Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis.

PURPOSE OF REVIEW: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications. RECENT FINDINGS: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.

New Drugs for Atherosclerosis.

Atherosclerosis, the underlying process that ultimately leads to clinical cardiovascular disease (CVD), is caused by the multifactorial interaction of various conditions, and dyslipidemia is widely acknowledged as 1 of the crucial risk factors in this process. Statin drugs have been shown to decrease low-density lipoprotein cholesterol and CVD morbidity as well as mortality and are therefore pivotal in CVD prevention. Despite the use of statin drugs, CVD remains a leading cause of mortality worldwide, which suggests that additional lipid-lowering therapies are warranted. Several novel therapeutic agents, which are described in this review, are now well on their way in their respective development paths and might revolutionize anti-atherosclerotic drug therapy.

-455G/A polymorphism and preprocedural plasma levels of fibrinogen show no association with the risk of clinical restenosis in patients with coronary stent placement.

The effect of preprocedural fibrinogen levels on in-stent restenosis is largely unknown. The -455G/A polymorphism of the fibrinogen beta-gene is associated with baseline plasma level or acute phase increase of fibrinogen. Therefore, we hypothesized that there is a relationship between this polymorphism and preprocedural fibrinogen level and clinical restenosis at follow-up among patients with coronary stent placement. The GENetic DEterminants of Restenosis (GENDER) project is a multicenter follow-up study that enrolled 3,146 consecutive patients after successful percutaneous coronary intervention. A coronary stent was placed in 2,309 patients. Of these, 2,257 (97.7%) patients were successfully genotyped for the -455G/A polymorphism. Plasma fibrinogen levels were measured at baseline in a subpopulation of 623 stented patients with the von Clauss method and patients were grouped into tertiles according to fibrinogen levels. Primary endpoint was target vessel revascularization (TVR); secondary combined endpoint was defined as death presumably from cardiac causes, MI not attributable to another coronary artery than the target vessel, and TVR. No association was observed between the -455G/A polymorphism and TVR or combined endpoint (p=0.99, p=0.97, respectively). Multivariate regression analysis revealed that the risk of TVR and combined endpoint was not higher for patients in the highest tertile for fibrinogen versus the lowest tertile (RR=0.60, 95% CI: 0.26-1.37 for TVR, RR=0.64, 95% CI: 0.29-1.44 for combined endpoint). In conclusion, the presence of -455G/A polymorphism in the fibrinogen beta-gene and preprocedural fibrinogen level is not associated with an increased risk of TVR or combined endpoint in a patient population with coronary stent placement. Therefore, these parameters are not worthwhile for stratifying patients at risk for restenosis pre-stenting.

A novel LCAT mutation (Phe382-->Val) in a kindred with familial LCAT deficiency and defective apolipoprotein B-100.

We studied a four-generation family (17 subjects) with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. A 30-year-old Caucasian male with corneal clouding and HDL cholesterol <0.1 mmol/l was a compound heterozygote for a novel mutation (Phe(382)-->Val), a previously reported mutation (Thr321-->Met) and a common variant (Thr208-->Ser) of the gene. Immunoreactive LCAT concentration (1.2 microg/ml), alpha-LCAT activity (13 nmol/ml per h) and cholesterol esterification rate (CER) (14 nmol/ml per h) in his plasma were, respectively, 14, 8 and 14% of the mean values in healthy subjects. The proband and 13 of his relatives also had familial defective apo B (FDB, Arg3500-->Gln). Six subjects had LCAT Phe382-->Val in combination with FDB. Plasma lipoprotein(a) (Lp(a)) was 24 nmol/l in the proband and 46-211 nmol/l in his father and siblings, consistent with expression of the 16 kringle 4 isoform. The proband had no signs of coronary heart disease (CHD), but his father, a paternal uncle and a female cousin had CHD before age 38 years.

Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease.

OBJECTIVE: To investigate the effect of intensive lipid lowering with high-dose atorvastatin on the incidence of major cardiovascular events compared with low-dose atorvastatin in patients with coronary artery disease and type 2 diabetes, with and without chronic kidney disease (CKD). PATIENTS AND METHODS: Following 8 weeks' open-label therapy with atorvastatin (10 mg/d), 10,001 patients with coronary artery disease were randomized to receive double-blind therapy with either 80 mg/d or 10 mg/d of atorvastatin between July 1, 1998, and December 31, 1999. Of 1501 patients with diabetes, renal data were available for 1431. Patients with CKD were defined as having a baseline estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2, using the Modification of Diet in Renal Disease equation. RESULTS: After a median follow-up of 4.8 years, 95 (17.4%) of 546 patients with diabetes and CKD experienced a major cardiovascular event vs 119 (13.4%) of 885 patients with diabetes and normal eGFRs (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.00-1.72; P<.05). Compared with 10 mg of atorvastatin, 80 mg of atorvastatin reduced the relative risk of major cardiovascular events by 35% in patients with diabetes and CKD (20.9% [57/273] vs 13.9% [38/273]; HR, 0.65; 95% CI, 0.43-0.98; P=.04) and by 10% in patients with diabetes and normal eGFR (14.1% [62/441] vs 12.8% [57/444]; HR, 0.90; 95% CI, 0.63-1.29; P=.56). The absolute risk reduction in patients with diabetes and CKD was substantial, yielding a number needed to treat of 14 to prevent 1 major cardiovascular event over 4.8 years. Both treatments were well tolerated. CONCLUSION: Patients with diabetes, stable coronary artery disease, and mild to moderate CKD experience marked reduction in cardiovascular events with intensive lipid lowering, in contrast to previous observations in patients with diabetes and end-stage renal disease. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00327691.