Olaf Stanger

DACH-LIGA Homocystein (German, Austrian and Swiss Homocysteine Society): Consensus Paper on the Rational Clinical Use of Homocysteine, Folic Acid and B-Vitamins in Cardiovascular and Thrombotic Diseases: Guidelines and Recommendations

Abstract About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a “new” risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 μmol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 μmol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteinemediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 μg of folate per day is difficult to maintain even with a balanced diet, and highrisk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 μmol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for, and treatment of, hyperhomocysteinemia can be recommended for the apparently healthy general population.

Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations

In Europe, neuropsychiatric diseases currently make up approximately a third of the total burden of disease. In 2004, 27% of the overall population was affected by at least one of the most frequent neuropsychiatric diseases such as Alzheimer’s dementia, Parkinson’s disease, stroke or depression. The annual costs of care exceed those of cancer, cardiovascular conditions and diabetes. In order to delay the onset or course of neurodegenerative diseases, the available potential should be utilized. As well as improving quality of life of patients and relatives, this may reduce the great financial burden caused by neurodegenerative disorders. However, the availability of established drugs or therapeutic agents is very limited. This paper reviews the state of current knowledge as to how homocysteine metabolism is relevant for neurodegenerative and other neuropsychiatric diseases, with particular emphasis on the evidence for prophylactic and therapeutic strategies. In the European countries, many people do not take the recommended daily minimum amount of folate and vitamin B12. Deficiency of these vitamins and secondary changes in the concentrations of associated metabolites, such as methylmalonic acid and homocysteine, may contribute to the onset and progression of neuropsychiatric diseases. This paper reviews the evidence regarding whether substitution of folate and vitamin B12 is beneficial, for example, in cerebrovascular disease, dementia and depression.

Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases.

Etwa die Hälfte aller Todesfälle sind auf Herz-Kreislauf-Erkrankungen bzw. deren Komplikationen zurückzuführen. Volkswirtschaft und Gesundheitswesen werden zusätzlich durch gewaltige Kosten für Arbeitsausfälle, Folgeerkrankungen und -behandlungen belastet, besonders unter dem Aspekt einer raschen Zunahme älterer Bevölkerungsschichten. Nachdem die konventionellen Risikofaktoren einen Teil der Fälle nicht erklären können, wird dem „neuen“ Risikofaktor Homocystein großes Interesse entgegen gebracht. Homocystein ist ein schwefelhaltiges Intermediärprodukt im Stoffwechsel der essentiellen Aminosäure Methionin. Defizite der Vitamine Folsäure, Vitamin B12 und B6 sowie eingeschränkte Enzymaktivitäten führen durch Abbauhemmung zur intrazellulären Konzentrationserhöhung von Homocystein. Zahlreiche retrospektive und prospektive Studien finden übereinstimmend eine unabhängige Beziehung zwischen bereits leicht erhöhtem Homocystein und kardiovaskulären Erkrankungen sowie der Gesamtmortalität. Eine Risikoerhöhung ist ab einem Homocysteinwert von etwa 9 μmol/l in einer linearen Dosis-Wirkungsbeziehung ohne Schwellenwert darstellbar. Die Hyperhomocysteinämie als unabhängiger Risikofaktor für Herz-Kreislauf-Erkrankungen wird für etwa 10% des Gesamtrisikos verantwortlich gemacht. Erhöhte Konzentrationen (moderate Hyperhomocysteinämie, > 12 μmol/l) gelten als zelltoxisch und werden bei 5–10% der Allgemeinbevölkerung und bei bis zu 40% der Patienten mit Gefäßerkrankungen gemessen. Zusätzliche Risikofaktoren (Rauchen, arterieller Hypertonus, Diabetes und Hyperlipidämie) können das Gesamtrisiko additiv oder durch Interaktion mit Homocystein synergistisch und überproportional erhöhen. Bei Hyperhomocysteinämie kommt es neben Veränderungen der Gefäßmorphologie zu einem Verlust der antithrombotischen Endothelfunktion und zur Induktion eines prokoagulatorischen Milieus. Den meisten der bekannten Schädigungen liegen Homocystein-vermittelte oxidative Stressbelastungen zugrunde. Zahlreiche Wirkstoffe, Medikamente, Erkrankungen und Lebensstilfaktoren beeinflussen den Homocystein-Stoffwechsel, zumeist als direkte oder indirekte Antagonisten von Kofaktoren und Enzymaktivitäten. Als häufigste Ursache erhöhter Homocysteinwerte gilt der Folsäuremangel. Die ausreichende Versorgung mit mindestens 400 μg Folat/Tag ist auch bei ausgewogener Ernährung schwierig und besonders für Risikogruppen häufig nicht realisierbar. Aufgrund der bereits vorliegenden Erkenntnisse wird zunehmend die Bestimmung und Behandlung erhöhter Homocysteinkonzentrationen bei Hochrisikogruppen und besonders von Patienten mit manifesten Gefäßerkrankungen gefordert. In beiden Fällen sollte zunächst eine Homocysteinbestimmung durchgeführt werden (Ausgangswert). Außer bei Manifestationen richtet sich das weitere Vorgehen nach dem Befund (Grafik). In Übereinstimmung mit anderen Arbeits- und Konsensusgruppen ist als Therapieziel ein Homocysteinspiegel < 10 μmol/l anzustreben. Durch Senkung erhöhter Homocysteinspiegel könnten, basierend auf verschiedenen Berechnungsgrundlagen, theoretisch bis zu 25% der kardiovaskulären Ereignisse vermieden werden. Auf Grund der billigen, potentiell effektiven und nebenwirkungsfreien Therapiemöglichkeit besteht ein außerordentlich günstiger Kosten-Nutzen-Quotient. Vor einer möglichen Empfehlung für die generelle Bestimmung und Behandlung erhöhter Homocysteinwerte bei Gesunden müssen erst die Ergebnisse derzeit laufender kontrolliert-randomisierter Interventionsstudien bekannt sein. About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and becoming larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a “new” risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiency and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 μmol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10 percent of total risk. Elevated plasma homocysteine levels (> 12 μmol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence overproportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and life style factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 μg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of < 10 μmol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25 percent of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of hyperhomocysteinemia can be recommended for the apparently healthy general population.

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

BackgroundThere is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy.MethodsThis study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease.ResultsHaplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046).ConclusionOur data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.

Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium

Abstract The endothelium exerts fundamental control over vascular tone, and injury to the endothelium followed by dysfunction is an early key event preceding manifestation of vessel pathology. Both elevated plasma homocysteine and low folate status have been identified as major and independent risk factors for atherosclerosis and have stirred an enormous and still increasing interest. The damaging effects of hyperhomocysteinemia on endothelial function are, at least in part, reversible through folate supplementation. Because of the inverse relationship between plasma folate and homocysteine levels, however, it is difficult to discriminate between their respective effects. Endothelial dysfunction refers mainly to reduced bioavailability of nitric oxide (NO), which is involved in homocysteinemediated vascular damage. Accumulating evidence further suggests that radical oxygen species are fundamentally involved in hyperhomocysteinemia. NO production is determined by cofactors such as tetrahydrobiopterin, which is oxidized and depleted in conditions of oxidant stress by peroxynitrite. Deficiency of tetrahydrofolate contributes to uncoupling, turning the NO synthase into a superoxide radical-producing enzyme. It appears that progression of vascular disease is likely to determine the multiple interactions between homocysteine, NO, oxygen radicals and folate. Folate has only recently been found to exert direct anti-oxidative effects and contribute to restoration of impaired NO metabolism. Understanding of the complex interactions between homocysteine, radicals, NO and folate offers promising perspectives in the individual treatment of vascular disease. Thus, preventive and therapeutic strategies may require a more distinct approach and better discrimination of target groups for greatest possible efficacy.

Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria.

Mutations in the gene for prothrombin (F2 20210A) and factor V (F5 1691A, factor V Leiden) are established risk factors for deep venous thrombosis (DVT). Recently, a mutation in the gene for factor XIII (F13 100T) leading to a Valine-Leucine exchange at amino acid position 34 has been reported to be protective against DVT. To analyze the role of these mutations for DVT in Austria, we analyzed their prevalence in 154 patients with documented DVT and 308 sex- and age-matched control subjects. Allele frequencies of F2 20210A, F5 1691A, and F13 100T were 0.018, 0.039, and 0.274 among controls, and 0.045, 0.120, and 0.211 among patients, respectively. Odds ratios for DVT associated with F2 20210A, F5 1691A, and F13 100T alleles were 2.5 (95% CI: 1.1-5.7), 3.4 (95% CI: 1.9-5.8), and 0.7 (95% CI: 0.5-1.0). We conclude that F2 20210A, F5 1691A, and F13 100T are common mutations in the Austrian population. F2 20210A and F5 1691 increase the risk for DVT, whereas F13 100T is associated with a decreased risk for DVT. Routinely, analysis of these mutations may help to analyze the individual risk for DVT.

Late dissection of the ascending aorta after previous cardiac surgery: risk, presentation and outcome.

OBJECTIVE Aortic dissection is a potentially life-threatening condition and may follow surgical interventions as a complication with distinct presentation and high mortality. Information on the incidence and etiology of aortic dissections following cardiac surgery is sparse and inconsistent. The true incidence of this entity may so far have been underestimated. METHODS Data of 223 operations on the thoracic aorta performed exclusively at our institution between January 1990 and May 2001 were analysed for clinical and prognostic features. Patients with Marfan syndrome and traumatic cases were not included. Cases of type A aortic dissection following cardiac surgery were investigated further. RESULTS Dissection of the ascending aorta occurred in 83 patients, of whom 11 (13.2%, six acute and five chronic) had undergone previous cardiac surgery (four aortic valve replacements (AVR), two double valve replacements (DVR), two AVR+coronary artery bypass grafts (CABG), three CABGs). The time interval between first operation and dissection was 0.2-17 years (median 3.3 years). Eight (72%) patients had arterial hypertension. The aortic diameter was >or=50mm in all 11 cases upon presentation. Dissections were treated with Bentall procedures (3), Cabrol procedure (1), supracoronary tube graft (6) including concomitant CABG (3) and AVR with local repair (1). Total in-hospital mortality was 54% (6/11), and 66% (4/6) in cases with acute dissection due to low cardiac output (3) and myocardial infarction (3). CONCLUSIONS Type-A aortic dissection can follow cardiac operations at any time with no typical interval or associated histology and with high overall hospital mortality. Male patients with arterial hypertension are at increased risk. Clinical presentation may differ from primary dissection with implications for management and risk estimation.

The role of hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T mutation in patients with retinal artery occlusion

PURPOSE Hyperhomocysteinemia has been established as an important risk factor for cardiovascular diseases. The aim of the present study was to investigate whether hyperhomocysteinemia and/or homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation are associated with an increased risk for retinal artery occlusion (RAO). DESIGN Retrospective case-control study. METHODS We studied 105 consecutive patients with retinal artery occlusion and 105 age and sex-matched control subjects. Fasting plasma homocysteine levels were determined by high-performance liquid chromatography, while genotypes of the MTHFR C677T mutation were determined by polymerase chain reaction. RESULTS Mean plasma homocysteine levels were significantly higher in patients with RAO compared with control subjects (12.2 +/- 4.8 micromol/l vs 10.3 +/- 3.4 micromol/l; P =.003). Hyperhomocysteinemia was defined by the 95th percentile of control plasma homocysteine levels as 15.8 micromol/l. Twenty (19.1%) patients with RAO exceeded this level and were therefore classified as hyperhomocysteinemic compared with 5 (4.8%) control subjects (P =.003). The odds ratio for these patients was calculated at 4.7 (95% confidence interval [CI], 1.5-15.1). Mean plasma folate levels were significantly lower in patients than in the control group (5.6 +/- 2.3 ng/ml vs. 6.3 +/- 2.5 ng/ml; P =.04). The prevalence of the homozygous genotype of methylenetetrahydrofolate reductase C677T mutation did not significantly differ between patients and controls. CONCLUSIONS Our results suggest that hyperhomocysteinemia, but not homozygosity, for the MTHFR C677T mutation is associated with RAO.

Vascular dysfunction in hyperhomocyst(e)inemia. Implications for atherothrombotic disease.

Abstract Elevated plasma homocyst(e)ine is currently accepted as a major, independent risk factor for atherosclerosis and venous thrombosis. Even moderate hyperhomocyst( e)inemia is prospectively associated with increased risk of mortality in patients with cardiovascular disease. However, the underlying mechanisms resulting in vascular damage are not clearly defined. The endothelium exerts fundamental control on the vascular tone, coagulation and fibrinolysis. Injury to the endothelium followed by dysfunction is an early key event preceding manifestation of vessel pathology. Acute and chronic exposure of endothelium to homocyst(e)ine induces impairment of endothelial function associated with altered homeostasis and morphologic changes of the vessel wall. Investigations of the role of homocyst(e)ine in the endothelium-dependent function in healthy subjects and cardiovascular patients have recently added important clinical insight with implications for the treatment of cardiovascular disease. Importantly, the damaging effects of hyperhomocyst(e)inemia on endothelial function are, at least in part, reversible in patients with established vascular disease, supporting further the hypothesis that homocyst(e)ine-lowering through vitamin supplementation may have vasoprotective effects.

The Mitochondrial T16189C Polymorphism Is Associated with Coronary Artery Disease in Middle European Populations

Background The pivotal role of mitochondria in energy production and free radical generation suggests that the mitochondrial genome could have an important influence on the expression of multifactorial age related diseases. Substitution of T to C at nucleotide position 16189 in the hypervariable D-loop of the control region (CR) of mitochondrial DNA (mtDNA) has attracted research interest because of its suspected association with various multifactorial diseases. The aim of the present study was to compare the frequency of this polymorphism in the CR of mtDNA in patients with coronary artery disease (CAD, n = 482) and type 2 diabetes mellitus (T2DM, n = 505) from two study centers, with healthy individuals (n = 1481) of Middle European descent in Austria. Methodology and Principal Findings CR polymorphisms and the nine major European haplogroups were identified by DNA sequencing and primer extension analysis, respectively. Frequencies and Odds Ratios for the association between cases and controls were calculated. Compared to healthy controls, the prevalence of T16189C was significantly higher in patients with CAD (11.8% vs 21.6%), as well as in patients with T2DM (11.8% vs 19.4%). The association of CAD, but not the one of T2DM, with T16189C remained highly significant after correction for age, sex and body mass index (BMI) and was independent of the two study centers. Conclusions and Significance Our results show for the first time a significant association of T16189C with CAD in a Middle European population. As reported in other studies, in patients with T2DM an association with T16189C in individuals of European decent remains questionable.