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C-Reactive Protein and Cardiovascular Disease: Clinical Aspects

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cardiovascular Medicine".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 36621

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Dr. Ahmed Sheriff

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1. Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité University Medicine, 12200 Berlin, Germany
2. Pentracor GmbH, 16761 Hennigsdorf, Germany
Interests: acute myocardial infarction; acute-phase proteins; apheresis; complement system; COVID-19; C-reactive protein; inflammation; innate immune system; organ damage; stroke
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Dear Colleagues,

C-reactive protein (CRP) is widely established as significant prognostic biomarker in cardiovascular disease (CVD). It has recently been recognized as mediator and driver of inflammatory processes during atherosclerosis and CVD, promoting the deterioration of tissue and organ damage. Still, CRP is not normally evaluated as part of the standard clinical procedure to obtain a certain prognosis of the clinical outcome. It is also widely ignored as a therapeutic target in anti-inflammatory therapies for treating CVD. Hence, CRP is a strongly undervalued molecule and only using it as biomarker for inflammation does not do its function justice. Therefore, there is a great need to shed a different light on the role of CRP in CVD and interpret clinical data not only in regard to CRP as biomarker but while keeping in mind that CRP itself functions as driver of tissue damage.

The present Special Issue aims to provide an overview of relevant studies and provide an outlook into the future perspective on this pivotal protein. This will not only provide valuable information on the potential for CRP-driven prognostic decisions in CVD patients but also identify obstacles that need to be overcome to address CRP therapeutically.

Dr. Ahmed Sheriff
Guest Editor

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Keywords

biomarkers
cardiovascular medicine
coronary artery disease
cytokines and chemokines
inflammation
immunotherapy
myocardial infarction
tissue repair

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 208 KiB

Open AccessEditorial

Special Issue “C-Reactive Protein and Cardiovascular Disease: Clinical Aspects”

by Ahmed Sheriff

J. Clin. Med. 2022, 11(13), 3610; https://doi.org/10.3390/jcm11133610 - 22 Jun 2022

Cited by 1 | Viewed by 1626

Abstract

This Special Issue focuses on the clinical relevance of C-reactive protein [...] Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

Research

Jump to: Editorial, Review

9 pages, 936 KiB

Open AccessArticle

by Ronnie Meilik, Hadas Ben-Assayag, Ahuva Meilik, Shlomo Berliner, David Zeltser, Itzhak Shapira, Ori Rogowski, Ilana Goldiner, Shani Shenhar-Tsarfaty and Asaf Wasserman

J. Clin. Med. 2022, 11(11), 3151; https://doi.org/10.3390/jcm11113151 - 1 Jun 2022

Cited by 5 | Viewed by 1557

Abstract

Background: Patients who are admitted to the Department of Internal Medicine with apparently normal C-reactive protein (CRP) concentration impose a special challenge due the assumption that they might not harbor a severe and potentially lethal medical condition. Methods: A retrospective cohort of all patients who were admitted to the Department of Internal Medicine with a CRP concentration of ≤31.9 mg/L and had a second CRP test obtained within the next 24 h. Seven day mortality data were analyzed. Results: Overall, 3504 patients were analyzed with a mean first and second CRP of 8.8 (8.5) and 14.6 (21.6) mg/L, respectively. The seven day mortality increased from 1.8% in the first quartile of the first CRP to 7.5% in the fourth quartile of the first CRP (p < 0.0001) and from 0.6% in the first quartile of the second CRP to 9.5% in the fourth quartile of the second CRP test (p < 0.0001), suggesting a clear relation between the admission CRP and in hospital seven day mortality. Conclusions: An association exists between the quartiles of CRP and 7-day mortality as well as sepsis related cause of death. Furthermore, the CRP values 24 h after hospital admission improved the discrimination. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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9 pages, 722 KiB

Open AccessArticle

Early Detection of Inflammation-Prone STEMI Patients Using the CRP Troponin Test (CTT)

by Rafael Y. Brzezinski, Ariel Melloul, Shlomo Berliner, Ilana Goldiner, Moshe Stark, Ori Rogowski, Shmuel Banai, Shani Shenhar-Tsarfaty and Yacov Shacham

J. Clin. Med. 2022, 11(9), 2453; https://doi.org/10.3390/jcm11092453 - 27 Apr 2022

Cited by 5 | Viewed by 2198

Abstract

Elevated concentrations of C-reactive protein (CRP) early during an acute coronary syndrome (ACS) may reflect the magnitude of the inflammatory response to myocardial damage and are associated with worse outcome. However, the routine measurement of both CRP and cardiac troponin simultaneously in the setting of ST-segment myocardial infarction (STEMI) is not used broadly. Here, we sought to identify and characterize individuals who are prone to an elevated inflammatory response following STEMI by using a combined CRP and troponin test (CTT) and determine their short- and long-term outcome. We retrospectively examined 1186 patients with the diagnosis of acute STEMI, who had at least two successive measurements of combined CRP and cardiac troponin (up to 6 h apart), all within the first 48 h of admission. We used Chi-Square Automatic Interaction Detector (CHAID) tree analysis to determine which parameters, timing (baseline vs. serial measurements), and cut-offs should be used to predict mortality. Patients with high CRP concentrations (above 90th percentile, >33 mg/L) had higher 30 day and all-cause mortality rates compared to the rest of the cohort, regardless of their troponin test status (above or below 118,000 ng/L); 14.4% vs. 2.7%, p < 0.01. Furthermore, patients with both high CRP and high troponin levels on their second measurement had the highest 30-day mortality rates compared to the rest of the cohort; 21.4% vs. 3.7%, p < 0.01. These patients also had the highest all-cause mortality rates after a median follow-up of 4.5 years compared to the rest of the cohort; 42.9% vs. 12.7%, p < 0.01. In conclusion, serial measurements of both CRP and cardiac troponin might detect patients at increased risk for short-and long-term mortality following STEMI. We suggest the future use of the combined CTT as a potential early marker for inflammatory-prone patients with worse outcomes following ACS. This sub-type of patients might benefit from early anti-inflammatory therapy such as colchicine and anti-interleukin-1ß agents. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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12 pages, 2883 KiB

Open AccessArticle

Seven COVID-19 Patients Treated with C-Reactive Protein (CRP) Apheresis

by Fabrizio Esposito, Harald Matthes and Friedemann Schad

J. Clin. Med. 2022, 11(7), 1956; https://doi.org/10.3390/jcm11071956 - 1 Apr 2022

Cited by 11 | Viewed by 2922

Abstract

Background: The fulminant course of COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with a high mortality rate and still lacks a causative treatment. C-reactive protein (CRP) has been shown to increase dramatically during the disease progression and correlates with deleterious outcomes. Selective CRP apheresis can reduce circulating CRP levels fast and effective. Methods: Seven hospitalized patients with documented severe COVID-19 progression, elevated CRP plasma levels (>100 mg/L) and signs of respiratory failure were treated with CRP apheresis. Two to twelve CRP apheresis sessions were performed generally in 24 h time intervals and depending on CRP plasma levels. Results: All patients had comorbidities. CRP apheresis reduced CRP plasma levels by up to 84% within a few hours, without exhibiting side effects in any patient. Despite signs of severe lung infiltration in all patients, only one patient died. The other patients showed improvements within the chest X-ray after CRP apheresis and were able to recover regardless of intubation and/or ECMO (4 patients). All remaining six patients were discharged from the hospital in good clinical condition. Conclusions: This case series presents a mortality rate of only 14%, which is dramatically lower than expected from the presented CRP levels as well as comorbidities and ventilation requirements. Our clinical observations regarding the here presented seven patients support the hypothesis that CRP is a candidate to be therapeutically targeted in the early stage of severe COVID-19. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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15 pages, 1028 KiB

Open AccessArticle

CRP Serum Levels Are Associated with High Cardiometabolic Risk and Clinical Disease Activity in Systemic Lupus Erythematosus Patients

by Karen Pesqueda-Cendejas, Isela Parra-Rojas, Paulina E. Mora-García, Margarita Montoya-Buelna, Adolfo I. Ruiz-Ballesteros, Mónica R. Meza-Meza, Bertha Campos-López, Melissa Rivera-Escoto, Barbara Vizmanos-Lamotte, Sergio Cerpa-Cruz and Ulises de la Cruz-Mosso

J. Clin. Med. 2022, 11(7), 1849; https://doi.org/10.3390/jcm11071849 - 26 Mar 2022

Cited by 13 | Viewed by 3068

Abstract

Systemic lupus erythematosus (SLE) patients have a higher frequency of cardiovascular risk factors such as high C-reactive protein (CRP) levels than the general population. CRP is considered a cardiovascular disease marker that could be related to SLE clinical disease activity. This study aimed to assess the association between CRP with cardiometabolic risk and clinical disease activity in SLE patients. A comparative cross-sectional study was conducted in 176 female SLE patients and 175 control subjects (CS) with median ages of 38 and 33 years, respectively; SLE patients were classified by the 1997 SLE-ACR criteria, and the clinical disease activity by the Mexican-SLEDAI (Mex-SLEDAI). CRP and lipid profile (triglycerides, cholesterol, HDL-C, and LDL-C) were quantified by turbidimetry and colorimetric-enzymatic assays, respectively. SLE patients had higher CRP levels than CS (SLE: 5 mg/L vs. CS = 1.1 mg/L; p < 0.001). In SLE patients, CRP levels ≥ 3 mg/L were associated with a higher risk of cardiometabolic risk status assessed by LAP index (OR = 3.01; IC: 1.04–8.7; p = 0.04), triglycerides/HDL-C index (OR = 5.2; IC: 2.1–12.8; p < 0.001), Kannel index (OR = 3.1; IC: 1.1–8.1; p = 0.03), Castelli index (OR = 6.6; IC: 2.5–17.8; p < 0.001), and high clinical disease activity (OR = 2.5: IC: 1.03–6.2; p = 0.04; and β coefficient = 5.8; IC: 2.5–9.4; R² = 0.15; p = 0.001). In conclusion, high CRP levels were associated with high cardiometabolic risk and clinical disease activity in SLE patients. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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10 pages, 1057 KiB

Open AccessArticle

Cardiac Glycosides Lower C-Reactive Protein Plasma Levels in Patients with Decompensated Heart Failure: Results from the Single-Center C-Reactive Protein-Digoxin Observational Study (C-DOS)

by Myron Zaczkiewicz, Katharina Kostenzer, Matthias Graf, Benjamin Mayer, Oliver Zimmermann and Jan Torzewski

J. Clin. Med. 2022, 11(7), 1762; https://doi.org/10.3390/jcm11071762 - 22 Mar 2022

Cited by 3 | Viewed by 2899

Abstract

Recent randomized controlled multi-center trials JUPITER, CANTOS and COLCOT impressively demonstrated the effect of anti-inflammatory therapy on secondary prevention of cardiovascular events. These studies also rapidly re-vitalized the question of whether the C-reactive protein (CRP), the prototype human acute phase protein, is actively involved in atherosclerosis and its sequelae. Direct CRP inhibition may indeed improve the specificity and effectiveness of anti-inflammatory intervention. In the present paper, we report on the final results of our single-center C-reactive protein-Digoxin Observational Study (C-DOS). Methods and Results: Based on the experimental finding that cardiac glycosides potently inhibit hepatic CRP synthesis on the transcriptional level in vitro, 60 patients with decompensated heart failure, NYHA III–IV, severely reduced Left Ventricular Ejection Fraction (LVEF < 40%), and elevated CRP plasma levels were treated by either digoxin + conventional heart failure therapy (30 patients) or by conventional heart failure therapy alone (30 patients). Plasma CRP levels in both groups were assessed for 21 d. Plasma CRP levels on d1, d3 and d21 were compared by regression analysis. CRP levels d21–d1 significantly declined in both groups. Notably, comparative CRP reduction d21–d3 in digoxin versus the control group also revealed borderline significance (p = 0.051). Conclusions: This small observational trial provides the first piece of evidence that cardiac glycosides may inhibit CRP synthesis in humans. In case of further pharmacological developments, cardiac glycosides may emerge as lead compounds for chemical modification in order to improve the potency, selectivity and pharmacokinetics of CRP synthesis inhibition in cardiovascular disease. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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10 pages, 1539 KiB

Open AccessArticle

C-Reactive Protein (CRP) Blocks the Desensitization of Agonistic Stimulated G Protein Coupled Receptors (GPCRs) in Neonatal Rat Cardiomyocytes

by Gerd Wallukat, Stephan Mattecka, Katrin Wenzel, Wieland Schrödl, Birgit Vogt, Patrizia Brunner, Ahmed Sheriff and Rudolf Kunze

J. Clin. Med. 2022, 11(4), 1058; https://doi.org/10.3390/jcm11041058 - 17 Feb 2022

Cited by 3 | Viewed by 2238

Abstract

Recently, C-reactive protein (CRP) was shown to affect intracellular calcium signaling and blood pressure in vitro and in vivo, respectively. The aim of the present study was to further investigate if a direct effect on G-protein coupled receptor (GPCR) signaling by CRP can be observed by using CRP in combination with different GPCR agonists on spontaneously beating cultured neonatal rat cardiomyocytes. All used agonists (isoprenaline, clenbuterol, phenylephrine, angiotensin II and endothelin 1) affected the beat rate of cardiomyocytes significantly and after washing them out and re-stimulation the cells developed a pronounced desensitization of the corresponding receptors. CRP did not affect the basal beating-rate nor the initial increase/decrease in beat-rate triggered by different agonists. However, CRP co-incubated cells did not exhibit desensitization of the respective GPCRs after the stimulation with the different agonists. This lack of desensitization was independent of the GPCR type, but it was dependent on the CRP concentration. Therefore, CRP interferes with the desensitization of GPCRs and has to be considered as a novel regulator of adrenergic, angiotensin-1 and endothelin receptors. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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11 pages, 855 KiB

Open AccessArticle

Association of C-Reactive Protein Velocity with Early Left Ventricular Dysfunction in Patients with First ST-Elevation Myocardial Infarction

by Magdalena Holzknecht, Christina Tiller, Martin Reindl, Ivan Lechner, Priscilla Fink, Patrick Lunger, Agnes Mayr, Benjamin Henninger, Christoph Brenner, Gert Klug, Axel Bauer, Bernhard Metzler and Sebastian Johannes Reinstadler

J. Clin. Med. 2021, 10(23), 5494; https://doi.org/10.3390/jcm10235494 - 24 Nov 2021

Cited by 9 | Viewed by 1999

Abstract

C-reactive protein velocity (CRPv) has been proposed as a very early and sensitive risk predictor in patients with ST-elevation myocardial infarction (STEMI). However, the association of CRPv with early left ventricular (LV) dysfunction after STEMI is unknown. The aim of this study was to investigate the relationship between CRPv and early LV dysfunction, either before or at hospital discharge, in patients with first STEMI. This analysis evaluated 432 STEMI patients that were included in the prospective MARINA-STEMI (Magnetic Resonance Imaging In Acute ST-elevation Myocardial Infarction. ClinicalTrials.gov Identifier: NCT04113356) cohort study. The difference of CRP 24 ± 8 h and CRP at hospital admission divided by the time (in h) that elapsed during the two examinations was defined as CRPv. Cardiac magnetic resonance (CMR) imaging was conducted at a median of 3 (IQR 2–4) days after primary percutaneous coronary intervention (PCI) for the determination of LV function and myocardial infarct characteristics. The association of CRPv with the CMR-derived LV ejection fraction (LVEF) was investigated. The median CRPv was 0.42 (IQR 0.21–0.76) mg/l/h and was correlated with LVEF (r_S = −0.397, p < 0.001). In multivariable linear as well as binary logistic regression analysis (adjustment for biomarkers and clinical and angiographical parameters), CRPv was independently associated with LVEF (β: 0.161, p = 0.004) and LVEF ≤ 40% (OR: 1.71, 95% CI: 1.19–2.45; p = 0.004), respectively. The combined predictive value of peak cardiac troponin T (cTnT) and CRPv for LVEF ≤ 40% (AUC: 0.81, 95% CI 0.77–0.85, p < 0.001) was higher than it was for peak cTnT alone (AUC difference: 0.04, p = 0.009). CRPv was independently associated with early LV dysfunction, as measured by the CMR-determined LVEF, revealing an additive predictive value over cTnT after acute STEMI treated with primary PCI. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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10 pages, 1903 KiB

Open AccessArticle

Improved Prognostic Value in Predicting Long-Term Cardiovascular Events by a Combination of High-Sensitivity C-Reactive Protein and Brachial–Ankle Pulse Wave Velocity

by Hack-Lyoung Kim, Woo-Hyun Lim, Jae-Bin Seo, Sang-Hyun Kim, Joo-Hee Zo and Myung-A Kim

J. Clin. Med. 2021, 10(15), 3291; https://doi.org/10.3390/jcm10153291 - 26 Jul 2021

Cited by 9 | Viewed by 2221

Abstract

Background: Both C-reactive protein (CRP) and arterial stiffness are associated with the development of cardiovascular disease (CVD). This study was performed to investigate whether a combination of these two measurements could improve cardiovascular risk stratification. Methods: A total of 6572 consecutive subjects (mean age, 60.8 ± 11.8 years; female, 44.2%) who underwent both high-sensitivity CRP (hs-CRP) and brachial–ankle pulse wave velocity (baPWV) measurement within 1 week were retrospectively analyzed. Major adverse cardiovascular events (MACE), including cardiovascular death, acute myocardial infarction, coronary revascularization, and stroke were assessed during the clinical follow-up. Results: During a mean follow-up period of 3.75 years (interquartile range, 1.78–5.31 years), there were 182 cases of MACE (2.8%). The elevated baPWV (≥1505 cm/s) (hazard ratio (HR), 4.21; 95% confidence interval (CI), 2.73–6.48; p < 0.001) and hs-CRP (≥3 mg/L) (HR, 1.57; 95% CI, 1.12–2.21; p < 0.001) levels were associated with MACE even after controlling for potential confounders. The combination of baPWV and hs-CRP further stratified the subjects’ risk (subjects with low baPWV and hs-CRP vs. subjects with high baPWV and hs-CRP; HR, 7.08; 95% CI, 3.76−13.30; p < 0.001). Adding baPWV information to clinical factors and hs-CRP had an incremental prognostic value (global Chi-square score, from 126 to 167, p < 0.001). Conclusions: The combination of hs-CRP and baPWV provided a better prediction of future CVD than either one by itself. Taking these two simple measurements simultaneously is clinically useful in cardiovascular risk stratification. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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Review

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11 pages, 287 KiB

Open AccessReview

Targeting C-Reactive Protein by Selective Apheresis in Humans: Pros and Cons

by Jan Torzewski, Patrizia Brunner, Wolfgang Ries, Christoph D. Garlichs, Stefan Kayser, Franz Heigl and Ahmed Sheriff

J. Clin. Med. 2022, 11(7), 1771; https://doi.org/10.3390/jcm11071771 - 23 Mar 2022

Cited by 15 | Viewed by 5142

Abstract

C-reactive protein (CRP), the prototype human acute phase protein, may be causally involved in various human diseases. As CRP has appeared much earlier in evolution than antibodies and nonetheless partly utilizes the same biological structures, it is likely that CRP has been the first antibody-like molecule in the evolution of the immune system. Like antibodies, CRP may cause autoimmune reactions in a variety of human pathologies. Consequently, therapeutic targeting of CRP may be of utmost interest in human medicine. Over the past two decades, however, pharmacological targeting of CRP has turned out to be extremely difficult. Currently, the easiest, most effective and clinically safest method to target CRP in humans may be the specific extracorporeal removal of CRP by selective apheresis. The latter has recently shown promising therapeutic effects, especially in acute myocardial infarction and COVID-19 pneumonia. This review summarizes the pros and cons of applying this novel technology to patients suffering from various diseases, with a focus on its use in cardiovascular medicine. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

16 pages, 999 KiB

Open AccessReview

The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus

by Helena Enocsson, Jesper Karlsson, Hai-Yun Li, Yi Wu, Irving Kushner, Jonas Wetterö and Christopher Sjöwall

J. Clin. Med. 2021, 10(24), 5837; https://doi.org/10.3390/jcm10245837 - 13 Dec 2021

Cited by 39 | Viewed by 9209

Abstract

C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren’s syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus. Full article

(This article belongs to the Special Issue C-Reactive Protein and Cardiovascular Disease: Clinical Aspects)

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