovascular diseases. Fluoxetine’s (antidepressant) role on cardiac diabetic complications remains unknown. We determined whether fluoxetine modifies cardiac vagal input and its serotonergic modulation in male Wistar diabetic rats. Diabetes was induced by alloxan and maintained for 28 days. Fluoxetine was administered the last 14 days (10 mg/kg/day; p.o). Bradycardia was obtained by vagal stimulation (3, 6 and 9 Hz) or i.v. acetylcholine administrations (1, 5 and 10 μg/kg). Fluoxetine treatment diminished vagally-induced bradycardia. Administration of 5-HT originated a dual action on the bradycardia, augmenting it at low doses and diminishing it at high doses, reproduced by 5-CT (5-HT_1/7 agonist). 5-CT did not alter the bradycardia induced by exogenous acetylcholine. Decrease of the vagally-induced bradycardia evoked by high doses of 5-HT and 5-CT was reproduced by L-694,247 (5-HT_1D agonist) and blocked by prior administration of LY310762 (5-HT_1D antagonist). Enhancement of the electrical-induced bradycardia by 5-CT (10 μg/kg) was abolished by pretreatment with SB269970 (5-HT₇ receptor antagonist). Thus, oral fluoxetine treatment originates a decrease in cardiac cholinergic activity and changes 5-HT modulation of bradycardic responses in diabetes: prejunctional 5-HT₇ receptors augment cholinergic-evoked bradycardic responses, whereas prejunctional 5-HT_1D receptors inhibit vagally-induced bradycardia. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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Review

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15 pages, 793 KiB

Open AccessReview

Aging of the Arterial System

by Roberto Castelli, Antonio Gidaro, Gavino Casu, Pierluigi Merella, Nicia I. Profili, Mattia Donadoni, Margherita Maioli and Alessandro P. Delitala

Int. J. Mol. Sci. 2023, 24(8), 6910; https://doi.org/10.3390/ijms24086910 - 07 Apr 2023

Cited by 11 | Viewed by 2050

Abstract

Aging of the vascular system is associated with deep changes of the structural proprieties of the arterial wall. Arterial hypertension, diabetes mellitus, and chronic kidney disease are the major determinants for the loss of elasticity and reduced compliance of vascular wall. Arterial stiffness [...] Read more.

Aging of the vascular system is associated with deep changes of the structural proprieties of the arterial wall. Arterial hypertension, diabetes mellitus, and chronic kidney disease are the major determinants for the loss of elasticity and reduced compliance of vascular wall. Arterial stiffness is a key parameter for assessing the elasticity of the arterial wall and can be easily evaluated with non-invasive methods, such as pulse wave velocity. Early assessment of vessel stiffness is critical because its alteration can precede clinical manifestation of cardiovascular disease. Although there is no specific pharmacological target for arterial stiffness, the treatment of its risk factors helps to improve the elasticity of the arterial wall. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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27 pages, 739 KiB

Open AccessReview

Inflammageing and Cardiovascular System: Focus on Cardiokines and Cardiac-Specific Biomarkers

by Marco Alfonso Perrone, Alberto Aimo, Sergio Bernardini and Aldo Clerico

Int. J. Mol. Sci. 2023, 24(1), 844; https://doi.org/10.3390/ijms24010844 - 03 Jan 2023

Cited by 11 | Viewed by 2966

Abstract

The term “inflammageing” was introduced in 2000, with the aim of describing the chronic inflammatory state typical of elderly individuals, which is characterized by a combination of elevated levels of inflammatory biomarkers, a high burden of comorbidities, an elevated risk of disability, frailty, [...] Read more.

The term “inflammageing” was introduced in 2000, with the aim of describing the chronic inflammatory state typical of elderly individuals, which is characterized by a combination of elevated levels of inflammatory biomarkers, a high burden of comorbidities, an elevated risk of disability, frailty, and premature death. Inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and rapid progression to heart failure. The great experimental and clinical evidence accumulated in recent years has clearly demonstrated that early detection and counteraction of inflammageing is a promising strategy not only to prevent cardiovascular disease, but also to slow down the progressive decline of health that occurs with ageing. It is conceivable that beneficial effects of counteracting inflammageing should be most effective if implemented in the early stages, when the compensatory capacity of the organism is not completely exhausted. Early interventions and treatments require early diagnosis using reliable and cost-effective biomarkers. Indeed, recent clinical studies have demonstrated that cardiac-specific biomarkers (i.e., cardiac natriuretic peptides and cardiac troponins) are able to identify, even in the general population, the individuals at highest risk of progression to heart failure. However, further clinical studies are needed to better understand the usefulness and cost/benefit ratio of cardiac-specific biomarkers as potential targets in preventive and therapeutic strategies for early detection and counteraction of inflammageing mechanisms and in this way slowing the progressive decline of health that occurs with ageing. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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23 pages, 3569 KiB

Open AccessReview

The Aging Heart: A Molecular and Clinical Challenge

by Davide Lazzeroni, Andrea Villatore, Gaia Souryal, Gianluca Pili and Giovanni Peretto

Int. J. Mol. Sci. 2022, 23(24), 16033; https://doi.org/10.3390/ijms232416033 - 16 Dec 2022

Cited by 12 | Viewed by 5814

Abstract

Aging is associated with an increasing burden of morbidity, especially for cardiovascular diseases (CVDs). General cardiovascular risk factors, ischemic heart diseases, heart failure, arrhythmias, and cardiomyopathies present a significant prevalence in older people, and are characterized by peculiar clinical manifestations that have distinct [...] Read more.

Aging is associated with an increasing burden of morbidity, especially for cardiovascular diseases (CVDs). General cardiovascular risk factors, ischemic heart diseases, heart failure, arrhythmias, and cardiomyopathies present a significant prevalence in older people, and are characterized by peculiar clinical manifestations that have distinct features compared with the same conditions in a younger population. Remarkably, the aging heart phenotype in both healthy individuals and patients with CVD reflects modifications at the cellular level. An improvement in the knowledge of the physiological and pathological molecular mechanisms underlying cardiac aging could improve clinical management of older patients and offer new therapeutic targets. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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19 pages, 1202 KiB

Open AccessReview

Heart Failure in Menopause: Treatment and New Approaches

by Jaqueline S. da Silva, Tadeu Lima Montagnoli, Mauro Paes Leme de Sá and Gisele Zapata-Sudo

Int. J. Mol. Sci. 2022, 23(23), 15140; https://doi.org/10.3390/ijms232315140 - 01 Dec 2022

Cited by 4 | Viewed by 2768

Abstract

Aging is an important risk factor for the development of heart failure (HF) and half of patients with HF have preserved ejection fraction (HFpEF) which is more common in elderly women. In general, sex differences that lead to discrepancies in risk factors and [...] Read more.

Aging is an important risk factor for the development of heart failure (HF) and half of patients with HF have preserved ejection fraction (HFpEF) which is more common in elderly women. In general, sex differences that lead to discrepancies in risk factors and to the development of cardiovascular disease (CVD) have been attributed to the reduced level of circulating estrogen during menopause. Estrogen receptors adaptively modulate fibrotic, apoptotic, inflammatory processes and calcium homeostasis, factors that are directly involved in the HFpEF. Therefore, during menopause, estrogen depletion reduces the cardioprotection. Preclinical menopause models demonstrated that several signaling pathways and organ systems are closely involved in the development of HFpEF, including dysregulation of the renin-angiotensin system (RAS), chronic inflammatory process and alteration in the sympathetic nervous system. Thus, this review explores thealterations observed in the condition of HFpEF induced by menopause and the therapeutic targets with potential to interfere with the disease progress. Full article

(This article belongs to the Special Issue Aging and Heart Disease)

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