Karl Stangl

Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease

Although three common MTHFR polymorphisms (C677T, A1298C, T1317C) have been reported, only polymorphism C677T has been investigated intensively as a risk factor for coronary artery disease (CAD). We investigated polymorphism frequencies, allelic associations and the effect of the resulting MTHFR genotypes on total plasma homocysteine (tHcy) levels and on coronary risk in a case-control study with 1000 angiographically confirmed Middle-European CAD patients and 1000 matched controls. Three out of four theoretically possible MTHFR haplotypes were detected: *1 (677C, 1298A), *2 (677T, 1298A), and *3 (677C, 1298C). The frequencies were *1: 36.4 and 34.4%; *2: 30.8 and 32.3%; and *3: 32.8 and 33.3%, in cases and controls, respectively. Only one patient was heterozygous for 1317C. None of the six resulting genotypes showed significant influence on tHcy levels. Moreover, there was no significant association with CAD risk or with disease severity or early disease manifestation. In the subgroup presenting with acute coronary syndromes, MTHFR genotypes *2/*3 and *3/*3 were surprisingly underrepresented (relative risk of *3/*3, 0.40; 95% confidence interval 0.20-0.79, P=0.009). We conclude from our genotype-based analysis that, in this well-fed Middle-European population, the observed common allelic variants of the MTHFR gene have no significant influence on tHcy levels or on the chronic process of CAD development.

Combined Treatment with Ramipril and Metoprolol Prevents Changes in the Creatine Kinase Isoenzyme System and Improves Hemodynamic Function in Rat Hearts after Myocardial Infarction

Beneficial effects of monotherapy with ACE inhibitors or beta-blockers on hemodynamic function after myocardial infarction are well known. Until now, the effects of combined treatment on cardiac function and energy metabolism have been poorly described. This study examines the effects of combined ramipril and metoprolol treatment on the creatine kinase (CK) system and hemodynamic function in rats after infarction. Wistar rats with experimental infarction were randomized for treatment with ramipril (R), metoprolol (M), combined treatment (MR), or placebo (P). Sham-operated (SO) animals served as controls. After 6 weeks, we assayed for CK isoenzymes and performed hemodynamic measurements. In P versus SO, left ventricular systolic pressures (dp/dtmax and dp/dtmin) diminished, whereas left ventricular end-diastolic pressure (LVEDP) increased. Decreased total CK activity and mitochondrial CK isoenzyme, increased CK-MB, and increased CK-BB isoenzymes were measured in P versus SO. With infarct size ≤45%, mitochondrial CK increased in M and R versus P. Combined treatment had an additional enhancing effect on mitochondrial CK isoenzyme level versus M and R, decreased LVEDP versus P, as well as increased dp/dtmax and dp/dtmin versus R. These results provide evidence of an interaction between normalization of energy metabolism and improvement in cardiac function due to a combination of ACE inhibition and beta blockade after myocardial infarction.

Interaction of CA repeat polymorphism of the endothelial nitric oxide synthase and hyperhomocysteinemia in acute coronary syndromes: evidence of gender-specific differences

We have recently shown that high CA repeat copy numbers (≥ 34 repeats) in intron 13 of the endothelial nitric oxide (eNOS) gene are associated with excess risk of coronary artery disease. Hyperhomocysteinemia interacts by several mechanisms with the NO system, thereby favoring endothelial dysfunction. Since hyperhomocysteinemia evidently promotes prothrombotic activation, we investigated a possible interaction among hyperhomocysteinemia, the eNOS CA repeat polymorphism, and acute coronary syndromes. The median value of homocysteine in our study population was 9.4xa0µmol/l. We accordingly determined the relative risk of acute coronary syndromes for homocysteine values higher than 9.4xa0µmol/l and 9.4xa0µmol/l or lower in the entire coronary artery disease group, and at different CA repeat cutoff values (34, 35, 36, 37, 38 CA repeats). For the entire coronary artery disease group (n=1000), homocysteine levels higher than 9.4xa0µmol/l were not significantly associated with acute coronary syndromes. Although the CA repeat copy numbers were not associated with acute coronary syndromes in the overall group, the relative risk among women with homocysteine higher than 9.4xa0µmol/l for developing acute coronary syndromes increased nonsignificantly from 0.98 at cutoff 34 CA repeats to 1.68 at 35 CA repeats and significantly to 4.89 at 36 CA repeats, 11.20 at 37 CA repeats, and 18.32 at 38 CA repeats. This effect modification was not observed in men. These data suggest gender-specific gene-environment interaction between the CA repeat eNOS polymorphism and homocysteine in acute coronary syndromes.

Hyperhomocysteinaemia and adverse events complicating coronary catheter interventions.

BACKGROUNDnSince hyperhomocysteinaemia is an independent risk factor for development of atherosclerosis as well as for arterial and venous thrombosis we investigated whether elevated homocysteine levels are associated with procedural excess risk which complicates coronary interventions including coronary angioplasty (PTCA), stenting, or directional coronary atherectomy (DCA).nnnDESIGNnConsecutive cases receiving coronary catheter interventions.nnnSETTINGnTertiary referral centre in Germany.nnnMETHODSnFasting total plasma homocysteine levels (tHcy) were determined in 648 consecutive coronary artery disease patients who underwent catheter interventions (272 PTCA, 102 DCA, and 274 stenting). Hyperhomocysteinaemia was defined as tHcy >/=15 micromol/l. The patients were investigated for a 30-day composite endpoint, including need for target-vessel revascularization, myocardial infarction, and death.nnnRESULTSnAmong the 648 patients, 78 (12%) demonstrated elevated tHcy levels. The composite endpoint occurred in 41 patients (6.3%). For the entire intervention group there was no evidence that hyperhomocysteinaemia was associated with excess procedural risk (odds ratio [OR]: 1.27; 95% confidence interval [CI]=0.52 to -3.13; P=0.62). In further analyses according to device, hyperhomocysteinaemia also failed to predict complications in the device related subgroups.nnnCONCLUSIONnThe results indicate that hyperhomocysteinaemia is not a major risk factor for 30-day adverse events complicating PTCA, DCA, or stenting.

Schwangerschaftsrisiken bei erworbenen Herzerkrankungen

Optimales Management von Schwangerschaften bei Patientinnen mit erworbenen Herzklappenfehlern setzt genaue Kenntnis der hämodynamischen Auswirkungen des Vitiums auf die schwangerschaftsbedingten kardiovaskulären Adaptationsvorgänge voraus. Mütterliches und fätales Risiko sind in Betracht zu ziehen und gegeneinander abzuwägen. Kritische Zeitpunkte, in denen die Patientinnen interdisziplinär engmaschig betreut werden sollten, sind v.a. die 30. – 32. Schwangerschaftswoche, in der ein maximaler Anstieg von Herzfrequenz, Herzzeitvolumen (HZV) und Plasmavolumen beobachtet wird, sowie die peripartale Phase. Stenosevitien werden generell durch die mechanisch bedingte Fixierung des HZV deutlich schlechter toleriert als Insuffizienzvitien. Therapeutische Ziele sind Senkung der Herzfrequenz und, bei pulmonalvenöser Kongestion, die Vorlastsenkung. Vaginale Entbindungen sind bei leicht- bis mittelgradigen Stenosevitien möglich, bei höherem Schweregrad ist eine Sectio caesarea vorzuziehen. Insuffizienzvitien werden bei normaler Pumpfunktion besser toleriert. Oft wird sogar durch den schwangerschaftsinduzierten Abfall des periphären Widerstandes eine Reduktion der Regurgitation beobachtet. Therapeutisch kann eine zusätzliche Nachlastsenkung bei Kontraindikationen gegen ACE-Hemmer und AT1-Antagonisten durch eine Kombinationstherapie aus Hydralazin und Nitraten oder Kalziumantagonisten erzielt werden. Peripartale Kardiomyopathien sind selten und mit einer hohen mütterlichen Mortalität von 25 – 50 % assoziiert. Die Therapieprinzipien unterscheiden sich – unter Beachtung der schwangerschaftsbedingten Kontraindikationen – nicht von denen anderer Herzinsuffizienzformen. Schwangerschaften bei hypertropher obstruktiver Kardiomyopathie werden meist gut überstanden, allerdings sind sowohl vereinzelte schwangerschaftsassoziierte Dekompensationen als auch plötzliche rhythmogene Todesfälle beschrieben worden. Seltene, lebensbedrohliche Komplikationen für Mutter und Fötus stellen aortale oder koronararterielle Dissektionen dar, die bei prädisponierten Patientinnen durch hormonelle und hämodynamische Adaptationsvorgänge in der Schwangerschaft auftreten können. Grundvoraussetzung für ein erfolgreiches Management einer Risikoschwangerschaft bei maternaler Herzerkrankung ist eine enge interdisziplinäre Zusammenarbeit und die engmaschige Betreuung der Patientinnen.