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)

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

A short review on CRP synthesis inhibition in cardiovascular disease

C-reactive Protein (CRP) is synthesized in the liver. Synthesis is stimulated via the IL-1ß/IL6 pathway. CRP activates the complement system via C1q and macrophages via Fcγ receptors. Since elevated CRP plasma levels are associated with increased cardiovascular risk, CRP may play a causal role in cardiovascular disease. One approach to transfer these observations into standard medical care would be to generate hepatic CRP synthesis inhibitors and use them in controlled clinical trials. Despite huge pharmacological efforts, the search for CRP synthesis inhibitors proved to be difficult. First, the antisense oligonucleotide RNA technology, although a promising idea, has not yet led to results feasible for clinical practice. Secondly, high throughput screening assays in search for hepatic CRP inhibitors were limited by the fact that primary human hepatocytes do not adequately grow in vitro. Use of genetically engineered hepatoma cells led to the observation that cardiac glycosides are capable of inhibiting CRP synthesis. Because of patent law considerations, however, pharmaceutical companies had limited interest in further pursuing this possible path. Upstream inhibition of IL-1ß and IL-6 by antibodies has shown positive results in cardiovascular clinical trials, but because of side effects none of these antibodies has yet received FDA approval. In contrast, long-term colchicine treatment, though not being a CRP-specific approach, has recently been approved by the FDA. Taken together, there is no compelling evidence until today that hepatic CRP synthesis can specifically, effectively and safely be inhibited in vivo in human medicine. Currently, other avenues appear more promising. Here, we summarize contemporary approaches to inhibit CRP synthesis and potential goals for future clinical trials

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)

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 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

C-Reactive Protein in Human Atherogenesis: Facts and Fiction

The role of C-reactive protein (CRP) in atherosclerosis is controversially discussed. Whereas initial experimental studies suggested a pathogenic role for CRP in atherogenesis, more recent genetic data from Mendelian randomization trials failed to provide evidence for a causative role of CRP in cardiovascular disease. Also, experimental results from laboratories all over the world were indeed contradictory, partly because of species differences in CRP biology and partly because data were not accurately evaluated. Here we summarize the published data from experimental work with mainly human material in order to avoid confusion based on species differences in CRP biology. Experimental work needs to be reevaluated after reconsideration of some traditional rules in research: (1) in order to understand a molecule’s role in disease it may be helpful to be aware of its role in physiology; (2) it is necessary to define the disease entity that experimental CRP research deals with; (3) the scientific consensus is as follows: do not try to prove your hypothesis. Specific CRP inhibition followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease

Impact of Bifurcation Involvement and Location in Chronic Total Occlusion Percutaneous Coronary Intervention:Insights From the EuroCTO Registry

Bifurcation involvement close to or within the occluded segment poses increasing difficulties for chronic total occlusion (CTO)-percutaneous coronary intervention (PCI). However, this variable is not considered in the angiography-based CTO scoring systems nor has been extensively investigated in large multicenter series. Accordingly, we analyzed a CTO-PCI registry involving 92 European centers to explore the incidence, angiographic and procedural characteristics, and outcomes specific to CTO-PCIs with bifurcation involvement. A total of 3,948 procedures performed between January and November 2023 were examined (33% with bifurcation involvement). Among bifurcation lesions, 38% and 37% were located within 5 mm of the proximal and distal cap, respectively, 16% within the CTO body, and in 9% of cases proximal and distal bifurcations coexisted. When compared with lesions without bifurcation involvement, CTO bifurcation lesions had higher complexity (J-CTO 2.33 ± 1.21 vs 2.11 ± 1.27, p &lt;0.001) and were associated with higher use of additional devices (dual-lumen microcatheter in 27.6% vs 8.4%, p &lt;0.001, and intravascular ultrasound in 32.2% vs 21.7%, p &lt;0.001). Radiation dose (1,544 [836 to 2,819] vs 1,298.5 [699.1 to 2,386.6] mGy, p &lt;0.001) and contrast volume (230 [160 to 300] vs 190 [130 to 250] ml, p &lt;0.001) were also higher. Technical success was similar (91.5% with bifurcation involvement vs 90.4% without bifurcation involvement, p = 0.271). However, the bifurcation lesions within the CTO segment (intralesion) were associated with lower technical success than the other bifurcation-location subgroups (83.7% vs 93.3% proximal, 93.4% distal, and 89.0% proximal and distal, p &lt;0.001). On multivariable analysis, the presence of an intralesion bifurcation was independently associated with technical failure (odds ratio 2.04, 95% confidence interval 1.24 to 3.35, p = 0.005). In conclusion, bifurcations are present in approximately one-third of CTOs who underwent PCI. PCI of CTOs with bifurcation can be achieved with high success rates except for bifurcations within the occluded segment, which were associated with higher technical failure.</p

Impact of Bifurcation Involvement and Location in Chronic Total Occlusion Percutaneous Coronary Intervention:Insights From the EuroCTO Registry

Bifurcation involvement close to or within the occluded segment poses increasing difficulties for chronic total occlusion (CTO)-percutaneous coronary intervention (PCI). However, this variable is not considered in the angiography-based CTO scoring systems nor has been extensively investigated in large multicenter series. Accordingly, we analyzed a CTO-PCI registry involving 92 European centers to explore the incidence, angiographic and procedural characteristics, and outcomes specific to CTO-PCIs with bifurcation involvement. A total of 3,948 procedures performed between January and November 2023 were examined (33% with bifurcation involvement). Among bifurcation lesions, 38% and 37% were located within 5 mm of the proximal and distal cap, respectively, 16% within the CTO body, and in 9% of cases proximal and distal bifurcations coexisted. When compared with lesions without bifurcation involvement, CTO bifurcation lesions had higher complexity (J-CTO 2.33 ± 1.21 vs 2.11 ± 1.27, p &lt;0.001) and were associated with higher use of additional devices (dual-lumen microcatheter in 27.6% vs 8.4%, p &lt;0.001, and intravascular ultrasound in 32.2% vs 21.7%, p &lt;0.001). Radiation dose (1,544 [836 to 2,819] vs 1,298.5 [699.1 to 2,386.6] mGy, p &lt;0.001) and contrast volume (230 [160 to 300] vs 190 [130 to 250] ml, p &lt;0.001) were also higher. Technical success was similar (91.5% with bifurcation involvement vs 90.4% without bifurcation involvement, p = 0.271). However, the bifurcation lesions within the CTO segment (intralesion) were associated with lower technical success than the other bifurcation-location subgroups (83.7% vs 93.3% proximal, 93.4% distal, and 89.0% proximal and distal, p &lt;0.001). On multivariable analysis, the presence of an intralesion bifurcation was independently associated with technical failure (odds ratio 2.04, 95% confidence interval 1.24 to 3.35, p = 0.005). In conclusion, bifurcations are present in approximately one-third of CTOs who underwent PCI. PCI of CTOs with bifurcation can be achieved with high success rates except for bifurcations within the occluded segment, which were associated with higher technical failure.</p