Does increased aortic stiffness predict reduced coronary flow velocity reserve in patients with suspected coronary artery disease?

PURPOSE: In recent studies, reduction in coronary flow velocity reserve (CFR) has been demonstrated in patients with increased aortic stiffness. Stress transoesophageal echocardiography (TEE) is a suitable method for the simultaneous evaluation of CFR and aortic stiffness parameters. The present study was designed to test whether increased echocardiography-derived aortic elastic modulus [E(p)] predicts impaired CFR in patients with suspected coronary artery disease (CAD). RESULTS: The present study comprised 158 patients with suspected CAD. A CFR value < 2 was considered abnormal. Both men grade of aortic atherosclerosis (AA) (as a morphologic characteristic) (1.31 ± 0.68 vs. 1.02 ± 0.89, p < 0.05) and aortic distensibility (E(p) as a functional characteristic) (892 ± 594 mmHg vs. 723 ± 495 mmHg, P < 0.05) were increased in subjects with CFR < 2. In ROC analysis, the cut-off value for E(p) to predict impaired CFR was ≥ 670 mmHg, with 61% sensitivity and 61% specificity (ROC area 0.60, p = 0.026). The logistic regression model identified higher AA grade (hazard ratio (HR) 2.01, p < 0.05) and increased E(p) as independent predictors of reduced CFR (HE 1.10, p < 0.05). CONCLUSION: Increased aortic stiffness predicts impaired CFR in patients with suspected CAD.

Na(+)/Ca(2+) exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart.

BACKGROUND AND PURPOSE: The Na(+)/Ca(2+) exchanger (NCX) may play a key role in myocardial contractility. The operation of the NCX is affected by the action potential (AP) configuration and the intracellular Na(+) concentration. This study examined the effect of selective NCX inhibition by 0.1, 0.3 and 1.0 microM SEA0400 on the myocardial contractility in the setting of different AP configurations and different intracellular Na(+) concentrations in rabbit and rat hearts. EXPERIMENTAL APPROACH: The concentration-dependent effects of SEA0400 on I(Na/Ca) were studied in rat and rabbit ventricular cardiomyocytes using a patch clamp technique. Starling curves were constructed for isolated, Langendorff-perfused rat and rabbit hearts. The cardiac sarcolemmal NCX protein densities of both species were compared by immunohistochemistry. KEY RESULTS: SEA0400 inhibited I(Na/Ca) with similar efficacy in the two species; there was no difference between the inhibitions of the forward or reverse mode of the NCX in either species. SEA0400 increased the systolic and the developed pressure in the rat heart in a concentration-dependent manner, for example, 1.0 microM SEA0400 increased the maximum systolic pressures by 12% relative to the control, whereas it failed to alter the contractility in the rabbit heart. No interspecies difference was found in the cardiac sarcolemmal NCX protein densities. CONCLUSIONS AND IMPLICATIONS: NCX inhibition exerted a positive inotropic effect in the rat heart, but it did not influence the contractility of the rabbit heart. This implies that the AP configuration and the intracellular Na(+) concentration may play an important role in the contractility response to NCX inhibition.

Relevance of anaesthesia for dofetilide-induced torsades de pointes in alpha1-adrenoceptor-stimulated rabbits.

BACKGROUND AND PURPOSE: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or alpha-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in alpha(1)-adrenoceptor-stimulated rabbits. EXPERIMENTAL APPROACH: Rabbits anaesthetized intravenously with pentobarbital, propofol or alpha-chloralose were infused simultaneously with the alpha(1)-adrenoceptor agonist phenylephrine (15 microg kg(-1) min(-1), i.v.) and dofetilide (0.04 mg kg(-1) min(-1), i.v.). The electrocardiographic QT interval, the T (peak)-T (end) interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. KEY RESULTS: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with alpha-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with alpha-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the alpha-chloralose and propofol anaesthesia groups. CONCLUSIONS AND IMPLICATIONS: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared.

Coronary flow reserve, insulin resistance and blood pressure response to standing in patients with normoglycaemia: is there a relationship?

AIMS: To establish the relationships between coronary flow reserve, cardiovascular autonomic function, and insulin resistance characterized by the homeostasis model assessment insulin resistance score in patients with normal carbohydrate metabolism according to the World Health Organization (WHO) and American Diabetes Association (ADA) criteria, and with morphologically normal epicardial coronary arteries. METHODS: Twenty-five patients [12 women and 13 men, mean (sd) age: 53 +/- 11 years] with normal coronary angiography were enrolled into the study. Coronary flow reserve was measured during stress transoesophageal echocardiography. Autonomic dysfunction was assessed by means of five standard cardiovascular reflex tests. The fasting serum glucose and insulin levels were determined and the homeostasis assessment model insulin resistance score was calculated. RESULTS: In patients with normal carbohydrate metabolism, negative correlations were observed between the coronary flow reserve and both the serum insulin level (r = -0.445, P = 0.026) and the homeostasis assessment model insulin resistance score (r = -0.449, P = 0.024). The systolic blood pressure response to standing also correlated with the coronary flow reserve (r = -0.519, P = 0.011). The heart rate response to deep breathing, the Valsalva ratio, the 30/15 ratio and the sustained handgrip test results were not correlated with the coronary flow reserve. CONCLUSIONS: Our data suggest the possible role of insulin resistance and early sympathetic nerve dysfunction in the development of decreased coronary flow reserve in patients without diabetes mellitus or impaired glucose tolerance.

Helicobacter pylori-induced immunological responses in patients with duodenal ulcer and in patients with cardiomyopathies.

The interaction between the bacteria and the host is a key factor determining the clinical consequences of H. pylori infection. The immune system plays an important role in either promoting or preventing the disease. The mucosal production of TNF-alpha, IL-6, IL-8 and IL-10 and the CagA status were investigated in H. pylori-positive patients with duodenal ulcer (DU). The concentrations of these cytokines in gastric antral mucosal specimens from patients infected with H. pylori (n = 40) were determined by ELISA and compared with data on mucosal specimens from H. pylori-negative patients (n = 12). The local TNF-alpha, IL-6 and IL-8 concentrations in the antral biopsy samples were significantly higher (p < 0.001) in the patients infected with H. pylori than in the samples from the H. pylori-negative subjects. CagA positivity was demonstrated in 39 (97.5%) of the 40 patients with DU, and in 41 (70.7%) of H. pylori-positive (58 of 100) healthy blood donors. In complementary studies focusing on extragastric disease, it was found that 57% of patients with ischaemic heart disease were seropositive as concerns H. pylori, and 91% of them had antibodies against human heat shock protein 60, too. This study suggests that, besides the bacterial virulence factor, the host response of an increased mucosal production of inflammatory cytokines can be relevant to the gastric pathophysiology in H. pylori-induced DU. At the same time, in ischaemic heart diseases the role of autoimmune processes induced by H. pylori cannot be excluded.

Prognostic significance of the dobutamine echocardiography test in idiopathic dilated cardiomyopathy.

Dobutamine stress echo provides potentially useful information on idiopathic dilated cardiomyopathy (IDC). From February 1, 1997, to October 1, 1999, 186 patients (131 men and 55 women, mean age 56 +/- 12 years) with IDC, ejection fraction <35%, and angiographically normal coronary arteries were studied by high-dose (up to 40 micro/kg/min) dobutamine echo in 6 centers, all quality controlled for stress echo reading. In all patients, wall motion score index (WMSI) (from 1 = normal to 4 = dyskinetic in a 16- segment model of the left ventricle) was evaluated by echo at baseline and peak dobutamine. One hundred eighty-four patients were followed up (mean 15 +/- 13 months) and only cardiac death was considered as an end point. There were 29 cardiac deaths. Significant parameters for survival prediction at univariate analysis are: DeltaWMSI (chi-square 20.1; p <0.0000), New York Heart Association (NYHA) class (chi-square 17.57; p <0.0000), rest ejection fraction (chi-square 10.41; p = 0.0013), angiotensin-converting enzyme inhibitors (chi-square 8.23; p = 0.0041), and hypertension (chi-square 8.08, p = 0.0045). In the multivariate stepwise analysis only DeltaWMSI and NYHA were independent predictors of outcome (DeltaWMSI = hazard ratio 0.02, p < 0.0000; NYHA class = hazard ratio 3.83, p < 0.0000). Kaplan-Meier survival estimates showed a better outcome for patients with a large inotropic response (DeltaWMSI > or =0.44, a cutoff identified by receiver-operating characteristic curves analysis) than for those with a small or no myocardial inotropic response to dobutamine (93.6% vs 69.4%, p = 0.00033). Thus, in patients with IDC, an extensive contractile reserve identified by high-dose dobutamine stress echocardiography is associated with a better survival.

Determinants of spontaneous baroreflex sensitivity in a healthy working population.

Baroreflex sensitivity (BRS) by the spontaneous sequence technique has been widely used as a cardiac autonomic index for a variety of pathological conditions. However, little information is available on determinants of the variability of spontaneous BRS and on age-related reference values of this measurement in a healthy population. We evaluated BRS as the slope of spontaneous changes in systolic blood pressure (BP) and pulse interval from 10 minutes BP (Finapres) and ECG recordings in 1134 healthy volunteers 18 to 60 years of age. Measurement of BRS could be obtained in 90% of subjects. Those with unmeasurable spontaneous BRS had a slightly lower heart rate but were otherwise not different from the rest of the population. BRS was inversely related to age (lnBRS, 3.24-0.03xage; r(2)=0.23; P:<0.0001) in both genders. In addition, univariate analysis revealed a significant inverse correlation between BRS and heart rate, body mass index, and BP. Sedentary lifestyle and regular alcohol consumption were also associated with lower BRS. However, only age, heart rate, systolic and diastolic BP, body mass index, smoking, and gender were independent predictors of BRS in a multivariate model, accounting for 47% of the variance of BRS. The present study provides reference values for spontaneous BRS in a healthy white population. Only approximately half of the variability of BRS could be explained by anthropometric variables and common risk factors, which suggests that a significant proportion of interindividual differences may reflect genetic heterogeneity.

Clinical value of left atrial appendage flow velocity for predicting of cardioversion success in patients with non-valvular atrial fibrillation.

BACKGROUND: Echocardiographic parameters for predicting cardioversion outcome in patients with non-valvular atrial fibrillation are not accurately defined. OBJECTIVE: To evaluate the role of left atrial appendage flow velocity detected by transoesophageal echocardiography for prediction of cardioversion outcome in patients with non-valvular atrial fibrillation enrolled in a prospective. multicentre, international study. METHODS: Four hundred and eight patients (257 males, mean age: 66 +/- 10 years) with non-valvular atrial fibrillation lasting more than 48 h but less than 1 year underwent transthoracic echocardiography and transoesophageal echocardiography before either electrical (n=324) or pharmacological (n=84) cardioversion. RESULTS: Cardioversion was successful in restoring sinus rhythm in 328 (80%) and unsuccessful in 80 patients (20%). Mean left atrial appendage peak emptying flow velocity was significantly higher in patients with successful than in those with unsuccessful cardioversion (32.4 +/- 17.7 vs 23.5 +/- 13.6 cm x s(-1); P<0.0001). At multivariate logistic regression analysis, three parameters proved to be independent predictors of cardioversion success: the atrial fibrillation duration <2 weeks (P=0.011, OR=4.9, CI 95%=1.9-12.7), the mean left atrial appendage flow velocity >31 cm x s(-1) (P=0.0013, OR=2.8, CI 95%=1.5-5.4) and the left atrial diameter <47 mm (P=0.093, OR=2.0, CI 95%=1.2-3.4). These independent predictors of cardioversion success outperformed other univariate predictors such as left ventricular end-diastolic diameter <58 mm, ejection fraction >56% and the absence of left atrial spontaneous echo contrast. CONCLUSION: In patients with non-valvular atrial fibrillation, measurement of the left atrial appendage flow velocity profile by transoesophageal echocardiography before cardioversion provides valuable information for prediction of cardioversion outcome.

[The clinical value of coronary flow reserve in ischemic heart disease as measured by dipyridamole stress transesophageal echocardiography]. / A dipyridamol-terheléses transoesophagealis echokardiográfia segítségével számított coronaria-áramlási rezerv klinikai értéke ischaemiás szívbetegségben.

The relationship between coronary flow reserve and the result of coronarography was examined. 152 patients were investigated by stress transoesophageal echocardiography and coronary angiography. The value of coronary flow reserve was significantly lower in cases of significant coronary stenosis than in those patients who had a normal coronarography (in patients with left anterior descending coronary artery stenosis: 1.77 +/- 0.47 vs in cases with normal coronary angiogram: 3.19 +/- 1.15). There was no difference in the value of CFR in those cases where not only LAD stenosis but CX or RC stenosis was also found. The value of coronary flow reserve was significantly higher in RC or CX patients than that of LAD patients. In patients with positive stress and negative coronarography (X syndrome) the coronary flow reserve was 1.23 +/- 0.2, which value was significantly lower as compared to patients with significant coronary stenosis.

Combined use of endoscopic CO2 laser excision of a marginal laryngeal tumor, radical neck dissection, and perioperative laterofixation of the opposite vocal cord.

We report the use of endoscopic laser excision of a marginal laryngeal tumor, radical neck dissection, and laterofixation of a paralyzed vocal cord in a 66-year-old man who had an early-stage right supraglottic endolaryngeal tumor and ipsilateral neck metastasis. He had a left vocal cord paralysis after a left pneumonectomy that was performed 5 years previously. The primary laryngeal tumor was excised by endoscopic CO2 laser resection, and a simultaneous radical neck dissection was carried out. Postoperatively, severe inspiratory dyspnea developed because of the surgical intervention on the right side causing moderate laryngeal edema and limited movement of the right vocal cord in addition to the paralyzed left side. An endolaryngeal laterofixation of the paralyzed left vocal cord was performed to provide the patient with an adequate airway instead of tracheostomy. This patient had a 2 years' follow-up without recurrence of tumor. In the meantime movement of the right vocal cord has returned, so that the patient's voice was socially acceptable and he has a functioning larynx.

[Impending paradoxical embolism]. / Fenyegetó paradox embolia esete.

The case history of a 49-year-old female patient is reported, who was operated on because of varicose vein in the left lower extremity. A few days after the operation serious signs of cerebrovascular insult appeared. The clinical picture and the result of an urgent transoesophageal echocardiography are described; a serpentine thrombus was found to be trapped in the patent foramen ovale. During continuous intravenous heparin treatment, the patient gradually recovered, but a residual neurological deficit could be detected on discharge from the hospital. Six days after the admission, repeated transoesophageal echocardiographic examination showed no signs of intracardiac thrombus. The clinical feature of the illness, the predisposing factors, the diagnostic and therapeutic possibilities are discussed.

The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells.

Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.

Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1.

The cyclooxygenases (COX)-1 and COX-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Whereas COX-1 is expressed ubiquitously, COX-2 is an immediate-early gene often associated with malignant transformation, and a role for the COX enzymes in tumor initiation and promotion is discussed. Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and indomethacin that block COX-1 and -2 have been shown to have beneficial effects for tumor patients. Therefore, these compounds have gained interest also among oncologists. However, the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood. The prostaglandin-dependent and -independent effect may both account for their antineoplastic action. We show here that tumor cells derived from different tumors regularly produce prostaglandin E(2) (PGE(2)) interfering with the function of monocytes. In particular, PGE(2) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell. This inhibition is most probably due to a modulation of the chemokine receptor CCR5 and the beta2-integrin Mac-1. Both down-regulation of CCR5 and reduced expression of Mac-1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues. Since both dysfunctions can be restored with NSAIDs, our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression.

Cytokine production and antibodies against heat shock protein 60 in cardiomyopathies of different origins.

OBJECTIVE: There is growing evidence that proinflammatory cytokines play an important role in a variety of cardiac pathophysiological conditions. The purpose of this study was to determine the circulating tumour necrosis factor (TNF) and interleukin-6 (IL-6) levels in patients with dilated cardiomyopathy (DCM) (n = 40) or ischaemic heart disease (IHD) (n = 38) in comparison with the corresponding data from patients with hypertrophic cardiomyopathy (HCM) (n = 10) or valvular aorta stenosis (AS) (n = 10) and from healthy blood donors (n = 20). METHODS: To investigate the possible sources of cytokines, the in vitro cytokine-inducing capacity of the patients' peripheral blood leucocytes was also measured. The TNF and IL-6 expression levels in the myocardium were investigated from biopsy specimens. The study of the immunological background of the cardiomyopathies was supplemented with screening of anti-heat shock protein 60 (Hsp60) antibodies in the sera of the patients. RESULTS: Elevated levels of circulating TNF (25-150 U/ml) and IL-6 (50-500 pg/ml) were found in 85% of the patients in the DCM and IHD groups, whereas only the IL-6 level was elevated (125-500 pg/ml) in the HCM patients. The in vitro TNF-alpha production was higher than in the normal controls only in the DCM group. The ventricular tissue of the DCM patients expressed TNF-alpha and IL-6. In vitro experiments were performed to examine the production of TNF and IL-6 by cultured rat cardiac myocytes (H9C2) under hypoxic conditions. Even a short hypoxic treatment resulted in cytokine production between 4 and 72 h following reoxygenization. Considerable amounts of anti-Hsp60 antibodies were found in 80% of the IHD patients and in 65% of the DCM patients. The in vitro cytokine production of leucocytes and the frequency of anti-Hsp60 positivity in patients with HCM or AS was not significantly different from those in the normal blood donors. CONCLUSIONS: These results demonstrate that TNF-alpha and IL-6 are of pathophysiological importance in some but not all types of cardiomyopathies, and the sources of cytokine production may differ. The mechanism of the development of primary DCM is still unknown; the high in vitro production of proinflammatory cytokines in the leucocytes of patients with DCM, the presence of TNF and IL-6 in their cardiac tissue and the high prevalence of anti-Hsp60 antibodies in their sera suggest a strong immunological background in the pathophysiology of the disease.

[Molecular genetics of the long QT syndrome: clinical aspects]. / A hosszú QT-szindróma molekuláris genetikája: klinikai vonatkozások.

The long QT syndrome (LQTS) is a heart disorder which is characterised by the prolongation of the QT interval of the surface electrocardiogram and is associated with malignant arrhythmias, syncopal episodes, torsade de pointes form ventricular tachycardias and an increased risk of sudden cardiac death. There are two familial forms of LQTS, the autosomal dominant Romano-Ward syndrome and the autosomal recessive Jervell-Lange-Nielsen syndrome which is associated with congenital senzorineural deaf-mutism. Recent advances in molecular genetics have allowed to identify mutations in four genes, KvLQT1 (11p15.5), HERG (7q35), SCN5A (3p21) and minK (21q22), which cause LQTS. There is a fifth genetic locus known on chromosome 4 (4q25-27), where the disease causing gene has not been identified yet. As LQTS genes code proteins which form sodium and potassium channels of the heart, LQTS can be regarded as the disease of cardiac ion channels. The KvLQT1 and minK genes code the slowly activating, delayed rectifier (Iks) potassium channel, the HERG gene code the rapidly activating, delayed rectifier (Ikr) potassium channel of the heart, while the SCN5A gene codes a cardiac sodium channel. Mutations in KvLQT1, minK and HERG genes affects repolarising, rectifier potassium currents, while SCN5A mutations cause delayed inactivation and reopening of the cardiac sodium channel, which initiates the depolarisation of cardiac cells. Both alterations result in a prolongation of cardiac repolarisation which is represented in the elongation of the QT interval. Elucidation of the genetic base of the disease provided new tools in the clinical management of LQTS. It has been shown that changes in the repolarisation parameters on the ECG may be predictive for the causative gene and different LQTS genes are associated with different clinical picture. More importantly, it is possible to use "gene-specific" therapy in LQTS which specifically targets ion channels affected by given gene mutations.

Endoscopic CO(2) laser therapy of selected cases of supraglottic marginal tumors.

Endoscopic CO(2) laser intervention can be used as conservation surgery for supraglottic laryngeal carcinomas in carefully selected patients. We analyzed retrospectively our experience in managing patients with early supraglottic carcinomas operated on at the Clinic of Otorhinolaryngology, Szeged, Hungary, during the 10-year period between 1987 and 1997. Conservation surgery was the treatment of choice in 187 patients, but only 23 (12%) were selected for endoscopic CO(2) laser surgery. Laser surgery was indicated predominantly for T1 cancer of the epiglottis (n = 15), but was also performed for T2 cancers (n = 8). Of the 23 supraglottic tumors treated, 16 had no signs of recurrence to date (1.5 to 9 years after surgery) a local control rate of 70%. Six patients with recurrences underwent salvage therapies that included repeated laser excisions (n = 3), radiotherapy (to 60 Gy), horizontal supraglottic laryngectomy and total laryngectomy. One patient was not resectable because of multiple metastases. Our experience with endolaryngeal CO(2) laser excision indicates that it is a reasonable method in selected cases of supraglottic tumors, but one-third of the patients required salvage treatment.