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Sixteen patients with exercise-induced ST-segment elevation and without a history of myocardial infarction or left ventricular aneurysm were studied. Fourteen complained of angina at rest, which was associated with ST-segment elevation in the same leads where it was recorded during exercise, and two patients had only exertional angina. Exercise-induced ST-segment elevation was generally reproducible in subsequent exercise tests performed in different hours of the day, but exercise tests repeated a mean of 15 months later did not induce this electrocardiographic abnormality. All patients had a marked susceptibility to coronary spasm, as shown by the response to the ergonovine test (12 positive tests in 12 patients) and by the occurrence of spontaneous spasm during coronary arteriography in two patients. In addition, coronary arteriography, performed in seven patients at the time of exercise-induced ST-segment elevation, revealed spasm of a major coronary vessel in all. In two patients we documented that exercise-induced ST-segment elevation was accompanied by a decreased coronary blood flow and increased coronary vascular resistance. We conclude that exercise-induced ST-segment elevation in patients without a history of myocardial infarction or left ventricular aneurysm is caused by coronary spasm of a major coronary vessel.

The forkhead/winged helix box (FOX) gene family comprises at least 43 different genes encoding transcriptional factors with a highly conserved DNA-binding domain. To date, mutations in members of the FOX gene family have been causally linked to a variety of different human diseases. We describe a three-generation Albanian pedigree in which a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality is segregated with a missense mutation (W148R) in the human FOXD4 gene. This mutation disrupts an extremely highly conserved tryptophan residue in the forkhead domain of FOXD4, possibly resulting in reduced DNA binding capacity and altered transcriptional activity. Our present findings widen the spectrum of diseases associated with genetic aberrations in the forkhead gene family.

The receptor for advanced glycation end products (RAGE) is thought to play a critical role in diabetic atherosclerosis. Accordingly, a functional -374T/A polymorphism in RAGE gene promoter has been associated with macrovascular complications in type 1 diabetic patients. However, the extent to which this common variant influences the risk of coronary artery disease (CAD) in the general population remains to be determined. We genotyped the -374T/A RAGE polymorphism in 259 non-diabetic individuals, of whom 175 had angiographically documented coronary artery disease (CAD patients) and 84 had normal coronary angiography (CAD-free control subjects). Homozygosity for the -374A allele was found in 9.7% of the CAD patients versus 22.6% of the CAD-free subjects (p=0.005). By means of a multiple logistic regression analysis, the AA genotype of the -374T/A polymorphism was shown to be independently associated with a reduced risk of CAD (adjusted odds ratio 0.33, 95% CI 0.15 to 0.73; p=0.006). Our observations suggest that the -374T/A polymorphism of the RAGE gene may reduce susceptibility to CAD, thus exerting a protective effect on coronary risk. Future pathophysiological studies may be worthwhile to clarify the mechanisms behind this association.

1. Although the high-frequency fluctuations in R—R interval (respiratory sinus arrhythmia) observed in heart transplant recipients are not a reliable marker of reinnervation because of a previously shown direct mechanical effect of breathing, the presence of a non-respiration-related low-frequency oscillation reflects rhythms generated outside the heart, and thus could be neurally mediated. 2. To evaluate the presence of reinnervation, the spontaneous variability in R—R interval was investigated, supine and after passive tilting, in 23 heart transplant recipients (age 43 years, range 23–64 years) and in 25 normotensive control subjects by autoregressive spectral analysis of low- and high-frequency spontaneous fluctuations in R—R interval and respiration. The response of R—R interval to amyl nitrite inhalation was also evaluated in five heart transplant recipients and eight control subjects. 3. Detectable low-frequency oscillations, unrelated to respiration, were present in 13/23 heart transplant recipients, particularly in those who were transplanted at least 20 months earlier (11/14). The natural logarithm of the power of low-frequency fluctuations was markedly lower than in control subjects (0.75 ± 0.21 versus 5.62 ± 0.20 ms2, P < 0.001). The low-frequency but not the high-frequency fluctuations correlated with time since transplantation (r = 0.44, P < 0.05). The subjects with low-frequency fluctuations showed a sudden decrease in R—R interval with amyl nitrite linearly related to the decrease in mean blood pressure (r ≧ 0.94). The slopes obtained in these heart transplant recipients were comparable (although of lower values) with those obtained in control subjects. The subjects with no low-frequency fluctuations showed no change in R—R interval despite a similar reduction in blood pressure. 4. Twenty months after transplantation signs of functional (reflex) reinnervation can be found in most heart transplant recipients.

Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors contribute significantly to the risk of coronary artery disease (CAD). Through its effects on endothelial function, coagulation, insulin resistance and lipid metabolism, the proinflammatory cytokine TNF could be involved in cardiovascular pathophysiology. The aim of our study is to analyze whether TNF gene promoter (-308 G/A; −857 G/A) and TNF receptor polymorphisms (TNFR1 MspA1 I exon 1 and TNFR2 Nla III exon 6) show involvement in CAD predisposition in a group of Italian patients compared with healthy controls. Genotyping was performed by PCR-RFLP. Consecutive Italian patients with angiographically proven CAD (n= 248) were compared with controls (n=241), matched for age, sex and geographical origins. CAD patients showed a higher frequency of the TNF −308 A allele than healthy controls (p=0.046). After stratification according to risk factors for CAD, our analysis revealed that CAD patients with diabetes (p=0.042) and CAD patients without hypertension (p=0.0495) displayed a higher frequency of the TNF −308 AA genotype compared with healthy controls. Our data stress the inflammatory nature of CAD and show a possible involvement of TNF −308G/A promoter polymorphisms in the predisposition to the development of this disease. The less frequent A allele seems to be a predisposing factor for development of CAD in particular pathological settings associated with the disease itself, such as diabetes.