Is coronary artery disease a multifactorial inherited disorder with a sex-influenced trait?

The genetic linkage of coronary artery disease is well-established. However, the transmission of this disease is not clearly defined. Although the Mendelian autosomal dominant pattern has been seen in familial hypercholesterolemia and mutant MEF2A induced familiar myocardial infarction, and a multifactorial genetic model has been proposed for non-familial CAD, the gender difference in this disease is not well explained. We hypothesized that CAD is a multifactorial inherited disorder with a sex-influenced trait, which shows an autosomal dominant pattern in men and autosomal recessive transmission in women. This hypothesis is supported by the facts including an age-dependent higher prevalence in men, the autosomal locations of CAD associated genes, the gender difference seen even in familiar CAD, and the potential gene-gene interactions between CAD associated genes on autosomal chromosomes and those found on the X chromosome. Further investigation of genetic components will provide not only the critical information about the etiology of CAD, but also help to clarify the confusion in the use of exogenous female hormones in the prevention and/or the treatment of the disease.     

Is slow coronary flow associated with inflammation?

Cardiologists are familiar with the phenomenon of slow progression of angiographic contrast in the coronary arteries in the absence of stenosis in the epicardial vessels in some patients presenting with chest pain. This phenomenon is called as coronary slow flow phenomenon, and firstly described in 1972, while it remains scantily studied. The pathophysiological mechanisms of coronary slow flow phenomenon remain uncertain. Several hypotheses however, have been suggested for slow coronary flow phenomenon, including a form of early phase of atherosclerosis, small vessel dysfunction, Hagen-Poiseuille's equation model, imbalance between vasoconstrictor and vasodilatory factors, and platelet function disorder. More recently, there has been mounting evidence that inflammation plays an important role in the initiation, development as well as evolution of atherosclerosis, suggesting that atherosclerosis is an inflammation disease. New evidence has also indicated that inflammation may be involved in the development of slow coronary flow phenomenon. Coronary slow flow phenomenon is an important clinical entity because it may be the cause of angina at rest or during exercise, acute myocardial infarction, and hypertension. Despite the good prognosis of this kind of patients, the chronic, frequent nature of the persistent uncomfortable chest can significantly impair the quality of life. Whether this is really a new kind of coronary disease involving in inflammation, however, is still unknown and deserves further investigation.     

Do young women with polycystic ovary syndrome show early evidence of preclinical coronary artery disease?

BACKGROUND: It is thought that women with polycystic ovary syndrome (PCOS) are at increased risk of developing cardiovascular diseases. METHODS: In this study, we used transthoracic echocardiography to measure coronary flow reserve (CFR) in 28 women with PCOS and in 26 healthy women. RESULTS: The PCOS and the control groups were similar in terms of age (27.1 +/- 4.5 versus 28.8 +/- 4.4 years) and BMI (26.6 +/- 5.7 versus 24.7 +/- 4.4 kg/m2). Fasting insulin levels and homeostasis model assessment insulin resistance index were higher in the PCOS group. LH, the LH/FSH ratio, total testosterone, free testosterone and androstenedione were higher in the PCOS group. FSH, estradiol, prolactin, progesterone, cholesterol, triglyceride and high-sensitive C-reactive protein were similar between the two groups, but homocysteine levels were higher in the PCOS group. Baseline diastolic peak f low velocity (DPFV) (25.0 +/- 4.6 versus 23.3 +/- 2.7 cm/s, P > 0.05), hyperaemic DPFV (71.2 +/- 12.8 versus 73.0 +/- 12.9 cm/s, P > 0.05) and CFR (2.8 +/- 0.8 versus 3.2 +/- 0.8 cm/s, P > 0.05) of the left anterior descending coronary artery were similar between the two groups. CONCLUSION: We conclude that in young women with PCOS and without cardiovascular risk factors, CFR is preserved.     

Crohn's disease associated with Sweet's syndrome and Sjögren's syndrome treated with infliximab

The association of Crohn''s disease (CD) and Sweet''s syndrome is rare and the presence of Sjögren''s syndrome in Crohn''s disease is even rarer, with only three reports found in the literature. We describe two cases of Crohn''s disease associated with Sweet''s syndrome, one of which is the first case of CD and Sweet''s concomitantly associated with Sjögren''s syndrome. Both cases responded rapidly to Infliximab therapy with complete resolution of the skin lesions.     

Is maternal duplication of 11p15 associated with Silver-Russell syndrome?

Background: Silver-Russell syndrome (SRS) is a heterogeneous malformation syndrome characterised by intrauterine and postnatal growth retardation (IUGR, PGR) and dysmorphisms. The basic causes are unknown, however in approximately 10% of patients a maternal uniparental disomy (UPD) of chromosome 7 or chromosomal aberrations can be detected. Four growth retarded children, two with SRS-like features, associated with maternal duplications of 11p15 have been described. Considering the involvement of this genomic region in Beckwith-Wiedemann overgrowth syndrome (BWS), we postulated that some cases of SRS—with an opposite phenotype to BWS—might also be caused by genomic disturbances in 11p15.

Methods: A total of 46 SRS patients were screened for genomic rearrangements in 11p15 by STR typing and FISH analysis.

Results: Two SRS patients with duplications of maternal 11p material in our study population (n = 46) were detected. In patient SR46, the duplicated region covered at least 9 Mb; FISH analysis revealed a translocation of 11p15 onto 10q. In patient SR90, additional 11p15 material (approximately 5 Mb) was translocated to the short arm of chromosome 15.

Conclusions: We suggest that diagnostic testing for duplication in 11p15 should be offered to patients with severe IUGR and PGR with clinical signs reminiscent of SRS. SRS is a genetically heterogeneous condition and patients with a maternal duplication of 11p15.5 may form an important subgroup.

     

Is any link between inflammation and coronary artery ectasia?

Coronary artery ectasia (CAE) is well-recognized, angiographic finding of abnormal coronary dilatation, and detected in 0.3-5.3% of angiographic studies. The gold standard for diagnosis this type of aneurysm is coronary angiography, which provides information about the size, sample, location and number of aneurysms. Despite growing prevalence in recent years, controversy still exists as to the pathogenetic mechanisms that underlie this entity. An increased incidence of CAE has been reported in several disorders. Examples include atherosclerotic vascular disease, heterozygous familial hypercholesterolemia, usage of substances including herbicide spray, acetylcholinesterase inhibitors and nitrates, previous arterial balloon angioplasty, polyarteritis nodosa and Kawasaki syndrome. In addition, possible factors contributing to CAE are imbalance between matrix metalloproteinase and tissue inhibitor of metalloproteinase, angiotensin converting enzyme genotype, elevated homocysteine levels, cocaine user, smoking, vascular trauma, nitrate use and diabetes. Emerging investigations have pinpointed inflammation as a central process in all stages of atherosclerosis. This inflammatory process culminates in acute thrombotic complications and clinical events, which is involved in different clinical settings of atherosclerotic diseases. Recent data have also showed that CAE is associated with inflammatory response presented as elevated inflammatory cytokines and C-reactive protein. Accordingly, more complete understanding of the pro- and anti-inflammatory circuits that operate during CAE in particular may foster the development of novel therapeutic approaches.     

Is HDL function as important as HDL quantity in the coronary artery disease risk assessment?

Over the past several decades, it has been clearly established that higher plasma concentrations of high-density lipoprotein (HDL) are related to lower risk of coronary artery disease (CAD). According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, the HDL level of <40 mg/dL is considered low and is one of the CAD risk predictors. However, in the last decade, several studies have indicated the importance of the quality of HDL as another potential measure for CAD risk assessment. The loss of normal biological function of HDL particles as a result of multifactorial actions of chronic inflammation and acute phase responses has suggested a new potential pathway in the pathophysiology of atherosclerosis. The concept of “dysfunctional HDL” or “proinflammatory HDL,” which exhibits chameleon-like properties of converting a positive force protecting arteries to a negative one, enhancing atherogenesis is now under active investigation. Measurements of this dysfunctional quality of HDL in cell-based or cell-free assays by analyzing anti-inflammatory functions may link these changes to in vivo assessments of vascular disease. This review provides details on functional and dysfunctional HDL and summarizes recent studies into dysfunctional HDL and its potential links to CAD.     

Ear lobe crease: a marker of coronary artery disease?

The ear lobe crease (ELC) has been defined as a deep wrinkle that extends backwards from the tragus to the auricle. It has been proposed that ELC is a predictor of coronary artery disease (CAD). In this review, we consider the possible association between ELC and CAD. Our aim is to systematically address all the relevant evidence in this field. There are many studies that support an association between ELC and CAD. However, other studies did not find such an association. A recent meta-analysis supports the hypothesis that ELC could be a marker of CAD. However, several limitations raise doubts as to whether we should accept this link.     

Is NOTCH4 associated with schizophrenia?

The NOTCH4 locus was reported to be associated with schizophrenia in our previous study but the subsequent replication by other workers has been inconsistent. To find out possible reasons for the poor replication, the present work was undertaken to analyse four functional single nucleotide polymorphisms (SNPs) (rs367398, rs915894, rs520692 and rs422951) at the NOTCH4 locus among 141 schizophrenic family trios of Chinese Han descent. Of these four SNPs, rs520692 was the only one associated with schizophrenia (P = 0.017); the other three, however, did not show any association with the illness, including rs367398 located in the promoter region, which had shown a strong association with the illness in our previous study conducted with British samples. Although these four SNPs analysed lie within a less than 4 kb segment of genomic DNA, the pattern of linkage disequilibrium between them was unexpected. The strongest linkage disequilibrium was shown only between rs367398 and rs520692 and between rs520692 and rs422951 in both parent and patient groups. This study raises the possibility that there might be two or more disease-underlying variants at the NOTCH4 locus or at a nearby locus, and that the allelic or locus heterogeneity may be one of the possible reasons for the poor replication of the NOTCH4 finding.     

Is autosomal recessive deafness associated with oculocutaneous albinism a “coincidence syndrome”?

Hearing impairment is frequently found associated with pigmentary disorders in many syndromes. However, total oculocutaneous albinism (OCA) associated with deafness has been described only once, by Ziprkowski and Adam (Arch Dermatol 89:151–155, 1964) in an inbred family. A syndrome associating deafness and OCA was suggested by the authors, but two separate recessive genes segregating in this inbred group were also proposed later by Fraser (OMIM # 220900). Combined deafness and total OCA were also observed by us in a family originally reported to be nonconsanguineous but in which haplotyping showed evidence of a common ancestry: the proband was affected by both diseases, one of his sisters had only OCA and another sister had only deafness. Both the proband and his deaf sister were found to be homozygotes for the 35delG mutation (GJB2 gene), the most frequent cause of hereditary deafness. Linkage analysis with markers close to the four known OCA loci excluded linkage to OCA1, OCA2, and OCA3, and homozygosity in markers near OCA4 locus was observed. Sequencing of the corresponding gene (MATP) revealed a c.1121delT mutation, which leads to a stop codon at position 397 (L374fsX397). Clearly, the combined occurrence of deafness and albinism in this pedigree was due to mutations in two different genes, showing autosomal recessive inheritance. We speculate that the putative syndrome reported by Ziprkowski and Adam might have resulted from the co-occurrence of autosomal recessive deafness and albinism in the same pedigree, as suggested by Fraser.     

What does my patient's coronary artery calcium score mean? Combining information from the coronary artery calcium score with information from conventional risk factors to estimate coronary heart disease risk

Background  

The coronary artery calcium (CAC) score is an independent predictor of coronary heart disease. We sought to combine information from the CAC score with information from conventional cardiac risk factors to produce post-test risk estimates, and to determine whether the score may add clinically useful information.     

Is cytomegalovirus associated with human colorectal tumorigenesis?

Despite the rapid advance in the understanding of molecular pathways underlying human colorectal tumorigenesis, the causes that initiate dysregulation of the pathways remain largely unknown. Human cytomegalovirus (CMV) has been implicated as a potential etiopathogenetic agent. To further investigate whether CMV participates in human colorectal tumorigenesis, we examined 23 colorectal hyperplastic polyps, 65 colorectal adenomas, and 51 colorectal adenocarcinomas by immunohistochemical analysis using 2 antibody mixtures that recognize CMV immediate early, early, and delayed gene products. The results show that while typical nuclear staining (with or without cytoplasmic positivity) was observed in control cases of CMV colitis, no nuclear positivity was detected in any cases studied. Focal and weak cytoplasmic staining was noted in a subset of cases, particularly when a higher antibody concentration was used. This staining was believed to be nonspecific, however, because it also was observed in normal-appearing colonic mucosa. In addition, polymerase chain reaction failed to detect the presence of CMV DNA in 24 selected cases showing nonspecific cytoplasmic immunostaining. These observations demonstrate an absence of CMV proteins and DNA in human colorectal adenocarcinomas and their precursor lesions.     

Large artery and coronary compliance in health and disease

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Coronary artery disease in Alström syndrome

Alström syndrome (ALMS) is a rare autosomal recessive condition, caused by mutations in the ALMS1 gene located on the short arm of chromosome 2. This gene codes for a protein linked with the centrosome, whose precise function is unknown. This condition was first described by Alström in 1959. ALMS is a multisystem condition that is characterised by childhood onset of blindness secondary to rod-cone retinal degeneration and dilated cardiomyopathy with heart failure, which often presents in infanthood and may recur later in life. Metabolic abnormalities including hypertriglyceridemia, liver steatosis, insulin resistance and type 2 diabetes mellitus are common, often occurring in association with obesity. Other abnormalities include endocrinological disturbances, such as thyroid disorder, growth hormone deficiency, hypogonadism and, in women, hyperandrogenism. This syndrome is also associated with sensorineural hearing loss, renal failure secondary to glomerulo-fibrosis, and fibrotic lung disease. Multiorgan fibrotic infiltration is the common feature in all cases. Considering the history of diabetes, hypertension, dyslipidemia, obesity and renal dysfunction in ALMS, it would be expected that this group of patients could develop coronary artery disease (CAD). But such cases have not been reported so far. We report a case of premature onset of CAD in one of the longest surviving patient with ALMS.