Genetic predisposition to atorvastatin-induced myopathy: a case report.

WHAT IS KNOWN AND OBJECTIVE: The major clinical complication of statins is a variety of muscle complaints ranging from myalgia to rhabdomyolysis. There is growing evidence that carriers of genetic polymorphisms in the enzymes and transporters implicated in statin disposition, particularly the SLCO1B1 gene, are at increased risk of myotoxicity. Our objective is to report on two cases of statin-induced myopathy occurring in a family with two patients who are carriers of the loss of function SLCO1B1 genetic variant and to briefly review the related literature. CASE SUMMARY: Patient 1, a 48-year-old man with history of coronary artery disease, experienced rapidly evolving muscle pain and weakness of the extremities during treatment with atorvastatin 40 mg. Patient 2, a 65-year-old man, father of patient 1, had symptoms similar to those of his son after 2 weeks' treatment with the same statin. Atorvastatin was stopped in both cases, and symptoms resolved. On the basis of family relationship between the two patients, it was possible to hypothesize a genetic basis for the myopathy. Genotyping showed the patients to be carriers of the rs4363657 polymorphism of SLCO1B1 gene. WHAT IS NEW AND CONCLUSION: The two cases reported here and the brief literature review emphasize the impact of genetic factors on the risk of myopathy with statins. Although genotyping all patients before initiating therapy is not recommended at present, pharmacogenetic testing may be useful for new patients who have a family history of statin-induced myopathy.

The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease.

AIMS: Gain-of-function variants of genes encoding coagulation factor V (F5 G1691A) and prothrombin (F2 G20210A) cause hypercoagulability and are established risk factors for venous thrombosis. A meta-analysis of 66,155 cases and 91,307 controls found that either polymorphism is associated with a moderately increased risk of coronary artery disease (CAD). Because genetic factors play a particularly important role when acute myocardial infarction (AMI) occurs in the young, we chose to replicate these results by investigating, in the frame of a case-control study, a large cohort of Italian patients who had AMI before the age of 45years. METHODS AND RESULTS: In 1880 patients with AMI (1680 men and 210 women) and an equal number of controls, the minor A allele of F5 G1691A (2.6% frequency in cases and 1.7% in controls) was associated with an increased risk of AMI, the association remaining significant after adjustment for traditional risk factors (OR, 1.66; 95% CI, 1.15-2.38; P=0.006). The positive association with AMI for the minor A allele of F2 G20210A (2.5% frequency in cases and 1.9% in controls) did not reach statistical significance (OR, 1.32; 95% CI, 0.96-1.80; P=0.159). CONCLUSIONS: In a large cohort of young AMI patients the gain-of-function variant F5 G1691A was associated with an increased risk of AMI. The findings on the variant F2 G20210A confirmed the previously reported results, but the association was statistically not significant. These data suggest that a number of young patients with AMI carry gene variants associated with a procoagulant phenotype.

Direct thrombin inhibitors for the treatment of acute coronary syndromes and during percutaneous coronary interventions.

As acute coronary syndromes are principally sustained by plaque complication and subsequent thrombus formation, anticoagulant therapy plays a central role in avoiding ischemic events; its main targets are thrombin activity and generation. Despite its limitations, such as its scarce ability to activate bound thrombin and its unpredictable pharmacological response, heparin is the most widely used drug for this purpose. Direct thrombin inhibitors are biologically superior to heparin principally because they inhibit clot-bound and circulating thrombin without interacting with other plasma proteins. Their clinical role in acute coronary syndromes and during coronary intervention has been tested in several trials. This article overviews the principal trials involving active-site direct thrombin inhibitors in acute coronary syndrome and during coronary intervention and compares their efficacy and safety with unfractionated heparin. It also describes ongoing trials and analyzes further clinical developments such as their use in addition to the glycoprotein IIb/IIIa inhibitors and the potential advantage possible with new agents orally administered.

Phenotype commitment in vascular smooth muscle cells derived from coronary atherosclerotic plaques: differential gene expression of endothelial nitric oxide synthase.

Unstable angina and myocardial infarction are the clinical manifestations of the abrupt thrombotic occlusion of an epicardial coronary artery as a result of spontaneous atherosclerotic plaque rupture or fissuring, and the exposure of highly thrombogenic material to blood. It has been demonstrated that the proliferation of vascular smooth muscle cells (VSMCs) and impaired bioavailabilty of nitric oxide (NO) are among the most important mechanisms involved in the progression of atherosclerosis. It has also been suggested that a NO imbalance in coronary arteries may be involved in myocardial ischemia as a result of vasomotor dysfunction triggering plaque rupture and the thrombotic response. We used 5' nuclease assays (TaqMan PCRs) to study gene expression in coronary plaques collected by means of therapeutic directional coronary atherectomy from 15 patients with stable angina (SA) and 15 with acute coronary syndromes (ACS) without ST elevation. Total RNA was extracted from the 30 plaques and the cDNA was amplified in order to determine endothelial nitric oxide synthase (eNOS) gene expression. Analysis of the results showed that the expression of eNOS was significantly higher (p<0.001) in the plaques from the ACS patients. Furthermore, isolated VSMCs from ACS and SA plaques confirmed the above pattern even after 25 plating passages. In situ RT-PCR was also carried out to co-localize the eNOS messengers and the VSMC phenotype. The eNOS gene was more expressed in ACS plaques and VSMCs cultured from them, thus indicating that: a) the expression of the most important differentiation markers is retained under in vitro conditions; and b) NO may play a pivotal role in coronary artery disease. Our findings suggest a new cell system model for studying the pathophysiology of unstable angina and myocardial infarction.

Identification of differentially expressed genes in coronary atherosclerotic plaques from patients with stable or unstable angina by cDNA array analysis.

The composition of atherosclerotic plaques is a crucial factor in determining rupture, thrombosis and clinical events. In this study, we analyzed gene expression in coronary plaques from patients with stable or unstable angina using gene arrays. Total RNA was extracted from eight plaques collected by therapeutic directional coronary atherectomy. cDNA probes, generated by amplification, were hybridized to nylon arrays containing 482 genes. Here we report the results for the inflammation, adhesion and hemostasis subsets. Many genes not previously associated with atherosclerosis, such as the lymphocyte adhesion molecule MadCAM, were expressed in the plaques. anova analysis showed higher tissue factor (TF) expression in unstable angina samples. Five genes were expressed at lower levels in unstable angina samples: anticoagulant protein S, cyclooxygenase (COX)-1, interleukin (IL)-7 and chemokines monocyte chemotactic protein (MCP)-1 and -2. Gene arrays provide a new approach to study plaque composition and identify candidate markers of plaque instability.

Thrombogenic potential of human coronary atherosclerotic plaques.

Higher levels of tissue factor (the initiator of blood coagulation) have been found in coronary atherosclerotic plaques of patients with unstable coronary artery disease, but it is not established whether they are associated with a different thrombotic response to in vivo plaque rupture. In 40 patients undergoing directional coronary atherectomy, prothrombin fragment 1 + 2, a marker of thrombin generation, was measured in intracoronary blood samples obtained proximally and distally to the coronary atherosclerotic plaque before and after the procedure. Before the procedure, plasma prothrombin fragment 1 + 2 levels were significantly increased across the lesion in patients with unstable, but not in those with stable, coronary disease (unstable, median increase, 0.37 nM; range, -0.35-1.16 nM) (stable, median increase, -0.065 nM; range, -0.58-1.06 nM) (P =.0021). After plaque removal, an increase in prothrombin fragment 1 + 2 across the lesion was observed only in patients with unstable coronary disease (unstable, median increase, 0.25 nM; range, -1.04-4.9 nM) (stable, 0.01 nM; range, -0.48-3.59 nM) (P =.036)]. There was a correlation between the tissue factor content of the plaque and the increase in thrombin generation across the lesion (rho = 0.33; P =.038). The higher tissue factor content found in plaques obtained from patients with unstable coronary disease was associated with a local increase in thrombin generation, thus suggesting a link with the in vivo thrombogenicity of the plaque.

Percutaneous coronary revascularisation in women.

Numerous studies of sex differences in morbidity and mortality after an episode of acute coronary disease shown unclear results. In particular is not clear if women undergoing coronary revascularization procedures have adverse in-hospital and long-term outcomes compared with men. Recent clinical trial have provided new insights into this problem. The influence on gender differences for the decision to undertake coronary angiography and percutaneous transluminal coronary angioplasty will be discussed.

Laboratory markers of hypercoagulability.

Investigations carried out over the last 40 years have demonstrated that coronary artery thrombosis is the critical event underlying myocardial infarction and unstable angina. The existence of a prolonged hypercoagulable state preceding the thrombotic event has been postulated for some time and significant associations have been established between the plasma concentrations of a number of hemostatic variables and the frequency of myocardial infarction. High plasma fibrinogen, factor VII/VIIa, tissue-type plasminogen activator and plasminogen activator inhibitor levels have been associated with at least as great a risk of developing myocardial (re)infarction or sudden death as high cholesterol levels, especially in the young. In the last year more sensitive assays have been developed, and they should allow a precise biochemical definition of hypercoagulable states. The significance of these new assays and their role in defining a hypercoagulable state in different conditions are analyzed.

Prothrombotic genetic markers.

The last decade has been characterized by an explosion of research studies on genetic epidemiology. In particular, as far as ischemic heart disease is concerned, a lot of research was focused on prothrombotic genetic risk factors. Unfortunately, the success of this approach in the field of venous thrombosis has not been replicated in the field of myocardial infarction. In the present editorial, a comment on the studies already available is provided and the possible limitations of the present approach are analyzed.

Hemostatic markers and prognosis in ischemic heart disease.

Failure of traditional risk factors in identifying patients who develop a cardiac event, has led investigators to focus on other factors involved in precipitating cardiac events. As acute or subacute thrombosis is the major complication of atherosclerotic plaque rupture, attention has been dedicated to prothrombotic markers as possible risk factors. Recently, the role of new laboratory markers in predicting the risk of cardiac events has been evaluated in large epidemiological studies. The results of these studies as well as the value and applicability of new prothrombotic markers in the clinical practice are discussed.

In vivo thrombin generation and activity during and after intravenous infusion of heparin or recombinant hirudin in patients with unstable angina pectoris.

In patients with unstable angina, intravenous heparin reduces thrombin activity but does not influence thrombin generation. Recombinant hirudin, a direct thrombin inhibitor, may be more effective in inhibiting both thrombin generation and activity. We measured the plasma levels of prothrombin fragment 1+2 (a marker of thrombin generation) and fibrinopeptide A (a marker of thrombin activity) in 67 patients with unstable angina enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial who were receiving either recombinant hirudin (31 patients) or heparin (36 patients). Blood samples were obtained at baseline (before any treatment), after 3 to 5 days of study drug infusion (immediately before discontinuation), and 1 month later. In the patients receiving recombinant hirudin, the prothrombin fragment 1+2 levels measured immediately before drug discontinuation were significantly lower than at baseline (P:=0.0014), whereas they had not changed in the patients receiving heparin; at this time point, the difference between patients receiving hirudin and those receiving heparin was statistically significant (P:=0.032). One month later, the prothrombin fragment 1+2 levels in both groups were similarly persistently high and did not differ from baseline. Fibrinopeptide A plasma levels at the end of infusion were significantly lower than at baseline in both treatment groups (P:=0. 0005 for hirudin and P:=0.042 for heparin) and remained lower after 1 month (P:=0.0001 for both hirudin and heparin). The fibrinopeptide A plasma levels were not different between patients treated with hirudin versus heparin at baseline, at the end of infusion, and after 1 month. Thus, in patients with unstable angina, in vivo thrombin generation and activity are reduced during intravenous infusion of recombinant hirudin. However, the inhibition of thrombin generation is not sustained, and after 1 month, the majority of patients have biochemical signs of increased thrombin generation.

Tissue factor in human coronary atherosclerotic plaques.

The rupture or fissuring of a coronary atherosclerotic plaque and subsequent thrombosis is considered the key event in the pathogenesis of unstable angina and myocardial infarction. Although plaque disruption frequently occurs during the evolution of atherosclerosis, only a minority of ruptured plaques develop thrombosis. The content and procoagulant activity of tissue factor in human coronary atherosclerotic plaques varies widely, and different studies confirm that it is higher in the plaques extracted from patients with unstable angina, myocardial infarction or histologic/angiographic evidence of coronary thrombosis than in those taken from patients with stable angina or uncomplicated coronary lesions. Variations in tissue factor content and activity may be responsible for the different thrombotic responses to human coronary atherosclerotic plaque rupture.

A novel polymorphism in intron 1a of the human factor VII gene (G73A): study of a healthy Italian population and of 190 young survivors of myocardial infarction.

We have identified a novel polymorphism located in intron 1a of the human factor VII gene, caused by the nucleotide change G to A at position + 73. In a population of 128 healthy individuals from northern Italy, the variant A73 allele had a frequency of 0.21, whereas the frequency of the previously reported 10 bp insertion allele located at -323 in the promoter region was 0.17 and that of the Q353 allele in the catalytic region of the factor VII gene was 0. 20. In 75% of the healthy individuals, the A73 allele was present together with the 10 bp insertion and the Q353 alleles, indicating a strong linkage disequilibrium. The concomitant presence of A73 with both the 10 bp and the Q353 alleles was associated with the lowest factor VII levels, measured as coagulant activity, activated factor VII and factor VII antigen. The G73A polymorphism was also evaluated in 190 survivors of myocardial infarction who had experienced the event before the age of 45 years and in 179 individuals with a negative exercise test matched with patients for sex, age and geographical origin. Patients carrying the A73 allele associated with lower factor VII levels tended to have a lower risk of myocardial infarction (adjusted odds ratio 0.54; 95% confidence intervals 0.29-0.99). In conclusion, we found a novel variant allele in intron 1a of the human factor VII gene that is often associated in healthy individuals with the 10 bp and Q353 alleles in the promoter and catalytic region of the same gene. This intronic mutation, alone or in association with other factor VII gene polymorphisms, might confer protection against myocardial infarction in the young.

Prothrombotic genetic risk factors in young survivors of myocardial infarction.

It has long been thought that an individual thrombotic tendency increases the risk of myocardial infarction, especially in young adults. Several "prothrombotic" genetic factors that may influence the individual thrombotic risk have been identified. To investigate the association between the risk of myocardial infarction at a young age and genetic factors thought to be associated with an increased tendency to thrombosis (the polymorphisms 4G/5G of the PAI-1 gene, PIA1/PIA2 of the platelet glycoprotein IIIa, C3550T of the platelet glycoprotein Ib gene, G10976A of the factor VII gene, C677T of the methylenetetrahydrofolate reductase gene, G1691A of the factor V gene, and G20210A of the prothrombin gene), we performed a case-control study evaluating 200 survivors (185 men, 15 women) of myocardial infarction who had experienced the event before the age of 45 years and 200 healthy subjects with a negative exercise test, individually matched for sex, age, and geographic origin with the cases. The presence of the PIA2 polymorphic allele was the only prothrombotic genetic factor associated with the risk of myocardial infarction at a young age. The odds ratio for carriers of the PIA2 allele compared with those of the PIA1 allele was 1.84 (95% confidence intervals (CI) 1.12 to 3.03). There was a significant interaction between the presence of the PIA2 allele and smoking: with their simultaneous presence, 46% (95% confidence intervals 11% to 81%) of premature myocardial infarctions were attributable to the interaction between the two factors. In conclusion, carrying the PIA2 polymorphic allele of platelet glycoprotein IIIa was the only genetic prothrombotic factor associated with the risk of developing myocardial infarction at a young age. The clinical expression of this genetic predisposition seems to be enhanced by smoking.