Approach to risk stratification of atherosclerotic cardiovascular disease: Use of biomarkers and imaging in a Canadian context

ObjectiveTo outline the 2021 Canadian Cardiovascular Society (CCS) dyslipidemia guidelines and to present the current approaches to cardiovascular risk stratification, including the incorporation of biomarkers and imaging tests.Sources of informationCurrent guidelines were reviewed and an Ovid MEDLINE literature search was performed.Main messageCardiovascular disease (CVD) is the leading cause of global mortality, with ischemic heart disease contributing to nearly half of these deaths. Risk stratification is undertaken to identify patients who would benefit from primary prevention for atherosclerotic CVD (ASCVD), but commonly used methods for risk stratification are imperfect. The CCS guidelines endorse that the presence of risk modifiers (family history of premature ASCVD, high-sensitivity C-reactive protein level ≥2.0 mg/L, lipoprotein[a] level ≥500 mg/L [≥50 mg/dL], or coronary artery calcium >0) supports the use of statin therapy in those at intermediate risk (Framingham risk score 10% to 19.9%) who do not otherwise meet the recommendations for statin use. The CCS guidelines recommend statin therapy in patients at intermediate risk when cholesterol levels are elevated (low-density lipoprotein cholesterol level ≥3.5 mmol/L, non–high-density lipoprotein cholesterol level ≥4.2 mmol/L, or apolipoprotein B level ≥1.05 g/L). In addition, statin therapy should be considered for patients at low risk (Framingham risk score 5% to 9.9%) with elevated cholesterol levels, especially if risk modifiers are present. When cholesterol levels are not elevated, evidence still favours the use of statins in intermediate-risk patients when risk modifiers are present and in men 50 years and older and women 60 years and older with 1 additional risk factor.ConclusionBiomarkers and imaging tests have the potential to improve ASCVD risk stratification by reclassifying any patient whose risk has been inaccurately estimated by traditional methods. Recently published guidelines by the CCS suggest the use of biomarkers and imaging in certain patient groups.

Cardiovascular disease (CVD) is the leading cause of disease burden in the world, and prevalent cases have nearly doubled since the 1990s.¹ A large proportion of CVD is caused by atherosclerosis.^1,2 Ischemic heart disease encompasses diseases of the heart due to atherosclerotic coronary artery disease (CAD), while atherosclerotic CVD (ASCVD) is a general term for diseases of the cardiovascular system due to cholesterol plaque buildup. Primary prevention of ASCVD involves treating patients who are at risk of developing, or who have already developed, atherosclerotic disease before they experience a cardiovascular event. Risk stratification is undertaken to identify patients who would benefit from primary prevention, but commonly used methods for risk stratification are imperfect. Traditionally, cardiovascular risk stratification involves a review of the patient’s risk factors, characteristic symptoms (if any), a physical examination, a resting electrocardiogram, and bloodwork.³ The risk of ASCVD can then be estimated using a risk score. The 2021 Canadian Cardiovascular Society (CCS) guidelines⁴ recommend the use of the Framingham risk score (FRS),⁵ which aims to predict an end point that includes myocardial infarction (MI), angina, coronary death, stroke, claudication, or congestive heart failure.⁶ Of note, there are several versions of the FRS that estimate different end points (eg, hard CAD, which includes CAD but not angina⁵). A patient may have different FRS estimations depending on which end point is used and may falsely be placed in a lower-risk group if the full complement of outcomes is not considered.Risk scores are not able to account for risk with complete accuracy, since traditional risk factors (smoking, hypertension, diabetes, dyslipidemia, age, and sex) account for only 65% to 85% of cardiovascular events.^7,8 When abdominal obesity, psychosocial factors, diet, alcohol consumption, and physical activity are also accounted for, 90% to 94% of cardiovascular events can be explained,⁹ but these factors are difficult to quantify and are impractical for the purposes of risk scores. Furthermore, cardiovascular risk in women is often underestimated^10,11: sex-specific differences in the rates of diagnosis and treatment of traditional risk factors, and sex-specific risk factors such as hypertensive disorders of pregnancy,^12,13 are not accounted for by most risk scores. Biomarkers and imaging tests may help close the detection gap by accounting for the risk not explained by traditional risk factors.¹⁴     

Multiple tachykinin binding sites in peripheral tissues and in brain

Tachykinin binding sites in guinea pig urinary bladder (GPUB), rat salivary gland (RSG), hamster urinary bladder (HUB), rat vas deferens (RVD) and rat cerebral cortex (RCC) were compared using ¹²⁵I-Bolton Hunter conjugates of substance P (¹²⁵I-BHSP), eledoisin (¹²⁵I-BHE) and neurokinin A (¹²⁵I-BHNKA). In typical SP-P tissues (GPUB, RSG) and in RCC, SP was the most potent displacer of ¹²⁵I-BHSP and [Glp⁶, D-Pro⁹]-SP(6–11) was 90 times less active than [Glp⁶, L-Pro⁹]-SP(6–11) while SP methyl ester (SPOMe) was 5–10 times more active than the Bolton Hunter conjugate of SPOMe (I-BHSPOMe). On the other hand, in typical SP-E tissues (HUB, RVD), neurokinin A was most potent in displacing ¹²⁵I-BHE and [Glp⁶,D-Pro⁹]-SP(6–11) was over 300 times more active than [Glp⁶,L-Pro⁹]-SP(6–11) while SPOMe was 160 times less active than I-BHSPOMe. In rat cerebral cortex, the rank order of potency of tachykinins and related analogues in displacing ¹²⁵I-BHE was distinct from that of peripheral SP-E sites, with neurokinin B being the most potent displacer, and SPOMe was over 1 000 times more active than I-BHSPOMe; ¹²⁵I-BHE binding sites in CNS may represent a third category of tachykinin receptor, designated SP-N.     

Percutaneous Penetration Kinetics of Nitroglycerin and Its Dinitrate Metabolites Across Hairless Mouse Skin in Vitro

The percutaneous penetration kinetics of the antianginal, nitroglycerin (GTN), and its primary metabolites, 1,2- and 1,3-glyceryl dinitrate (1,2- and 1,3-GDN), were evaluated in vitro, using full-thickness hairless mouse skin. GTN and the 1,2- and 1,3-GDNs were applied (a) in aqueous solution as pH 7.4 phosphate-buffered saline (PBS) and (b) incorporated into lipophilic ointment formulations. The cutaneous transformation of GTN to its dinitrate metabolites was detected, but no interconversion between 1,2-GDN and 1,3-GDN was observed. Following application of the nitrates in PBS solution, all three compounds exhibited steady-state transport kinetics. The steady-state flux of GTN (8.9 ± 1.5 nmol cm^–2 hr^–1) was significantly greater (P < 0.05) than those of 1,2-GDN (0.81 ± 0.54 nmol cm^–2 hr^–1) and 1,3-GDN (0.72 ± 0.20 nmol cm^–2 hr^–1). The corresponding permeability coefficient () for GTN (20 ± 3 × 10^–3 cm hr^–1) was significantly larger than the corresponding values for 1,2-GDN (1.4 ± 0.9 × 10^–3 cm hr^–1) and 1,3-GDN (1.2 ± 0.4 × 10^–3 cm hr^–1), which were statistically indistinguishable (P > 0.05). Further analysis of the transport data showed that the differences between GTN and the GDNs could be explained by the relative stratum corneum/water partition coefficient (K _s) values of the compounds. The apparent partition parameters, defined as = K _s · h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 ± 2.5 × 10^–2 cm for GTN and 1.91 ± 1.07 × 10^–2 and 1.81 ± 0.91 × 10^–2 cm for 1,2- and 1,3-GDN, respectively. However, when the nitrates were administered in an ointment base, the apparent partition parameter (') and permeability coefficient (') of GTN markedly decreased, to 2.51 ± 0.75 × 10^–2 cm and 1.6 ± 0.3 × 10^–3 cm hr^–1, respectively. In contrast, the ' and ' results for 1,2- and 1,3-GDN were not significantly different (P > 0.05) from the corresponding and values, which were measured following dosing as aqueous solutions. As a result, the steady-state fluxes of all three nitrates from the ointment formulation were comparable (GTN, 154 ± 28 nmol cm^–2 hr^–1; 1,2-GDN, 162 ± 22 nmol cm^–2 hr^–1; 1,3-GDN, 162 ± 34 nmol cm^–2 hr^–1). It follows that the dinitrates can be as efficiently delivered across the skin as GTN when a suitable formulation is employed. This finding may support transdermal therapy using 1,2- or 1,3-GDN if, indeed, they are found to be pharmacologically effective.     

Type II collagen-induced otospongiosis-like lesions in rats

Otospongiosis-like lesions were induced in rats by immunizing them with type II collagen. After seven months' immunization, the rats were killed and processed for histologic study. We found otospongiotic lesions in the bony cochlea, vestibule, semicircular canal, and in the regions near the oval window and round window. The spongiotic lesions in the otic capsules were similar to human otospongiosis and were characterized by the following types of microscopic appearances. 1) The classic type showed enlarged vascular spaces with congestion, macrophages, fibroblasts, and sometimes osteoclasts. 2) The fibrotic type showed vascular spaces filled with fibrous tissues. 3) The osteoporotic type had a porous appearance and was devoid of content. 4) The sclerotic type showed bone spaces partially or entirely being replaced by new bone with blue mantles and a mosaic appearance. Some spongiotic lesions showed a mixture of the above types. The findings suggest that this animal model may provide important information to help understand the process of human otosclerosis.     

Factors Associated with High Myopia After 7 Years of Follow-up in the Correction of Myopia Evaluation Trial (COMET) Cohort

Purpose: To evaluate factors associated with the development of high myopia (worse than ?6.00 D) over 7 years of follow-up in the COMET cohort. Methods: COMET enrolled 469 ethnically diverse children (6–11 years) with myopia between ?1.25 and ?4.50 D. They were randomized to either progressive addition lenses (PALs) or single vision lenses (SVLs), and followed for 5 years in their original lens assignment and 2 additional years wearing either spectacles (PALs or SVLs) or contact lenses. Refractive error was measured annually by cycloplegic autorefraction and axial length by A-Scan ultrasonography. Myopia for each child was defined as the mean spherical equivalent refractive error (SER) of the 2 eyes. Analyses were based on 7 years of follow-up. Time to high myopia was analyzed by Cox proportional hazard models and linear regression. Parental refraction data were available from 240 COMET subjects. Results: Younger (6–7 years) versus older (11 years) age at baseline was a significant risk factor (adjusted hazard ratio (HR) = 6.6, 95% CI = 3.4, 12.7) for having high myopia within 7 years. More (SER from ?2.26 to ?4.50 D) vs. less (SER from ?1.25 to ?2.25 D) baseline myopia was also a significant risk factor for high myopia at 7 years (adjusted HR = 7.4, 95% CI = 4.4, 12.4). Gender, ethnicity, and treatment assignment were not associated with the risk of high myopia within 7 years. Increased number of myopic parents was associated with a significant risk of high myopia in the children (p = 0.008). Conclusions: Children who developed high myopia during 7 years of follow-up were younger and had more myopia at baseline. They also were more likely to have two myopic parents. These children may be at greater risk for sight-threatening conditions later in life.     

Impact of blinking on ocular surface and tear film parameters

Purpose

To investigate the influence of blinking on tear film parameters, ocular surface characteristics, and dry eye symptomology.

Endothelins and their inhibition in the human skin microcirculation: ET[1-31], a new vasoconstrictor peptide

AIMS: Endothelin-1 (ET-1([1-21])) is an extremely potent vasoconstrictor in the human skin microcirculation and is generated from larger precursor peptides. The aims of the present study were to assess the vasoactive effects of these precursors as well as endothelin blockade in the human skin microcirculation, in vivo. METHODS: Six healthy volunteers received intradermal injections of a range of doses of big ET-1([1-38]), ET-1([1-31]), ET-1([1-21]), BQ-123 (ET(A) receptor antagonist), BQ-788 (ET(B) receptor antagonist), phosphoramidon [endothelin converting enzyme (ECE) inhibitor] or saline control (0.9%). Skin blood flow (SBF) was measured using standard laser Doppler flowmetry. RESULTS: Big ET-1([1-38]), ET-1([1-31]) and ET-1([1-21]) reduced SBF when compared with saline control (P < 0.01 for all). Big ET-1([1-38]) and ET-1([1-31]) were less potent than ET-1([1-21]) as defined by skin vasoconstriction. Phosphoramidon, BQ-123 and BQ-788, given alone, all caused vasodilatation in the human skin microcirculation (P < 0.01 for all). CONCLUSIONS: In the human skin microcirculation, big ET-1([1-38]) and ET-1([1-31]) are less potent vasoconstrictors than ET-1([1-21]). The effects of big ET-1([1-38]) and phosphoramidon suggest the presence of endogenous ECE activity in the skin. In contrast to skeletal muscle resistance vessels, ET-1([1-21]) contributes to the maintenance of skin microvascular tone through both ET(A) and ET(B) receptor-mediated vasoconstriction.