Hypercholesterolemia is one of the primary risk factors for atherosclerotic coronary disease. Statins have revolutionised lipid management with their proven ability to reduce circulating cholesterol levels and have even demonstrated regression of coronary plaques. Interestingly, statins have also been shown to have anti-inflammatory and anti-thrombotic activities, with several studies having shown statin therapy to be associated with a significant reduction in venous thromboembolism.  However, the mechanisms by which statins achieve this remain obscure.

In this basic science study Owens et al explore this question using a variety of pre-clinical models and human cells from patients with familial hypercholesterolemia (FH).  The authors demonstrate that hypercholesterolemia per se is associated with increased platelet reactivity and an increased tendency to thrombosis. The key factor appears to be oxidized low-density lipoprotein (oxLDL) particles which are present in the circulation of patients with coronary artery disease and also in patients with FH.  Elevated levels of oxLDL in plasma induces expression of the procoagulant protein tissue factor (TF) in monocytes. Genetic knockout of TF reduced coagulation despite hypercholesterolemia, consistent with a major role for monocyte-derived TF in the activation of coagulation. Furthermore, treatment with simvastatin was able to reduce levels of oxLDL, leading to reductions in monocyte TF expression and decreases in coagulation activation and inflammation even without significant reductions in total cholesterol.

Conclusions

Hypercholesterolemia induces a pro-thrombotic state through the actions of oxidised LDL particles on monocyte production of tissue factor.  Statins effectively inhibit this pathway and may be important in reducing atherothrombosis.

• Owens AP 3rd, Passa m FH, Antoniak S, et al.  Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.   J Clin Invest. 2012 Feb 1;122(2):558-68.

Dilated cardiomyopathy (DCM) is the most common form of non-ischemic cardiomyopathy.  While clinical evaluation identifies 30 to 50% of DCM patients as having a relative who is affected or likely to be affected, indicating a possible genetic cause, pathogenic mutations are found in only 20 to 30% of patients.  Therefore a large degree of uncertainty remains regarding the genetic causes of DCM.  TTN, the gene encoding titin, has been implicated in cardiomyopathy but has been incompletely studied, owing to technical challenges posed by the large size of its coding sequence (approximately 100 kb), translating into one of the largest human proteins, composed of approximately 33,000 amino acids.

In this study, using next generation sequencing technology, Herman et al., analysed TTN in 312 subjects with DCM, 231 subjects with hypertrophic cardiomyopathy (HCM), and 249 controls.  72 unique mutations that altered titin were found with significantly higher frequency among subjects with DCM (54 of 203 [27%]) than among subjects with HCM (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families with high (>95%) observed penetrance after the age of 40 years. Mutations associated with DCM were overrepresented in the A-band but were absent from the Z-disk and M-band regions of titin. Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)).

Conclusions:

Mutations in the protein titin are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic DCM. Not only does this study advance diagnostic tools for genetic screening of patients and families but it opens the door to a more fundamental understanding of the pathophysiology of DCM and the prospect of more targeted therapeutics.

• Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG and Seidman CE. Truncations of titin causing dilated cardiomyopathy.  N Engl J Med. 2012 Feb 16;366(7):619-28.

In recent years it has become clear that treatment of coronary artery disease – and in particular percutaneous coronary intervention (PCI) – must be guided by imaging techniques that give some information on the extent of myocardial ischaemia.  While nuclear medicine techniques such as SPECT (single-photon emission computed tomography) have become widespread, and have a high negative predictive value, they still expose patients to ionising radiation.  Furthermore, the sensitivity of SPECT has been noted to vary.  Cardiac Magnetic Resonance Imaging (MRI), is a potential alternative that uses no ionising radiation, provides high-resolution images, and is capable of assessing various cardiac parameters in one comprehensive examination.

The CE-MARC study (Clinical Evaluation of MAgnetic Resonance imaging in Coronary heart disease) was designed to provide a real-world comparison of stress perfusion MRI and SPECT, using coronary angiography as the gold standard.  752 patients with stable angina (not including those who had had previous bypass surgery) were recruited over a three year period.  Of these, 378 were assigned to CMR then SPECT, while 374 were assigned to SPECT then CMR.  Overall 39% of patients had significant coronary disease as detected by X-ray angiography.  For multiparametric CMR the sensitivity was 86·5% (95% CI 81·8—90·1), and specificity 83·4% (79·5—86·7), compared to the sensitivity of SPECT which was 66·5% (95% CI 60·4—72·1), and specificity 82·6% (78·5—86·1).  The sensitivity and negative predictive value of CMR and SPECT differed significantly (p<0·0001 for both) but specificity and positive predictive value did not (p=0·916 and p=0·061, respectively).

Conclusions:

This large, prospective trial of stress perfusion MRI shows its high diagnostic accuracy and superiority over SPECT imaging.  As such CE-MARC is a landmark trial that is likely to challenge the current dominance of nuclear imaging for the assessment of myocardial perfusion.

• Greenwood JP, Maredia N, Younger JF et al.  Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial.  Lancet 2011;379:453-460

Hypoperfusion of the anterior wall and septum seen on MRI (left) and SPECT (centre). Angiography demonstrates this to be due to LAD and diagonal disease.