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16 pages, 1946 KiB

Open AccessArticle

Angiopoietins, Vascular Endothelial Growth Factors and Secretory Phospholipase A₂ in Ischemic and Non-Ischemic Heart Failure

by Gilda Varricchi, Stefania Loffredo, Leonardo Bencivenga, Anne Lise Ferrara, Giuseppina Gambino, Nicola Ferrara, Amato de Paulis, Gianni Marone and Giuseppe Rengo

J. Clin. Med. 2020, 9(6), 1928; https://doi.org/10.3390/jcm9061928 - 19 Jun 2020

Cited by 21 | Viewed by 2511

Abstract

Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. In contrast to ischemic heart failure (IHF), the diagnosis of non-ischemic heart failure (NIHF) is established in the absence of coronary artery disease. Angiopoietins (ANGPTs), vascular endothelial growth [...] Read more.

Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. In contrast to ischemic heart failure (IHF), the diagnosis of non-ischemic heart failure (NIHF) is established in the absence of coronary artery disease. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A₂ (sPLA₂s) are proinflammatory mediators and key regulators of endothelial cells. In the present manuscript, we analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA₂ in patients with IHF and NIHF compared to healthy controls. The concentrations of ANGPT1, ANGPT2 and their ratio significantly differed between HF patients and healthy controls. Similarly, plasma levels of VEGF-D and sPLA₂ activity were higher in HF as compared to controls. Concentrations of ANGPT2 and the ANGPT2/ANGPT1 ratio (an index of vascular permeability) were increased in NIHF patients. VEGF-A and VEGF-C concentrations did not differ among the three examined groups. Interestingly, VEGF-D was selectively increased in IFH patients compared to controls. Plasma activity of sPLA₂ was increased in IHF and NIHF patients compared to controls. Our results indicate that several regulators of vascular permeability and smoldering inflammation are specifically altered in IHF and NIHF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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15 pages, 1928 KiB

Open AccessArticle

Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing

by Damiano Magrì, Vittoria Mastromarino, Giovanna Gallo, Elisabetta Zachara, Federica Re, Piergiuseppe Agostoni, Dario Giordano, Speranza Rubattu, Maurizio Forte, Maria Cotugno, Maria Rosaria Torrisi, Simona Petrucci, Aldo Germani, Camilla Savio, Antonello Maruotti, Massimo Volpe, Camillo Autore, Maria Piane and Beatrice Musumeci

J. Clin. Med. 2020, 9(6), 1636; https://doi.org/10.3390/jcm9061636 - 28 May 2020

Cited by 14 | Viewed by 2995

Abstract

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without [...] Read more.

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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12 pages, 681 KiB

Open AccessArticle

Effects of Caloric Intake and Aerobic Activity in Individuals with Prehypertension and Hypertension on Levels of Inflammatory, Adhesion and Prothrombotic Biomarkers—Secondary Analysis of a Randomized Controlled Trial

by En-Young N. Wagner, Suzi Hong, Kathleen L. Wilson, Karen J. Calfas, Cheryl L. Rock, Laura S. Redwine, Roland von Känel and Paul J. Mills

J. Clin. Med. 2020, 9(3), 655; https://doi.org/10.3390/jcm9030655 - 28 Feb 2020

Cited by 2 | Viewed by 2381

Abstract

Background: Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been [...] Read more.

Background: Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been examined so far. Methods: Sixty-eight sedentary prehypertensive and mildly hypertensive individuals (mean age ± SEM: 45 ± 1 years; mean BP: 141/84 ± 1/1 mmHg) were randomized to one of three 12-week intervention groups: cardio training and caloric reduction, cardio training alone, or wait-list control group. Plasma levels of inflammatory, adhesion and prothrombotic biomarkers were assessed. In a second step, intervention groups were combined to one sample and multivariate regression analyses were applied in order to account for exercise and diet behavior changes. Results: There were no significant differences among the intervention groups. In the combined sample, greater caloric reduction was associated with a larger increase of sICAM-3 (p = 0.026) and decrease of C-reactive protein (p = 0.018) as a result of the interventions. More cardio training was associated with increases of sICAM-3 (p = 0.046) as well as interleukin-6 (p = 0.004) and a decrease of tumor necrosis factor-α (p = 0.017) levels. Higher BP predicted higher plasminogen activator inhibitor (PAI)-1 (p = 0.001), and greater fitness predicted lower PAI-1 levels (p = 0.006) after the intervention. Conclusions: In prehypertensive and hypertensive patients, plasma levels of the adhesion molecule sICAM-3 and inflammatory biomarkers have different response patterns to cardio training with and without caloric reduction. Such anti-inflammatory and anti-thrombotic effects may have implications for the prevention of atherothrombotic cardiovascular disease among individuals at increased risk. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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13 pages, 467 KiB

Open AccessArticle

The Impact of the Circadian Genes CLOCK and ARNTL on Myocardial Infarction

by Ivana Škrlec, Jakov Milić and Robert Steiner

J. Clin. Med. 2020, 9(2), 484; https://doi.org/10.3390/jcm9020484 - 10 Feb 2020

Cited by 21 | Viewed by 3928

Abstract

The circadian rhythm regulates various physiological mechanisms, and its disruption can promote many disorders. Disturbance of endogenous circadian rhythms enhances the chance of myocardial infarction (MI), showing that circadian clock genes could have a crucial function in the onset of the disease. This [...] Read more.

The circadian rhythm regulates various physiological mechanisms, and its disruption can promote many disorders. Disturbance of endogenous circadian rhythms enhances the chance of myocardial infarction (MI), showing that circadian clock genes could have a crucial function in the onset of the disease. This case-control study was performed on 1057 participants. It was hypothesized that the polymorphisms of one nucleotide (SNP) in three circadian clock genes (CLOCK, ARNTL, and PER2) could be associated with MI. Statistically significant differences, estimated by the Chi-square test, were found in the distribution of alleles and genotypes between MI and no-MI groups of the CLOCK (rs6811520 and rs13124436) and ARNTL (rs3789327 and rs12363415) genes. According to the results of the present study, the polymorphisms in the CLOCK and ARNTL genes could be related to MI. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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16 pages, 7246 KiB

Open AccessArticle

Levosimendan Improves Oxidative Balance in Cardiogenic Shock/Low Cardiac Output Patients

by Elena Grossini, Serena Farruggio, Daniele Pierelli, Virginia Bolzani, Lidia Rossi, Piero Pollesello and Carolina Monaco

J. Clin. Med. 2020, 9(2), 373; https://doi.org/10.3390/jcm9020373 - 30 Jan 2020

Cited by 15 | Viewed by 2465

Abstract

The beneficial effects exerted by levosimendan against cardiac failure could be related to the modulation of oxidative balance. We aimed to examine the effects of levosimendan in patients with cardiogenic shock or low cardiac output on cardiac systo-diastolic function and plasma oxidants/antioxidants (glutathione, [...] Read more.

The beneficial effects exerted by levosimendan against cardiac failure could be related to the modulation of oxidative balance. We aimed to examine the effects of levosimendan in patients with cardiogenic shock or low cardiac output on cardiac systo-diastolic function and plasma oxidants/antioxidants (glutathione, GSH; thiobarbituric acid reactive substances, TBARS). In four patients undergoing coronary artery bypass grafting or angioplasty, cardiovascular parameters and plasma GSH and TBARS were measured at T0 (before levosimendan infusion), T1 (1 h after the achievement of the therapeutic dosage of levosimendan), T2 (end of levosimendan infusion), T3 (72 h after the end of levosimendan infusion), and T4 (end of cardiogenic shock). We found an improvement in the indices of systolic (ejection fraction, cardiac output, cardiac index) and diastolic (E to early diastolic mitral annular tissue velocity, E/’; early to late diastolic transmitral flow velocity, EA) cardiac function at early T2. A reduction of central venous pressure and pulmonary wedge pressure was also observed. Plasma levels of GSH and TBARS were restored by levosimendan at T1, as well. The results obtained indicate that levosimendan administration can regulate oxidant/antioxidant balance as an early effect in cardiogenic shock/low cardiac output patients. Modulation of oxidative status on a mitochondrial level could thus play a role in exerting the cardio-protection exerted by levosimendan in these patients. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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14 pages, 1803 KiB

Open AccessArticle

Association of Trimethylamine, Trimethylamine N-oxide, and Dimethylamine with Cardiovascular Risk in Children with Chronic Kidney Disease

by Chien-Ning Hsu, Guo-Ping Chang-Chien, Sufan Lin, Chih-Yao Hou, Pei-Chen Lu and You-Lin Tain

J. Clin. Med. 2020, 9(2), 336; https://doi.org/10.3390/jcm9020336 - 25 Jan 2020

Cited by 35 | Viewed by 3781

Abstract

Chronic kidney disease (CKD) is associated with high risk for cardiovascular disease (CVD). Gut microbiota-dependent metabolites trimethylamine (TMA), trimethylamine N-oxide (TMAO), and dimethylamine (DMA) have been linked to CKD and CVD. We examined whether these methylamines are correlated with cardiovascular risk in CKD [...] Read more.

Chronic kidney disease (CKD) is associated with high risk for cardiovascular disease (CVD). Gut microbiota-dependent metabolites trimethylamine (TMA), trimethylamine N-oxide (TMAO), and dimethylamine (DMA) have been linked to CKD and CVD. We examined whether these methylamines are correlated with cardiovascular risk in CKD children. A total of 115 children and adolescents with CKD stage G1–G4 were enrolled in this cross-sectional study. Children with CKD stage G2–G4 had higher plasma levels of DMA, TMA, and TMAO, but lower urinary levels of DMA and TMAO than those with CKD stage G1. Up to 53% of CKD children and adolescents had blood pressure (BP) abnormalities on 24-h ambulatory BP monitoring (ABPM). Plasma TMA and DMA levels inversely associated with high BP load as well as estimated glomerular filtration rate (eGFR). Additionally, CKD children with an abnormal ABPM profile had decreased abundance of phylum Cyanobacteria, genera Subdoligranulum, Faecalibacterium, Ruminococcus, and Akkermansia. TMA and DMA are superior to TMAO when related to high BP load and other CV risk factors in children and adolescents with early-stage CKD. Our findings highlight that gut microbiota-dependent methylamines are related to BP abnormalities and CV risk in pediatric CKD. Further studies should determine whether these microbial markers can identify children at risk for CKD progression. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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12 pages, 267 KiB

Open AccessArticle

Resistin and Cardiac Arrest—A Prospective Study

by Raluca M. Tat, Adela Golea, Rodica Rahaian, Ştefan C. Vesa and Daniela Ionescu

J. Clin. Med. 2020, 9(1), 57; https://doi.org/10.3390/jcm9010057 - 25 Dec 2019

Cited by 4 | Viewed by 2324

Abstract

The systemic response to ischemia-reperfusion that occurs after a cardiac arrest (CA) followed by the return of spontaneous circulation leads to endothelial toxicity and cytokine production, both responsible for the subsequent occurrence of severe cardiocirculatory dysfunction and early death. Resistin is emerging as [...] Read more.

The systemic response to ischemia-reperfusion that occurs after a cardiac arrest (CA) followed by the return of spontaneous circulation leads to endothelial toxicity and cytokine production, both responsible for the subsequent occurrence of severe cardiocirculatory dysfunction and early death. Resistin is emerging as a biomarker of proinflammatory status and myocardial ischemic injury and as a mediator of endothelial dysfunction. The study aimed to analyze the possible associations between several clinical and biological variables and the serum levels of resistin in CA survivors. Forty patients with out-of-hospital resuscitated CA, were enrolled in the study. Demographic, clinical and laboratory data (including serum resistin measurements at admission and at 6, 12, 24, 48 and 72 h) were recorded. For resistin, we calculated the area under the curve (AUC) using the trapezoidal method with measurements from 0 to 12 h, 0 to 24 h, 0 to 48 h and 0 to 72 h. Fifteen (37.5%) patients died in the first 72 h after CA. Cardiovascular comorbidities were present in 65% of patients. The majority of patients had post-CA shock (29 (72.5%)). Resistin serum levels rose in the first 12–24 h and decreased in the next 48–72 h. In univariate analysis, advanced age, longer duration of resuscitation, high sequential organ failure assessment score, high lactate levels, presence of cardiovascular comorbidities and the post-CA shock were associated with higher resistin levels. In multivariate analysis, post-CA shock or cardiovascular comorbidities were independently associated with higher AUCs for resistin for 0–12 h and 0–24 h. The only identified variable to independently predict higher AUCs for resistin for 0–48 h and 0–72 h was the presence of post-CA shock. Our data demonstrate strong independent correlation between high serum resistin levels, cardiac comorbidities and post-CA shock. The impact of the post-CA shock on serum concentration of resistin was greater than that of cardiac comorbidities. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

12 pages, 1448 KiB

Open AccessArticle

Neopterin is Associated with Disease Severity and Outcome in Patients with Non-Ischaemic Heart Failure

by Lukas Lanser, Gerhard Pölzl, Dietmar Fuchs, Günter Weiss and Katharina Kurz

J. Clin. Med. 2019, 8(12), 2230; https://doi.org/10.3390/jcm8122230 - 17 Dec 2019

Cited by 11 | Viewed by 2593

Abstract

Inflammation and immune activation play an important role in the pathogenesis of cardiac remodelling in patients with heart failure. The aim of this study was to assess whether biomarkers of inflammation and immune activation are linked to disease severity and the prognosis of [...] Read more.

Inflammation and immune activation play an important role in the pathogenesis of cardiac remodelling in patients with heart failure. The aim of this study was to assess whether biomarkers of inflammation and immune activation are linked to disease severity and the prognosis of heart failure patients. In 149 patients (65.8% men, median age 49.7 years) with heart failure from nonischaemic cardiomyopathy, the biomarkers neopterin and C-reactive protein were tested at the time of diagnosis. Patients were followed-up for a median of 58 months. During follow-up, nineteen patients died, five had a heart transplantation, two needed a ventricular assistance device, and twenty-one patients had to be hospitalised because of heart failure decompensation. Neopterin concentrations correlated with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations (rs = 0.399, p < 0.001) and rose with higher New York Heart Association (NYHA) class (I: 5.60 nmol/L, II: 6.90 nmol/L, III/IV: 7.80 nmol/L, p = 0.033). Higher neopterin levels were predictive for an adverse outcome (death or hospitalisation due to HF decompensation), independently of age and sex and of established predictors in heart failure such as NYHA class, NT-proBNP, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LV-EF) (HR 2.770; 95% CI 1.419–5.407; p = 0.003). Patients with a neopterin/eGFR ratio ≥ 0.133 (as a combined marker for immune activation and kidney function) had a more than eightfold increased risk of reaching an endpoint compared to patients with a neopterin/eGFR ratio ≤0.065 (HR 8.380; 95% CI 2.889–24.308; p < 0.001). Neopterin is associated with disease severity and is an independent predictor of prognosis in patients with heart failure. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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15 pages, 2072 KiB

Open AccessArticle

Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor

by Luca Liberale, Erik W. Holy, Alexander Akhmedov, Nicole R. Bonetti, Fabian Nietlispach, Christian M. Matter, François Mach, Fabrizio Montecucco, Jürg H. Beer, Francesco Paneni, Frank Ruschitzka, Peter Libby, Thomas F. Lüscher and Giovanni G. Camici

J. Clin. Med. 2019, 8(12), 2072; https://doi.org/10.3390/jcm8122072 - 26 Nov 2019

Cited by 65 | Viewed by 5090

Abstract

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1β antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present [...] Read more.

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1β antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present study explored the potential link between IL-1β, NETs, and tissue factor (TF)—the key trigger of the coagulation cascade—in atherothrombosis. To this end, ST-elevation myocardial infarction (STEMI) patients from the Swiss multicenter trial SPUM-ACS were retrospectively and randomly selected based on their CRP levels. In particular, 33 patients with STEMI and high C-reactive protein (CRP) levels (≥ 10 mg/L) and, 33 with STEMI and low CRP levels (≤ 4 mg/L) were investigated. High CRP patients displayed elevated circulating IL-1β, NETosis, and NET-associated TF plasma levels compared with low CRP ones. Additionally, analysis of patients stratified by circulating IL-1β levels yielded similar results. Moreover, NETosis and NET-associated TF plasma levels correlated positively in the whole population. In addition to the above, translational research experiments provided mechanistic confirmation for the clinical data identifying IL-1β as the initial trigger for the release of the pro-coagulant, NET-associated TF. In conclusion, blunted TF presentation by activated neutrophils undergoing NETosis may provide a mechanistic explanation to reduced secondary atherothrombotic events as observed in canakinumab-treated patients in CANTOS. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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8 pages, 470 KiB

Open AccessArticle

We are What We Eat: Impact of Food from Short Supply Chain on Metabolic Syndrome

by Gaetano Santulli, Valeria Pascale, Rosa Finelli, Valeria Visco, Rocco Giannotti, Angelo Massari, Carmine Morisco, Michele Ciccarelli, Maddalena Illario, Guido Iaccarino and Enrico Coscioni

J. Clin. Med. 2019, 8(12), 2061; https://doi.org/10.3390/jcm8122061 - 23 Nov 2019

Cited by 49 | Viewed by 3760

Abstract

Food supply in the Mediterranean area has been recently modified by big retail distribution; for instance, industrial retail has favored shipments of groceries from regions that are intensive producers of mass food, generating a long supply chain (LSC) of food that opposes short [...] Read more.

Food supply in the Mediterranean area has been recently modified by big retail distribution; for instance, industrial retail has favored shipments of groceries from regions that are intensive producers of mass food, generating a long supply chain (LSC) of food that opposes short supply chains (SSCs) that promote local food markets. However, the actual functional role of food retail and distribution in the determination of the risk of developing metabolic syndrome (MetS) has not been studied hitherto. The main aim of this study was to test the effects of food chain length on the prevalence of MetS in a population accustomed to the Mediterranean diet. We conducted an observational study in Southern Italy on individuals adhering to the Mediterranean diet. We examined a total of 407 subjects (41% females) with an average age of 56 ± 14.5 years (as standard deviation) and found that being on the Mediterranean diet with a SSC significantly reduces the prevalence of MetS compared with the LSC (SSC: 19.65%, LSC: 31.46%; p: 0.007). Our data indicate for the first time that the length of food supply chain plays a key role in determining the risk of MetS in a population adhering to the Mediterranean diet. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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11 pages, 652 KiB

Open AccessArticle

The Circulating GRP78/BiP Is a Marker of Metabolic Diseases and Atherosclerosis: Bringing Endoplasmic Reticulum Stress into the Clinical Scenario

by Josefa Girona, Cèlia Rodríguez-Borjabad, Daiana Ibarretxe, Joan-Carles Vallvé, Raimon Ferré, Mercedes Heras, Ricardo Rodríguez-Calvo, Sandra Guaita-Esteruelas, Neus Martínez-Micaelo, Núria Plana and Lluís Masana

J. Clin. Med. 2019, 8(11), 1793; https://doi.org/10.3390/jcm8111793 - 26 Oct 2019

Cited by 40 | Viewed by 4906

Abstract

Background: Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/BiP) is a protein associated with endoplasmic reticulum stress and is upregulated by metabolic alterations at the tissue-level, such as hypoxia or glucose deprivation, and it is hyper-expressed in fat tissue of obese individuals. Objective: To investigate [...] Read more.

Background: Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/BiP) is a protein associated with endoplasmic reticulum stress and is upregulated by metabolic alterations at the tissue-level, such as hypoxia or glucose deprivation, and it is hyper-expressed in fat tissue of obese individuals. Objective: To investigate the role of the GRP78/BiP level as a metabolic and vascular disease biomarker in patients with type 2 diabetes (DM), obesity and metabolic syndrome (MS). Methods: Four hundred and five patients were recruited, of whom 52.5% were obese, 72.8% had DM, and 78.6% had MS. The intimae media thickness (cIMT) was assessed by ultrasonography. The plasma GRP78/BiP concentration was determined, and its association with metabolic and vascular parameters was assessed. Circulating GRP78/BiP was also prospectively measured in 30 DM patients before and after fenofibrate/niacin treatment and 30 healthy controls. Results: In the cross-sectional study, the GRP78/BiP level was significantly higher in the patients with obesity, DM, and MS. Age-, gender- and BMI-adjusted GRP78/BiP was directly associated with LDL-cholesterol, non-HDL-cholesterol, triglycerides, apoB, and cIMT. GRP78/BiP was positively associated to carotid plaque presence in the adjusted model, irrespective of obesity, DM and MS. In the prospective study, nicotinic acid treatment produced a significant reduction in the GRP78/BiP levels that was not observed with fenofibrate. Conclusions: GRP78/BiP plasma concentrations are increased in patients with both metabolic derangements and subclinical atherosclerosis. GRP78/BiP could be a useful marker of metabolic and cardiovascular risk. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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13 pages, 2289 KiB

Open AccessArticle

Transient Laterality of Cerebral Oxygenation Changes in Response to Head-of-Bed Manipulation in Acute Ischemic Stroke

by Naoki Katayama, Keiichi Odagiri, Akio Hakamata, Naoki Inui, Katsuya Yamauchi and Hiroshi Watanabe

J. Clin. Med. 2019, 8(10), 1739; https://doi.org/10.3390/jcm8101739 - 19 Oct 2019

Cited by 1 | Viewed by 3355

Abstract

Background: Cerebral oxygenation monitoring provides important information for optimizing individualized management in patients with acute ischemic stroke (AIS). Although changes in cerebral oxygenation are known to occur in response to head-of-bed (HOB) elevation within 72 h after onset, changes in cerebral oxygenation during [...] Read more.

Background: Cerebral oxygenation monitoring provides important information for optimizing individualized management in patients with acute ischemic stroke (AIS). Although changes in cerebral oxygenation are known to occur in response to head-of-bed (HOB) elevation within 72 h after onset, changes in cerebral oxygenation during stroke recovery are unclear. We compared changes in total- (tHb), oxygenated- (HbO₂), and deoxygenated-hemoglobin (deoxyHb) concentrations in response to HOB manipulation between the timeframes within 72 h and 7–10 days after AIS onset. Methods: We measured forehead ΔtHb, ΔHbO₂, and ΔdeoxyHb in response to HOB elevation (30°) within 72 h (first measurement) and 7–10 days (second measurement) after AIS onset using time-resolved near-infrared spectroscopy. Results: We enrolled 30 participants (mean age 72.8 ± 11.3 years; 13 women) with a first AIS. There were no significant differences in ΔtHb, ΔHbO₂, or ΔdeoxyHb measurements on the infarct or contra-infarct side. At the first measurement, ΔtHb, ΔHbO₂, and ΔdeoxyHb measured on the contra-infarct side did not correlate with those measured on the infarct side: ΔtHb (r = 0.114, p = 0.539); ΔHbO₂ (r = 0.143, p = 0.440); ΔdeoxyHb (r = 0.227, p = 0.221). Notably, at the second measurement, correlation coefficients of ΔtHb and ΔHbO₂ between the contra-infarct and infarct sides were statistically significant: ΔtHb (r = 0.491, p = 0.008); ΔHbO₂ (r = 0.479, p = 0.010); ΔdeoxyHb (r = 0.358, p = 0.054). Conclusion: Although changes in cerebral oxygenation in response to HOB elevation had a laterality difference between hemispheres within 72 h of AIS onset, the difference had decreased, at least partially, 7–10 days after AIS onset. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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12 pages, 1329 KiB

Open AccessArticle

Increased Citrullinated Histone H3 Levels in the Early Post-Resuscitative Period Are Associated with Poor Neurologic Function in Cardiac Arrest Survivors—A Prospective Observational Study

by Lisa-Marie Mauracher, Nina Buchtele, Christian Schörgenhofer, Christoph Weiser, Harald Herkner, Anne Merrelaar, Alexander O. Spiel, Lena Hell, Cihan Ay, Ingrid Pabinger, Bernd Jilma and Michael Schwameis

J. Clin. Med. 2019, 8(10), 1568; https://doi.org/10.3390/jcm8101568 - 01 Oct 2019

Cited by 8 | Viewed by 2665

Abstract

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest [...] Read more.

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest survivors. This study prospectively included adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors with cardiac origin, who were subjected to targeted temperature management. Plasma levels of specific (citrullinated histone H3, H3Cit) and putative (cell-free DNA (cfDNA) and nucleosomes) biomarkers of NET formation were assessed at 0 and 12 h after admission. The primary outcome was neurologic function on day 30 after admission, which was assessed using the five-point cerebral performance category (CPC) score, classifying patients into good (CPC 1–2) or poor (CPC 3–5) neurologic function. The main variable of interest was the effect of H3Cit level quintiles at 12 h on 30 day neurologic function, assessed by logistic regression. The first quintile was used as a baseline reference. Results are given as crude odds ratio (OR) with 95% confidence interval (95% CI). Sixty-two patients (79% male, median age: 57 years) were enrolled. The odds of poor neurologic function increased linearly, with 0 h levels of cfNDA (crude OR 1.8, 95% CI: 1.2–2.7, p = 0.007) and nucleosomes (crude OR 1.7, 95% CI: 1.0–2.2, p = 0.049), as well as with 12 h levels of cfDNA (crude OR 1.6, 95% CI: 1.1–2.4, p = 0.024), nucleosomes (crude OR 1.7, 95% CI: 1.1–2.5, p = 0.020), and H3Cit (crude OR 1.6, 95% CI: 1.1–2.3, p = 0.029). Patients in the fourth (7.9, 95% CI: 1.1–56, p = 0.039) and fifth (9.0, 95% CI: 1.3–63, p = 0.027) H3Cit quintile had significantly higher odds of poor 30 day neurologic function compared to patients in the first quintile. Increased plasma levels of H3Cit, 12 h after admission, are associated with poor 30 day neurologic function in adult OHCA survivors, which may suggest a contribution of NET formation to post-resuscitative brain damage and therefore provide a therapeutic target in the future. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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17 pages, 992 KiB

Open AccessArticle

Altered Metabolomic Profile in Patients with Peripheral Artery Disease

by Ahmed Ismaeel, Marco E. Franco, Ramon Lavado, Evlampia Papoutsi, George P. Casale, Matthew Fuglestad, Constance J. Mietus, Gleb R. Haynatzki, Robert S. Smith, William T. Bohannon, Ian Sawicki, Iraklis I. Pipinos and Panagiotis Koutakis

J. Clin. Med. 2019, 8(9), 1463; https://doi.org/10.3390/jcm8091463 - 14 Sep 2019

Cited by 22 | Viewed by 4287

Abstract

Peripheral artery disease (PAD) is a common atherosclerotic disease characterized by narrowed or blocked arteries in the lower extremities. Circulating serum biomarkers can provide significant insight regarding the disease progression. Here, we explore the metabolomics signatures associated with different stages of PAD and [...] Read more.

Peripheral artery disease (PAD) is a common atherosclerotic disease characterized by narrowed or blocked arteries in the lower extremities. Circulating serum biomarkers can provide significant insight regarding the disease progression. Here, we explore the metabolomics signatures associated with different stages of PAD and investigate potential mechanisms of the disease. We compared the serum metabolites of a cohort of 26 PAD patients presenting with claudication and 26 PAD patients presenting with critical limb ischemia (CLI) to those of 26 non-PAD controls. A difference between the metabolite profiles of PAD patients from non-PAD controls was observed for several amino acids, acylcarnitines, ceramides, and cholesteryl esters. Furthermore, our data demonstrate that patients with CLI possess an altered metabolomic signature different from that of both claudicants and non-PAD controls. These findings provide new insight into the pathophysiology of PAD and may help develop future diagnostic procedures and therapies for PAD patients. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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9 pages, 740 KiB

Open AccessArticle

Severity of Coronary Atherosclerosis and Risk of Diabetes Mellitus

by Iginio Colaiori, Raffaele Izzo, Emanuele Barbato, Danilo Franco, Giuseppe Di Gioia, Antonio Rapacciuolo, Jozef Bartunek, Costantino Mancusi, Maria Angela Losi, Teresa Strisciuglio, Maria Virginia Manzi, Giovanni de Simone, Bruno Trimarco and Carmine Morisco

J. Clin. Med. 2019, 8(7), 1069; https://doi.org/10.3390/jcm8071069 - 21 Jul 2019

Cited by 10 | Viewed by 3270

Abstract

Background: Cardio-vascular target organ damage predicts the onset of type 2 diabetes mellitus (DM) in hypertensive patients. Whether an increased incidence of DM is also in relation to the severity of coronary atherosclerosis is unknown. Objective: We evaluated the onset of DM in [...] Read more.

Background: Cardio-vascular target organ damage predicts the onset of type 2 diabetes mellitus (DM) in hypertensive patients. Whether an increased incidence of DM is also in relation to the severity of coronary atherosclerosis is unknown. Objective: We evaluated the onset of DM in relation to the extent and severity of coronary atherosclerosis, using the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score (SS), in patients with stable angina or acute coronary syndromes, referred for coronary angiography (CA). Methods: Non-diabetic patients that underwent CA for the first time were included, and the SS was computed. Predictors of DM onset in low, medium, and high SSs were investigated. Results: Five hundred and seventy patients were included, and the mean SS was 6.3 ± 7.6. During a median follow-up of 79 months (interquartile range (IQR): 67–94), 74 patients (13%) developed DM. The risk of DM onset was significantly higher in the patients with a medium or high SS (hazard ratio (HR)—95% confidence interval (CI): 16 (4–61), p < 0.0001; and 30 (9–105), p < 0.0001, vs low SS, respectively), even after adjustment for obesity, history of hypertension, impaired fasting glucose, and cardiovascular therapy. Conclusions: The severity and extent of the coronary atherosclerosis, evaluated by the SS, is a strong and independent predictor of the development of DM in patients, referred to CA. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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10 pages, 536 KiB

Open AccessArticle

Depressed Myocardial Energetic Efficiency Increases Risk of Incident Heart Failure: The Strong Heart Study

by Maria-Angela Losi, Raffaele Izzo, Costantino Mancusi, Wenyu Wang, Mary J. Roman, Elisa T. Lee, Barbara V. Howard, Richard B. Devereux and Giovanni de Simone

J. Clin. Med. 2019, 8(7), 1044; https://doi.org/10.3390/jcm8071044 - 17 Jul 2019

Cited by 27 | Viewed by 2755

Abstract

An estimation of myocardial mechano-energetic efficiency (MEE) per unit of left ventricular (LV) mass (MEEi) can significantly predict composite cardiovascular (CV) events in treated hypertensive patients with normal ejection fraction (EF), after adjustment for LV hypertrophy (LVH). We have tested whether MEEi predicts [...] Read more.

An estimation of myocardial mechano-energetic efficiency (MEE) per unit of left ventricular (LV) mass (MEEi) can significantly predict composite cardiovascular (CV) events in treated hypertensive patients with normal ejection fraction (EF), after adjustment for LV hypertrophy (LVH). We have tested whether MEEi predicts incident heart failure (HF), after adjustment for LVH, in the population-based cohort of a “Strong Heart Study” (SHS) with normal EF. We included 1912 SHS participants (age 59 ± 8 years; 64% women) with preserved EF (≥50%) and without prevalent CV disease. MEE was estimated as the ratio of stroke work to the “double product” of heart rate times systolic blood pressure. MEEi was calculated as MEE/LV mass, and analyzed in quartiles. During a follow-up study of 9.2 ± 2.3 years, 126 participants developed HF (7%). HF was preceded by acute myocardial infarction (AMI) in 94 participants. A Kaplan-Meier plot, in quartiles of MEEi, demonstrated significant differences, substantially due to the deviation of the lowest quartile (p < 0.0001). Using AMI as a competing risk event, sequential models of Cox regression for incident HF (including significant confounders), demonstrated that low MEEi predicted incident HF not due to AMI (p = 0.026), after adjustment for significant effect of age, LVH, prolonged LV relaxation, diabetes, and smoking habits with negligible effects for sex, hypertension, antihypertensive therapy, obesity, and hyperlipemia. Low LV mechano-energetic efficiency per unit of LVM, is a predictor of incident, non-AMI related, HF in subjects with initially normal EF. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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15 pages, 845 KiB

Open AccessArticle

The Polymorphisms of the Peroxisome-Proliferator Activated Receptors’ Alfa Gene Modify the Aerobic Training Induced Changes of Cholesterol and Glucose

by Agnieszka Maciejewska-Skrendo, Maciej Buryta, Wojciech Czarny, Pawel Król, Michal Spieszny, Petr Stastny, Miroslav Petr, Krzysztof Safranow and Marek Sawczuk

J. Clin. Med. 2019, 8(7), 1043; https://doi.org/10.3390/jcm8071043 - 17 Jul 2019

Cited by 11 | Viewed by 3158

Abstract

Background: PPARα is a transcriptional factor that controls the expression of genes involved in fatty acid metabolism, including fatty acid transport, uptake by the cells, intracellular binding, and activation, as well as catabolism (particularly mitochondrial fatty acid oxidation) or storage. PPARA gene polymorphisms [...] Read more.

Background: PPARα is a transcriptional factor that controls the expression of genes involved in fatty acid metabolism, including fatty acid transport, uptake by the cells, intracellular binding, and activation, as well as catabolism (particularly mitochondrial fatty acid oxidation) or storage. PPARA gene polymorphisms may be crucial for maintaining lipid homeostasis and in this way, being responsible for developing specific training-induced physiological reactions. Therefore, we have decided to check if post-training changes of body mass measurements as well as chosen biochemical parameters are modulation by the PPARA genotypes. Methods: We have examined the genotype and alleles’ frequencies (described in PPARA rs1800206 and rs4253778 polymorphic sites) in 168 female participants engaged in a 12-week training program. Body composition and biochemical parameters were measured before and after the completion of a whole training program. Results: Statistical analyses revealed that PPARA intron 7 rs4253778 CC genotype modulate training response by increasing low-density lipoproteins (LDL) and glucose concentration, while PPARA Leu162Val rs1800206 CG genotype polymorphism interacts in a decrease in high-density lipoproteins (HDL) concentration. Conclusions: Carriers of PPARA intron 7 rs4253778 CC genotype and Leu162Val rs1800206 CG genotype might have potential negative training-induced cholesterol and glucose changes after aerobic exercise. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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21 pages, 6015 KiB

Open AccessArticle

Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease

by Ioannis Drosos, Maria Pavlaki, Maria Del Pilar Ortega Carrillo, Adriani Kourkouli, Katja Buschmann, Fotios Konstantinou, Rajinikanth Gogiraju, Magdalena L. Bochenek, Georgios Chalikias, Christos Tortopidis, Christian F. Vahl, Dimitrios Mikroulis, Dimitrios Tziakas, Thomas Münzel, Stavros Konstantinides and Katrin Schäfer

J. Clin. Med. 2019, 8(7), 1000; https://doi.org/10.3390/jcm8071000 - 09 Jul 2019

Cited by 14 | Viewed by 4660

Abstract

Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared [...] Read more.

Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Perioperatively collected C-PVAT and IMA-PVAT were analyzed using histology, immunohistochemistry, real time PCR, and PVAT-conditioned medium using cytokine arrays. C-PVAT exhibited increased PECAM-1 (platelet endothelial cell adhesion molecule 1)-positive vessel density. The number of lymphatic vessels expressing lymphatic vessel endothelial hyaluronan receptor-1 or podoplanin was also elevated in C-PVAT and associated with higher inflammatory cell numbers, increased intercellular adhesion molecule 1 (ICAM1) expression, and fibrosis. Significantly higher expression of regulators of lymphangiogenesis such as vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor-3 was observed in C-PVAT compared to IMA-PVAT. Cytokine arrays identified angiopoietin-2 as more highly expressed in C-PVAT vs. IMA-PVAT. Findings were confirmed histologically and at the mRNA level. Stimulation of human lymphatic endothelial cells with recombinant angiopoietin-2 in combination with VEGF-C enhanced sprout formation. Our study shows that PVAT surrounding atherosclerotic arteries exhibits more extensive lymphangiogenesis, inflammation, and fibrosis compared to PVAT surrounding a non-diseased vessel, possibly due to local angiopoietin-2, VEGF-C, and VEGF-D overexpression. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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15 pages, 1370 KiB

Open AccessArticle

Effects of Fructose or Glucose on Circulating ApoCIII and Triglyceride and Cholesterol Content of Lipoprotein Subfractions in Humans

by Bettina Hieronimus, Steven C. Griffen, Nancy L. Keim, Andrew A. Bremer, Lars Berglund, Katsuyuki Nakajima, Peter J. Havel and Kimber L. Stanhope

J. Clin. Med. 2019, 8(7), 913; https://doi.org/10.3390/jcm8070913 - 26 Jun 2019

Cited by 15 | Viewed by 4330

Abstract

ApoCIII and triglyceride (TG)-rich lipoproteins (TRL), particularly, large TG-rich lipoproteins particles, have been described as important mediators of cardiovascular disease (CVD) risk. The effects of sustained consumption of dietary fructose compared with those of sustained glucose consumption on circulating apoCIII and large TRL [...] Read more.

ApoCIII and triglyceride (TG)-rich lipoproteins (TRL), particularly, large TG-rich lipoproteins particles, have been described as important mediators of cardiovascular disease (CVD) risk. The effects of sustained consumption of dietary fructose compared with those of sustained glucose consumption on circulating apoCIII and large TRL particles have not been reported. We measured apoCIII concentrations and the TG and cholesterol content of lipoprotein subfractions separated by size in fasting and postprandial plasma collected from men and women (age: 54 ± 8 years) before and after they consumed glucose- or fructose-sweetened beverages for 10 weeks. The subjects consuming fructose exhibited higher fasting and postprandial plasma apoCIII concentrations than the subjects consuming glucose (p < 0.05 for both). They also had higher concentrations of postprandial TG in all TRL subfractions (p < 0.05, effect of sugar), with the highest increases occurring in the largest TRL particles (p < 0.0001 for fructose linear trend). Compared to glucose consumption, fructose consumption increased postprandial TG in low-density lipoprotein (LDL) particles (p < 0.05, effect of sugar), especially in the smaller particles (p < 0.0001 for fructose linear trend). The increases of both postprandial apoCIII and TG in large TRL subfractions were associated with fructose-induced increases of fasting cholesterol in the smaller LDL particles. In conclusion, 10 weeks of fructose consumption increased the circulating apoCIII and postprandial concentrations of large TRL particles compared with glucose consumption. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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Review

Jump to: Research

24 pages, 2622 KiB

Open AccessReview

Complexity of TNF-α Signaling in Heart Disease

by Filip Rolski and Przemysław Błyszczuk

J. Clin. Med. 2020, 9(10), 3267; https://doi.org/10.3390/jcm9103267 - 12 Oct 2020

Cited by 74 | Viewed by 9156

Abstract

Heart disease is a leading cause of death with unmet clinical needs for targeted treatment options. Tumor necrosis factor alpha (TNF-α) represents a master pro-inflammatory cytokine that plays an important role in many immunopathogenic processes. Anti-TNF-α therapy is widely used in treating autoimmune [...] Read more.

Heart disease is a leading cause of death with unmet clinical needs for targeted treatment options. Tumor necrosis factor alpha (TNF-α) represents a master pro-inflammatory cytokine that plays an important role in many immunopathogenic processes. Anti-TNF-α therapy is widely used in treating autoimmune inflammatory disorders, but in case of patients with heart disease, this treatment was unsuccessful or even harmful. The underlying reasons remain elusive until today. This review summarizes the effects of anti-TNF-α treatment in patients with and without heart disease and describes the involvement of TNF-α signaling in a number of animal models of cardiovascular diseases. We specifically focused on the role of TNF-α in specific cardiovascular conditions and in defined cardiac cell types. Although some mechanisms, mainly in disease development, are quite well known, a comprehensive understanding of TNF-α signaling in the failing heart is still incomplete. Published data identify pathogenic and cardioprotective mechanisms of TNF-α in the affected heart and highlight the differential role of two TNF-α receptors pointing to the complexity of the TNF-α signaling. In the light of these findings, it seems that targeting the TNF-α pathway in heart disease may show therapeutic benefits, but this approach must be more specific and selectively block pathogenic mechanisms. To this aim, more research is needed to better understand the molecular mechanisms of TNF-α signaling in the failing heart. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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11 pages, 563 KiB

Open AccessReview

Natriuretic Peptides, Cognitive Impairment and Dementia: An Intriguing Pathogenic Link with Implications in Hypertension

by Giovanna Gallo, Franca Bianchi, Maria Cotugno, Massimo Volpe and Speranza Rubattu

J. Clin. Med. 2020, 9(7), 2265; https://doi.org/10.3390/jcm9072265 - 16 Jul 2020

Cited by 7 | Viewed by 2491

Abstract

The natriuretic peptides (NPs) belong to a family of cardiac hormones that exert relevant protective functions within the cardiovascular system. An increase of both brain and atrial natriuretic peptide levels, particularly of the amino-terminal peptides (NT-proBNP and NT-proANP), represents a marker of cardiovascular [...] Read more.

The natriuretic peptides (NPs) belong to a family of cardiac hormones that exert relevant protective functions within the cardiovascular system. An increase of both brain and atrial natriuretic peptide levels, particularly of the amino-terminal peptides (NT-proBNP and NT-proANP), represents a marker of cardiovascular damage. A link between increased NP levels and cognitive decline and dementia has been reported in several human studies performed both in general populations and in cohorts of patients affected by cardiovascular diseases (CVDs). In particular, it was reported that the elevation of NP levels in dementia can be both dependent and independent from CVD risk factors. In the first case, it may be expected that, by counteracting early on the cardiovascular risk factor load and the pathological processes leading to increased aminoterminal natriuretic peptide (NT-proNP) level, the risk of dementia could be significantly reduced. In case of a link independent from CVD risk factors, an increased NP level should be considered as a direct marker of neuronal damage. In the context of hypertension, elevated NT-proBNP and mid-regional (MR)-proANP levels behave as markers of brain microcirculatory damage and dysfunction. The available evidence suggests that they could help in identifying those subjects who would benefit most from a timely antihypertensive therapy. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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22 pages, 2084 KiB

Open AccessReview

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

by Celestino Sardu, Jessica Gambardella, Marco Bruno Morelli, Xujun Wang, Raffaele Marfella and Gaetano Santulli

J. Clin. Med. 2020, 9(5), 1417; https://doi.org/10.3390/jcm9051417 - 11 May 2020

Cited by 366 | Viewed by 28192

Abstract

The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) [...] Read more.

The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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12 pages, 1273 KiB

Open AccessReview

Functional Role of Natriuretic Peptides in Risk Assessment and Prognosis of Patients with Mitral Regurgitation

by Giovanna Gallo, Maurizio Forte, Rosita Stanzione, Maria Cotugno, Franca Bianchi, Simona Marchitti, Andrea Berni, Massimo Volpe and Speranza Rubattu

J. Clin. Med. 2020, 9(5), 1348; https://doi.org/10.3390/jcm9051348 - 05 May 2020

Cited by 8 | Viewed by 2419

Abstract

The management of mitral valve regurgitation (MR), a common valve disease, represents a challenge in clinical practice, since the indication for either surgical or percutaneous valve replacement or repair are guided by symptoms and by echocardiographic parameters which are not always feasible. In [...] Read more.

The management of mitral valve regurgitation (MR), a common valve disease, represents a challenge in clinical practice, since the indication for either surgical or percutaneous valve replacement or repair are guided by symptoms and by echocardiographic parameters which are not always feasible. In this complex scenario, the use of natriuretic peptide (NP) levels would serve as an additive diagnostic and prognostic tool. These biomarkers contribute to monitoring the progression of the valve disease, even before the development of hemodynamic consequences in a preclinical stage of myocardial damage. They may contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations, thus requiring surgical management rather than a conservative approach. This article provides a comprehensive overview of the available evidence on the role of NPs in the management, risk evaluation, and prognostic assessment of patients with MR both before and after surgical or percutaneous valve repair. Despite largely positive evidence, a series of controversial findings exist on this relevant topic. Recent clinical trials failed to assess the role of NPs following the interventional procedure. Future larger studies are required to enable the introduction of NP levels into the guidelines for the management of MR. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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16 pages, 748 KiB

Open AccessFeature PaperReview

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

by Jessica Gambardella, Angela Lombardi, Marco Bruno Morelli, John Ferrara and Gaetano Santulli

J. Clin. Med. 2020, 9(4), 1096; https://doi.org/10.3390/jcm9041096 - 12 Apr 2020

Cited by 19 | Viewed by 4605

Abstract

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing [...] Read more.

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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12 pages, 767 KiB

Open AccessReview

The Vasoactive Mas Receptor in Essential Hypertension

by Amalie L. Povlsen, Daniela Grimm, Markus Wehland, Manfred Infanger and Marcus Krüger

J. Clin. Med. 2020, 9(1), 267; https://doi.org/10.3390/jcm9010267 - 18 Jan 2020

Cited by 52 | Viewed by 8639

Abstract

The renin–angiotensin–aldosterone system (RAAS) has been studied extensively, and with the inclusion of novel components, it has become evident that the system is much more complex than originally anticipated. According to current knowledge, there are two main axes of the RAAS, which counteract [...] Read more.

The renin–angiotensin–aldosterone system (RAAS) has been studied extensively, and with the inclusion of novel components, it has become evident that the system is much more complex than originally anticipated. According to current knowledge, there are two main axes of the RAAS, which counteract each other in terms of vascular control: The classical vasoconstrictive axis, renin/angiotensin-converting enzyme/angiotensin II/angiotensin II receptor type 1 (AT₁R), and the opposing vasorelaxant axis, angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor (MasR). An abnormal activity within the system constitutes a hallmark in hypertension, which is a global health problem that predisposes cardiovascular and renal morbidities. In particular, essential hypertension predominates in the hypertensive population of more than 1.3 billion humans worldwide, and yet, the pathophysiology behind this multifactorial condition needs clarification. While commonly applied pharmacological strategies target the classical axis of the RAAS, discovery of the vasoprotective effects of the opposing, vasorelaxant axis has presented encouraging experimental evidence for a new potential direction in RAAS-targeted therapy based on the G protein-coupled MasR. In addition, the endogenous MasR agonist angiotensin-(1-7), peptide analogues, and related molecules have become the subject of recent studies within this field. Nevertheless, the clinical potential of MasR remains unclear due to indications of physiological-biased activities of the RAAS and interacting signaling pathways. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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37 pages, 1792 KiB

Open AccessReview

by Richard Myles Turner and Munir Pirmohamed

J. Clin. Med. 2020, 9(1), 22; https://doi.org/10.3390/jcm9010022 - 20 Dec 2019

Cited by 112 | Viewed by 16096

Abstract

Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, [...] Read more.

Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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19 pages, 2139 KiB

Open AccessReview

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure—Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

by Piero Pollesello, Tuvia Ben Gal, Dominique Bettex, Vladimir Cerny, Josep Comin-Colet, Alexandr A. Eremenko, Dimitrios Farmakis, Francesco Fedele, Cândida Fonseca, Veli-Pekka Harjola, Antoine Herpain, Matthias Heringlake, Leo Heunks, Trygve Husebye, Visnja Ivancan, Kristjan Karason, Sundeep Kaul, Jacek Kubica, Alexandre Mebazaa, Henning Mølgaard, John Parissis, Alexander Parkhomenko, Pentti Põder, Gerhard Pölzl, Bojan Vrtovec, Mehmet B. Yilmaz and Zoltan Papp Show full author list Hide full author list

J. Clin. Med. 2019, 8(11), 1834; https://doi.org/10.3390/jcm8111834 - 01 Nov 2019

Cited by 15 | Viewed by 4061

Abstract

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but—per definition—causes the rise in age of patients experiencing acute [...] Read more.

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but—per definition—causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio- and vasoactive drugs used in the hospitalization phase to stabilize the patient’s hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g., catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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36 pages, 2037 KiB

Open AccessReview

A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse

by Aristides Tsatsakis, Anca Oana Docea, Daniela Calina, Konstantinos Tsarouhas, Laura-Maria Zamfira, Radu Mitrut, Javad Sharifi-Rad, Leda Kovatsi, Vasileios Siokas, Efthimios Dardiotis, Nikolaos Drakoulis, George Lazopoulos, Christina Tsitsimpikou, Panayiotis Mitsias and Monica Neagu

J. Clin. Med. 2019, 8(9), 1295; https://doi.org/10.3390/jcm8091295 - 23 Aug 2019

Cited by 80 | Viewed by 15331

Abstract

Drugs of abuse are associated with stroke, especially in young individuals. The major classes of drugs linked to stroke are cocaine, amphetamines, heroin, morphine, cannabis, and new synthetic cannabinoids, along with androgenic anabolic steroids (AASs). Both ischemic and hemorrhagic stroke have been reported [...] Read more.

Drugs of abuse are associated with stroke, especially in young individuals. The major classes of drugs linked to stroke are cocaine, amphetamines, heroin, morphine, cannabis, and new synthetic cannabinoids, along with androgenic anabolic steroids (AASs). Both ischemic and hemorrhagic stroke have been reported due to drug abuse. Several common mechanisms have been identified, such as arrhythmias and cardioembolism, hypoxia, vascular toxicity, vascular spasm and effects on the thrombotic mechanism, as causes for ischemic stroke. For hemorrhagic stroke, acute hypertension, aneurysm formation/rupture and angiitis-like changes have been implicated. In AAS abuse, the effect of blood pressure is rather substance specific, whereas increased erythropoiesis usually leads to thromboembolism. Transient vasospasm, caused by synthetic cannabinoids, could lead to ischemic stroke. Opiates often cause infective endocarditis, resulting in ischemic stroke and hypereosinophilia accompanied by pyogenic arthritis, provoking hemorrhagic stroke. Genetic variants are linked to increased risk for stroke in cocaine abuse. The fact that case reports on cannabis-induced stroke usually refer to the young population is very alarming. Full article

(This article belongs to the Special Issue Cardiovascular Disease: From Molecular Mechanisms to Clinical Therapies)

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