Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria

doi:10.1016/0026-0495(83)90045-8

Metabolism

Volume 32, Issue 4, April 1983, Pages 363-370

https://doi.org/10.1016/0026-0495(83)90045-8 Get rights and content

Abstract

Precocious atherosclerosis occurs in homocystinuria due to cystathionine β-synthase deficiency and there is evidence that homocysteine may produce endothelial damage. Mild homocysteinemia has been reported in heterozygotes after methionine loads and it has been suggested that they could have an increased risk of atherogenesis. We measured plasma amino acids before and after a methionine load (100 mg per kg) in 17 obligatory heterozygotes, in 20 men under 50 yr with established ischemic heart disease, and in matched controls, to determine whether methionine loading allows identification of heterozygotes, and whether there is an altered rate of methionine metabolism in patients with premature coronary artery disease. The obligate heterozygotes had higher mean plasma concentrations of methionine and total homocysteine at 4, 8 and 12 hours after the load than their controls, and lower concentrations of total cysteine and taurine in fasting and all post load samples; however, there was considerable overlap of measurements in heterozygotes and their controls even when differential weightings were applied. There were no differences in mean plasma concentrations of methionine, total homocysteine or total cysteine between the patients with ischemic heart disease and their controls at any measurement point. However, two patients with premature coronary artery disease, identical twins, had persistent elevation of total plasma homocysteine and an exaggerated homocysteine response to methionine. Oral folate restored homocysteine concentrations before and after methionine to normal. We conclude that heterozygotes for cystathionine β-synthase deficiency have a reduced ability to metabolise methionine but that under normal western dietary conditions they are unlikely to have elevated plasma homocysteine concentrations, presumably because of enhanced homocysteine remethylation; because of this they are unlikely to have an increased risk of atherogenesis. With these small numbers we could show no evidence for a predominance of heterozygotes among patients with established premature coronary vascular disease, but two patients, identical twins, had persistent mild homocysteinemia responsive to folic acid which could have constituted an additional risk factor for atherogenesis.

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Homocysteinemia and vascular disease: Where we stand in 2022
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Cardiovascular manifestations of intermediate and major hyperhomocysteinemia due to vitamin B12 and folate deficiency and/or inherited disorders of one-carbon metabolism: A 3.5-year retrospective cross-sectional study of consecutive patients
2021, American Journal of Clinical Nutrition
The association of moderate hyperhomocysteinemia (HHcy) (15–30 μmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy.
We sought to evaluate the association of intermediate (30–100 μmol/L) and severe (>100 μmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes.
We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing.
We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 μmol/L, 27% Hcy >50 μmol/L (44/165) and 3% Hcy >100 μmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6–60.4 compared with 12.1–28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up.
The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.
Local pharmacological induction of angiogenesis: Drugs for cells and cells as drugs
2019, Advanced Drug Delivery Reviews
Citation Excerpt :
Ischemia onset is usually gradual, caused by changes in the vessel walls leading to stenosis, but can progress to dangerous levels (CLI, crescendo angina pectoris) and be suddenly aggravated by a blood clot that either rapidly forms at a wall lesion (thrombosis) and occludes the lumen or has formed there but is transported to another location in the vasculature where it finally occludes a vessel (embolus) [21,22]. On the microlevel, a diffuse obliteration process of small vessels and capillaries can lead to ischemia as well, triggered by metabolic aberrances such as hyperglycaemia in diabetes, but also homocystinuria and inflammatory conditions such as lupus erythematosus [23–25]. Damage of retinal capillaries, nerves and loss of filtration function of renal glomeruli are all manifestations of capillary injury [26–28].
The past decades have seen significant advances in pro-angiogenic strategies based on delivery of molecules and cells for conditions such as coronary artery disease, critical limb ischemia and stroke. Currently, three major strategies are evolving. Firstly, various pharmacological agents (growth factors, interleukins, small molecules, DNA/RNA) are locally applied at the ischemic region. Secondly, preparations of living cells with considerable bandwidth of tissue origin, differentiation state and preconditioning are delivered locally, rarely systemically. Thirdly, based on the notion, that cellular effects can be attributed mostly to factors secreted in situ, the cellular secretome (conditioned media, exosomes) has come into the spotlight. We review these three strategies to achieve (neo)angiogenesis in ischemic tissue with focus on the angiogenic mechanisms they tackle, such as transcription cascades, specific signalling steps and cellular gases. We also include cancer-therapy relevant lymphangiogenesis, and shall seek to explain why there are often conflicting data between in vitro and in vivo. The lion's share of data encompassing all three approaches comes from experimental animal work and we shall highlight common technical obstacles in the delivery of therapeutic molecules, cells, and secretome. This plethora of preclinical data contrasts with a dearth of clinical studies. A lack of adequate delivery vehicles and standardised assessment of clinical outcomes might play a role here, as well as regulatory, IP, and manufacturing constraints of candidate compounds; in addition, completed clinical trials have yet to reveal a successful and efficacious strategy. As the biology of angiogenesis is understood well enough for clinical purposes, it will be a matter of time to achieve success for well-stratified patients, and most probably with a combination of compounds.
Conformational status of cytochrome c upon N-homocysteinylation: Implications to cytochrome c release
2017, Archives of Biochemistry and Biophysics
Citation Excerpt :
Thus, we conclude that loss of heme-Met80 interaction is responsible for the activation of peroxidase activity in HTL modified cyt c. In support of our observation, it has been demonstrated that disruption of cyt c heme coordination is responsible for mitochondrial injury during ischemia [41] which is also a common complication under homocysteinemic conditions [20,42–44]. Furthermore, in ischemic mouse model, the levels of cyt c homocysteinylation were shown to increase in brain [20].
One of the proposed mechanisms of homocysteine (Hcy) toxicity is the post-translational modification of proteins by its metabolite, homocysteine thiolactone (HTL). Incubation of proteins with HTL has been shown to form covalent adducts with ε-amino group of lysine residues of protein (called N-homocysteinylation) which ultimately results in structural and functional alterations of the modified proteins. In the present study, the effects of HTL on the conformational and heme status of cytochrome c (cyt c) were investigated. Spectroscopic analyses revealed that HTL-modified cyt c undergoes certain conformational alterations leading to disturbed heme-Trp distance and packing of the apolar groups. These alterations were accompanied with the reduction of the heme moiety and activation of peroxidase-like function of cyt c, which is known to be a crucial event for initiation of the intrinsic apoptotic pathway. Further structural characterization revealed that disruption of the heme-Met80 interaction, thereby converting the hexa-coordinate cyt c to a penta-coordinate species (with a free heme ligand), was responsible for the activation of the peroxidase activity. The study provides insights for the possible role of cyt c N-homocysteinylation in eliciting its toxicity and cell death.
Diagnosis of cystathionine beta-synthase deficiency by genetic analysis
2014, Journal of the Neurological Sciences
Citation Excerpt :
A controversial issue with regard to CBS deficiency is potential pathological consequences of being a heterozygous carrier of a CBS mutation [15-17]. This is important because an association between increased plasma homocysteine and cardiovascular disease has been reported [18-21]. To the best of our knowledge, we here report for the first time clinical findings and genetic analysis of Iranian patients affected with CBS deficiency.
Intellectual disability like other common diseases is often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. We present diagnosis of cystathionine beta-synthase (CBS) deficiency in a multiply affected Iranian family with obvious intellectual disability based on whole genome SNP homozygosity mapping. Diagnosis based on clinical presentations had not been made because of unavailability of appropriate medical services. Genetic analysis led to identification of homozygous c.346G>A in CBS that causes p.Gly116Arg in the encoded protein, cystathionine beta-synthase. CBS is the most common causative gene of homocystinurea. Later, the same mutation was found in three other apparently unrelated Iranian homocystinuria patients. p.Gly116Arg was reported once before in a Turkish patient, suggesting it may be a common CBS deficiency causing mutation in the Middle East. Clinical features of the patients are reported that evidence to variable presentations caused by the same mutation. Finally, observations in heterozygous carriers of the mutation suggest data that a single allele of the p.Gly116Arg causing mutation may have phenotypic consequences, including cardiac related phenotypes. Our study attests to the powers of genetic analysis for diagnosis especially for some forms of intellectual disability, with known genetic causing agents.
Genotype-independent in vivo oxidative stress following a methionine loading test: Maximal platelet activation in subjects with early-onset thrombosis
2011, Thrombosis Research
Citation Excerpt :
Moderate hyperhomocysteinemia (HHcy), a common metabolic abnormality (5-10% of the general population), has been associated with an abnormally high risk of thrombotic events [1–5].
methionine ingestion (100 mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high.
In 96 subjects [54 M/42 F, 40.4 ± 12.3 yrs old; 28 with the 68 bp844 ins of the Cystathionine-β-synthase gene (CBSins+); 20 homozygotes for the C677T mutation of the methylene-tetrahydrofolate reductase gene (MTHFR++); 13 with the combination of the two, and 35 without any of them], we have evaluated in vivo oxidative stress and platelet activation, as reflected by urinary excretions of 8-iso-PGF_2α and of 11-dehydro-TXB₂ respectively, before and after a methionine load test (PML). A history of early-onset thrombosis (18 arterial, 32 venous, 2 both) was present in 52/96 of them.
Baseline; tHcy was highest in MTHFR++ carriers (p < 0,05); 8-iso-PGF_2α and 11-dehydro-TXB₂ levels were independent of sex, MTHFR++ and/or CBSins + (p > 0.05). PML; The ~ 3-fold increase (p < 0.01 vs baseline) in tHcy reached a plateau within 6–8 hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p = 0.000). 8-iso-PGF_2α and 11-dehydro-TXB₂ increase reached a maximum within 4 hrs. 11-dehydro-TXB₂ increase was highest (p = 0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB₂ and a history of thrombosis independently predicted PML 11-dehydro-TXB₂ (β = 0.287, p = 0.000 and β = 0.308, p = 0.026, respectively).The PML increase in 8-iso-PGF_2α or in 11-dehydro-TXB₂ were comparable in the different genotypes (p > 0.05).
regardless genotypes associated with moderate hyperhomocysteinemia, following a methionine loading test, in vivo oxidative stress and platelet activation occur, being the latter maximal in subjects with a history of early-onset thrombosis.

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^☆: Supported in part by grants to one of us (DELW) from the National Health and Medical Research Council of Australia and the Ramaciotti Foundations.

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Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria☆

Abstract

Metabolism

Atherosclerosis

J Pediatr

Clin Chim Acta

Blood

Disorders of transsulfuration

Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis

Am J Pathol

Morphologic studies in a patient with homocystinuria due to 5, 10-methylene-tetrahydrofolate reductase deficiency

Pediatr Res

Vascular lesions in two patients with congenital homocystinuria due to different defects of remethylation

J Inher Metab Dis

Homocystinemia. Vascular injury and arterial thrombosis

N Engl J Med

Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis

J Clin Invest

Production of arteriosclerosis by homocysteinemia

Am J Pathol