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As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on “residual cardiovascular disease risk”. During this review process we found 989 papers that started off with residual CVD risk after initiating statin therapy, continued with papers on residual CVD risk after initiating therapy to increase high-density lipoprotein-cholesterol (HDL-C), followed by papers on residual CVD risk after initiating therapy to decrease triglyceride (TG) levels. Later on, papers dealing with elevated levels of lipoprotein remnants and lipoprotein(a) [Lp(a)] reported new risk factors of residual CVD risk. And as new risk factors are being discovered and new therapies are being tested, residual CVD risk will be reduced further. As we move from CVD risk reduction to improvement of patient management, a paradigm shift from a reductionistic approach towards a holistic approach is required. To that purpose, a personalized treatment dependent on the individual’s CVD risk factors including lipid profile abnormalities should be configured, along the line of P5 medicine for each individual patient, i.e., with Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive approaches.

Fernanda A Orsi,1,2 Willem M Lijfering,2,3 Arnoud Van der Laarse,4,5 L Renee Ruhaak,4 Frits R Rosendaal,2 Suzanne C Cannegieter,2–3,6 Christa Cobbaert41Department of Clinical Pathology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; 3Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; 4Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands; 5Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 6Department of Internal Medicine, Section of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The NetherlandsPurpose: Apolipoproteins C-I, C-II, C-III and E have been associated with risk of arterial thrombotic diseases. We investigated whether these apolipoproteins have prothrombotic properties and are associated with risk of venous thromboembolism (VTE).Patients and methods: A total of 127 VTE patients and 299 controls were randomly selected from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study (1999–2004), in the Netherlands. The apolipoproteins were quantified using mass spectrometry (LC/MS/MS), and their levels were analyzed as continuous variable (per SD increase).Results: In controls, increases in levels of apolipoproteins were associated with increases in levels of vitamin K-dependent factors, factor XI, antithrombin and clot lysis time. Additionally, increasing apolipoproteins C-III and E levels were associated with higher factor VIII and von Willebrand factor levels. Levels of C-reactive protein were not associated with any apolipoprotein. The age- and sex-adjusted odds ratios of apolipoproteins E, C-III, CII and CI to the risk of venous thrombosis were 1.21 (95% CI, 0.98–1.49), 1.19 (95% CI, 0.99–1.44), 1.24 (95% CI, 0.95–1.61) and 1.06 (95% CI, 0.87–1.30) per SD increase, respectively. These odds ratios did not attenuate after adjustments for statin use, estrogen use, BMI, alcohol use, and self-reported diabetes.Conclusions: Levels of apolipoproteins C-I, C-II, C-III and E are associated with those of several coagulation factors. However, whether these apolipoproteins are also associated with an increased risk of VTE remains to be established.Keywords: thrombosis, proteomics, lipids, cholesterol, coagulation, risk factors

While the heart regenerates poorly in mammals, efficient heart regeneration occurs in zebrafish. Studies in zebrafish have resulted in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. To identify which processes occur in proliferating cardiomyocytes we have used a single-cell RNA-sequencing approach. We uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the nonproliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Furthermore, we find that the metabolic reprogramming of border zone cardiomyocytes is induced by Nrg1/ErbB2 signaling and is important for their proliferation. This mechanism is conserved in murine hearts in which cardiomyocyte proliferation is induced by activating ErbB2 signaling. Together these results demonstrate that glycolysis regulates cardiomyocyte proliferation during heart regeneration.

Currently available data on the energetics of isolated muscle preparations are based on bouts of less than 10 muscle contractions, whereas metabolic energy consumption is mostly relevant during steady state tasks such as locomotion. In this study we quantified the energetics of small fiber bundles of mouse soleus muscle during prolonged (2 min) series of contractions. Bundles (N = 9) were subjected to sinusoidal length changes, while measuring force and oxygen consumption. Stimulation (five pulses at 100 Hz) occurred either during shortening or during lengthening. Movement frequency (2–3 Hz) and amplitude (0.25–0.50 mm; corresponding to ± 4–8% muscle fiber strain) were close to that reported for mouse soleus muscle during locomotion. The experiments were performed at 32°C. The contributions of cross-bridge cycling and muscle activation to total metabolic energy expenditure were separated using blebbistatin. The mechanical work per contraction cycle decreased sharply during the first 10 cycles, emphasizing the importance of prolonged series of contractions. The mean ± SD fraction of metabolic energy required for activation was 0.37 ± 0.07 and 0.56 ± 0.17 for concentric and eccentric contractions, respectively (both 0.25 mm, 2 Hz). The mechanical efficiency during concentric contractions increased with contraction velocity from 0.12 ± 0.03 (0.25 mm 2 Hz) to 0.15 ± 0.03 (0.25 mm, 3 Hz) and 0.16 ± 0.02 (0.50 mm, 2 Hz) and was -0.22 ± 0.08 during eccentric contractions (0.25 mm, 2 Hz). The percentage of type I fibers correlated positively with mechanical efficiency during concentric contractions, but did not correlate with the fraction of metabolic energy required for activation.

Fish may be extremely hypoxia resistant. We investigated how muscle fibre size and oxidative capacity in zebrafish (Danio rerio) adapt during severe chronic hypoxia. Zebrafish were kept for either 3 or 6 weeks under chronic constant hypoxia (CCH) (10% air/90%N2 saturated water). We analyzed cross-sectional area (CSA), succinate dehydrogenase (SDH) activity, capillarization, myonuclear density, myoglobin (Mb) concentration and Mb mRNA expression of high and low oxidative muscle fibres. After 3 weeks of CCH, CSA, SDH activity, Mb concentration, capillary and myonuclear density of both muscle fibre types were similar as under normoxia. In contrast, staining intensity for Mb mRNA of hypoxic high oxidative muscle fibres was 94% higher than that of normoxic controls (P