Vibrio coralliilyticus infection triggers a behavioural response and perturbs nutritional exchange and tissue integrity in a symbiotic coral.

Under homoeostatic conditions, the relationship between the coral Pocillopora damicornis and Vibrio coralliilyticus is commensal. An increase in temperature, or in the abundance of V. coralliilyticus, can turn this association pathogenic, causing tissue lysis, expulsion of the corals' symbiotic algae (genus Symbiodinium), and eventually coral death. Using a combination of microfluidics, fluorescence microscopy, stable isotopes, electron microscopy and NanoSIMS isotopic imaging, we provide insights into the onset and progression of V. coralliilyticus infection in the daytime and at night, at the tissue and (sub-)cellular level. The objective of our study was to connect the macro-scale behavioural response of the coral to the micro-scale nutritional interactions that occur between the host and its symbiont. In the daytime, polyps enhanced their mucus production, and actively spewed pathogens. Vibrio infection primarily resulted in the formation of tissue lesions in the coenosarc. NanoSIMS analysis revealed infection reduced 13C-assimilation in Symbiodinium, but increased 13C-assimilation in the host. In the night incubations, no mucus spewing was observed, and a mucus film was formed on the coral surface. Vibrio inoculation and infection at night showed reduced 13C-turnover in Symbiodinium, but did not impact host 13C-turnover. Our results show that both the nutritional interactions that occur between the two symbiotic partners and the behavioural response of the host organism play key roles in determining the progression and severity of host-pathogen interactions. More generally, our approach provides a new means of studying interactions (ranging from behavioural to metabolic scales) between partners involved in complex holobiont systems, under both homoeostatic and pathogenic conditions.

Using NanoSIMS coupled with microfluidics to visualize the early stages of coral infection by Vibrio coralliilyticus.

BACKGROUND: Global warming has triggered an increase in the prevalence and severity of coral disease, yet little is known about coral/pathogen interactions in the early stages of infection. The point of entry of the pathogen and the route that they take once inside the polyp is currently unknown, as is the coral's capacity to respond to infection. To address these questions, we developed a novel method that combines stable isotope labelling and microfluidics with transmission electron microscopy (TEM) and nanoscale secondary ion mass spectrometry (NanoSIMS), to monitor the infection process between Pocillopora damicornis and Vibrio coralliilyticus under elevated temperature. RESULTS: Three coral fragments were inoculated with 15N-labeled V. coralliilyticus and then fixed at 2.5, 6 and 22 h post-inoculation (hpi) according to the virulence of the infection. Correlative TEM/NanoSIMS imaging was subsequently used to visualize the penetration and dispersal of V. coralliilyticus and their degradation or secretion products. Most of the V. coralliilyticus cells we observed were located in the oral epidermis of the fragment that experienced the most virulent infection (2.5 hpi). In some cases, these bacteria were enclosed within electron dense host-derived intracellular vesicles. 15N-enriched pathogen-derived breakdown products were visible in all tissue layers of the coral polyp (oral epidermis, oral gastrodermis, aboral gastrodermis), at all time points, although the relative 15N-enrichment depended on the time at which the corals were fixed. Tissues in the mesentery filaments had the highest density of 15N-enriched hotspots, suggesting these tissues act as a "collection and digestion" site for pathogenic bacteria. Closer examination of the sub-cellular structures associated with these 15N-hotspots revealed these to be host phagosomal and secretory cells/vesicles. CONCLUSIONS: This study provides a novel method for tracking bacterial infection dynamics at the levels of the tissue and single cell and takes the first steps towards understanding the complexities of infection at the microscale, which is a crucial step towards understanding how corals will fare under global warming.

The association between dental status and temporomandibular osseous changes: a morphological study on Roman-Byzantine skeletons.

The aim of this study was to evaluate the association between dental status and the prevalence and severity of osseous changes in the temporomandibular joints of human skulls from the Roman-Byzantine period. Fifty-eight skulls from 36 men and 22 women between the ages of 19 and 63 years were studied, and the following parameters were evaluated: morphological osseous changes in the articular surface of the condyles, tooth wear and molar support. A significant correlation between age and dental wear or loss of molar support was observed, although no correlation was noted between age and morphological osseous changes in the condyles. The loss of molar support was significantly correlated with morphological osseous changes of the condyles, whereas no significant correlation was found between dental wear and condylar changes. This study demonstrates that the loss of molar support can serve as a predictor of osseous changes in the condyle. Reduced molar support may be one of the aetiologies associated with morphological osseous changes in temporomandibular joints. Further studies should to be performed to investigate this potential correlation.

[Severe limitation of mouth opening].

Limitation of mouth opening is a common source of referral to an orofacial pain clinic with a proposed diagnosis of Temporomandibular Joint Dysfunction (TMD). The word "trismus" is defined by the American academy of orofacial pain as: "Myospasm of masticatory muscles specifically causing limited jaw opening; early symptom of tetanus". Therefore, once trismus is suspected, TMD should be ruled out. However, it is not uncommon to find the usage of this term to describe severe limitation of opening by causes other than myospasm, therefore posing the risk of misdiagnosis. The purpose of this article is to describe the differential diagnosis of hard end limitation of opening with emphasis on the clinical tools used to differentiate between muscle source of hard end limitation and other sources of hard end limitation. Several cases of hard end limitation of mouth opening are presented and through them major principles of orofacial diagnosis are discussed.

[Do temporomandibular disorders really exist?].

Temporomandibular Disorders (TMD) is a collective term embracing a number of clinical problems that involve the muscles of mastication, the temporomandibular joint (TMJ) and associated structures or both. This group of disorders has been identified as the chief cause of pain, which is not of dental origin, in the orofacial area, and is defined as a subgroup in the category of musculoskeletal disorders. These disorders impair the quality of life of those suffering from them due to the extent of the pain and the chronic nature of its symptoms. It is known that chronic pain causes the development of psychological disturbances (anxiety, depression, etc.). The most common symptoms of TMD are the pain that usually appears as the result of mandibular activity (speaking or chewing), and is usually located in the masticulatory muscles, in the preauricular area and the temporomandibular joint (TMJ). Additional common symptoms are: a. restriction in jaw movement; b. asymmetry in jaw movement; c. noises from the joint. Patients suffering from TMD are likely to exhibit additional symptoms: hypertrophy of the muscles of mastication (an adaptive and asymptomatic phenomenon), abnormal occlusar erosion due to nighttime or daytime bruxism, or teeth grinding. Most functional temporomandibular disorders have similar signs and symptoms. As a result, diagnosis of the various disorders presents a serious problem. Functional temporomandibular disorders are often accompanied by mental symptoms such as depression, anxiety and/or somatization on various levels. One of today's accepted methods of classification also refers to the mental aspect and thus enables, for the first time, a suitable scientific comparison of the epidemiological, diagnostic and treatment data in the various studies. This method, initiated by Dworkin and LeResche (1992) is known as Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The purpose of this method is to classify every subgroup of TMD according to agreed upon, clear and measurable diagnostic criteria, both from the physical (AXIS I) and the mental (AXIS II) aspect. The method includes a scale which grades the extent of severity, damage and limitations caused by the illness, in a manner which now can make scientific comparisons between the various studies and between the population of patients and the general population. Temporomandibular disorders are very common and affect between 30%-50% of the population, and appear to be more prevalent among women than among men. Studies conducted on youth revealed significant relationships between oral parafunctions (especially chewing gum and "jaw playing"), and functional temporomandibular disorders. The significance of this finding is in the need to warn young people of the possible risks of engaging in intensive oral practices. The high prevalence of signs and symptoms among the Israeli population obligates us, in our opinion, to change the physical examination for identification of these disorders, to a routine procedure in all dental clinics in Israel.

Effect of stabilization splint therapy on pain during chewing in patients suffering from myofascial pain.

Masticatory myofascial pain (MFP) condition is a musculoskeletal disorder that compromises the functional capacities of the masticatory system. As such, the incorporation of an intensive chewing test as a discriminatory exercise for the diagnosis of this condition and evaluation of treatment success has considerable potential. Various splint designs have been used successfully, which have posed a question of whether the therapeutic effect of the splint is a placebo or has some other curative properties. The purpose of this study was to evaluate the efficacy of the stabilization appliance to reduce signs and symptoms in MFP patients and to compare the pain experience during the chewing test between two groups of patients, with and without splints. Myofascial pain patients (n = 37) who reported exacerbation of pain in function participated in the study. Patients perfomed a 9-min chewing test, followed by 9-min rest and marked their pain intensity on a visual analogue scale every 3 min. Of the 37 patients, 21 received a stabilization flat occlusal splint for night use and 16 were equally monitored clinically without a splint. At the end of 8 weeks, a second clinical examination and chewing test were performed. Student's t-test was used to analyse differences between study groups. Analysis of variance and covariance (ancova) with repeated measures was applied to analyse the effect of treatment. Level of pain at baseline prior to the chewing test (P0) was introduced as a co-variant. At baseline both groups showed relatively high scores of pain intensity and did not show any significant differences among the collected variables. At the end of the experiment, the splint group had a statistically significant reduction in pain intensity, in mean muscle sensitivity to palpation and in the pain experience during the chewing test compared with no change in the controls. A stabilization splint has a therapeutic value beyond its placebo effects. Thus, it should be an integral part of the treatment modalities in MFP disorder patients. An intensive chewing test is an effective tool to evaluate the treatment modality efficacy in MFP patients.

Cephalometric and polysomnographic analyses of functional magnetic system therapy in patients with obstructive sleep apnea.

The therapeutic effect of a functional magnetic system on obstructive sleep apnea and the system's operating mechanism have not been examined. Two hypotheses are postulated: a functional magnetic system increases the size of the oral cavity airway passage, or it increases the pharyngeal space. Twenty-eight patients with mild-to-moderate obstructive sleep apnea were examined; 10 patients (9 men and 1 woman; aged, 50.5 +/- 2.6 years) met the study criteria. After baseline nocturnal polysomnography and daytime tiredness self-evaluation, a functional magnetic system was inserted. The functional magnetic system is a mandibular repositioning appliance that uses a pair of attractive magnets (Sm2Co17), placed opposite each other in the jaws, which results in an advancement-to-opening ratio of 1:2. After 8 weeks of functional magnetic system treatment, polysomnography, daytime tiredness, and nighttime snoring were evaluated, and cephalogram radiographs with and without the appliance were taken. It was found that the respiratory disturbance index decreased significantly; minimal oxygen saturation increased significantly, reaching a normal value; day time tiredness improved; snoring declined; the oral cavity anterior region increased significantly, and the pharyngeal airway passages did not change. Reduction in the respiratory disturbance index and enlargement of the anterior oral cavity area were highly and significantly correlated. In conclusion, the functional magnetic system is a reliable mandibular repositioning appliance that has no apparent adverse effects. A functional magnetic system operates by increasing the anterior region of the oral cavity, mainly vertically, with no change in the posterior oral cavity region and pharyngeal airway passages.

Oral habits among adolescent girls and their association with symptoms of temporomandibular disorders.

AIM: To evaluate the contribution of certain parafunctional activities to the presence of temporomandibular disorder (TMD) symptoms among teenage girls, with special emphasis to gum chewing and jaw play. METHODS: A total of 323 girls, aged 15-16 years, were randomly selected from a religious junior high school. The girls responded to a questionnaire on oral habits and TMD symptoms. RESULTS: Gum chewing was a very prevalent habit (62.4%), performed daily (mean chewing time 3.95 h day-1). Girls who chewed intensively (more than 4 h day-1) showed associations with pain in the ear area during function and at rest, as well as with joint noises. Jaw play, although reported by only 14.3%, was significantly associated with pain in the ear area during function and at rest, feeling of tiredness of the jaw while chewing, joint noises, catch and lock. All oral parafunctions, except chewing gum, were associated with jaw play and with each other. CONCLUSIONS: Jaw play was the most detrimental habit in TMD; intensive gum chewing was a potentially contributing factor for joint noises and pain. Oral parafunctions (except chewing gum) were significantly associated between themselves and suggest a behavioural pattern of "jaw hyperactivity".

Oral motor parafunctions among heavy drug addicts and their effects on signs and symptoms of temporomandibular disorders.

AIMS: To investigate the prevalence of temporomandibular disorders (TMD), bruxism, and other oral habits among drug addicts compared to a normal, non-addicted, matched control population, and to assess the detrimental effect of long-term drug abuse on the parameters studied. METHODS: Subjects included 55 drug-addicted patients (51 males and 4 females) randomly selected from long-term addicts using "hard" narcotics and attending a methadone maintenance center and a control group of 52 normal non-addicted individuals (48 males and 4 females) matched to the addicts for age, gender, and socioeconomic status. A clinical examination and a questionnaire were used. One examiner determined that all questions were correctly understood and answered, and a second examiner performed the clinical examinations and was unaware of the results of the questionnaire. RESULTS: The addicted group had a high prevalence of orofacial motor behavior (bruxing, clenching) as well as signs and symptoms of TMD (morning headache, joint noises, joint and masticatory muscle tenderness to palpation, and tooth wear) compared to the controls. Active (voluntary) jaw opening was significantly smaller, although within an acceptable range when compared to the controls. CONCLUSION: Long-term drug abuse detrimentally affects the stomatognathic system, as expressed in a high prevalence of oral motor behavior and signs and symptoms of TMD.

Splints and stress transmission to teeth: an in vitro experiment.

OBJECTIVE: To determine the influence of hard and soft splints with two thicknesses on the stress transmission to the tooth supporting the splint and the opposite tooth. METHODS: Continuous vertical forces up to 500N were applied to two opposite first molar phantom teeth using a universal loading machine. Deformation was detected by strain gauges attached to the cervical area of the buccal and lingual aspects of the lower tooth. Strain, as a function of force, was collected and the slope, defined as the compliance (in microS/N) of the system, was calculated. RESULTS: The highest compliance was found with hard splints. When splints were constructed on the upper molar, the highest compressive compliance was registered on the buccal side (2.8 microS/N) and tension compliance on the lingual side (-0.35 microS/N). When constructed on the lower tooth, the opposite was found. Soft splints resulted in compression on both the buccal and lingual sides when adjusted to the upper or lower tooth. A higher compliance was found on the buccal side (1.26 microS/N), while on the lingual side, the values varied (0.48-0.78 microS/N). CONCLUSIONS: Soft splints are more efficient in protecting teeth against the damage of bending forces although there is an increase of compression forces. The tooth opposing a hard splint is exposed to a higher risk of bending forces.

Generalized joint laxity and its relation with oral habits and temporomandibular disorders in adolescent girls.

A group of 248 girls, aged 15-16 years, were randomly selected and examined both clinically and by questionnaire with regard to the signs and symptoms of temporomandibular disorders (TMD), generalized joint laxity (GJL), range of mandibular opening, temporomandibular joint (TMJ) hypermobility and presence of oral parafunctions. The prevalence of GJL was 43% and that of TMJ hypermobility (TMJH) was 27.3%. A significant, albeit weak, correlation was found between the two. In the presence of joint click, both active and passive opening were significantly larger. When either muscle or joint sensitivity to palpation was present, the difference between the active and passive range of mouth opening increased significantly. The presence of reported clicks was negatively associated with GJL. This association was not valid in the presence of parafunction. Some of the signs and symptoms of TMD affected the range of mouth opening. In the presence of joint clicks, the mean active and passive mandibular opening were significantly larger. In the presence of joint and muscle sensitivity to palpation, the difference between passive and active mouth opening was larger. This was possibly because of the effect of pain on the full active range of opening, which was invalid in the registration of the passive mandibular opening. GJL, when present, did not seem to jeopardize the health of the stomatognathic system as expressed in the signs and symptoms of TMD. There was a negative association between GJL and the presence of reported joint clicks and catch. When a parafunction was present in addition to GJL, this association was invalid but not reversed, as has been previously reported.

Oral habits and their association with signs and symptoms of temporomandibular disorders in adolescent girls.

A group of 248 randomly selected high school girls, aged 15-16 years, completed a questionnaire and were examined clinically with regard to various oral habits and signs and symptoms of temporomandibular disorders (TMD). Common habits reported in the literature, such as gum chewing, nail biting, biting foreign objects, clenching and bruxism, eating seeds and crushing ice, as well as two less reported habits, 'jaw play' and continuous arm leaning, were evaluated. The most outstanding finding was the high prevalence and intensity of gum chewing among our study group: 92% of the girls chewed daily and 48% chewed gum for more than 3 h a day (intensive gum chewing). Statistically significant associations were found between intensive gum chewing and muscle sensitivity (P<0.001) and joint noises (P<0. 05), and between crushing ice and muscle sensitivity to palpation (P<0.005). A positive association was found between 'jaw play' and joint disturbances: reported joint noises (P<0.01), catching of the joint (P<0.01) and joint tension (P<0.001). A positive association was also found between arm leaning and reported joint noises (P<0. 05), catching (P<0.05), and joint tension (P<0.005). There was no association between the presence of bruxism and muscle sensitivity to palpation or joint disturbances. The potential harmful effects of intensive gum chewing, 'jaw play', continuous arm leaning and ice crushing are presented in this study. In light of these findings, the professional community should address these habits with proper data gathering, examination and consultation.

Topical application of capsaicin for the treatment of localized pain in the temporomandibular joint area.

AIMS: To determine the effectiveness of topical capsaicin cream application on localized pain in the temporomandibular joint (TMJ) area. METHODS: A randomized, double-blind, placebo-controlled study was conducted on 30 patients suffering from unilateral pain in the TMJ area. Patients were randomly divided into experimental and placebo groups; they were instructed to apply 0.025% capsaicin cream or its vehicle to the painful TMJ area 4 times daily for 4 weeks. Subjective parameters of present pain, most severe pain, effect of pain on daily activities, and pain relief were assessed each week on a visual analog scale. Muscle and joint sensitivity to palpation on the painful and contralateral joints and maximal mouth opening (assisted/passive and non-assisted/active) were examined weekly by the same experienced examiner. RESULTS: Capsaicin cream produced no statistically significant influence on measured variables when compared to placebo. Both experimental and placebo groups showed statistically significant improvement in most variables during the experiment. CONCLUSION: The factor of time had a major effect in the non-specific improvement of the parameters assessed. The placebo effect played an important role in the treatment of patients with pain in the TMJ area.

The coronoid process as a cause of mandibular hypomobility--case reports.

In an attempt to draw the clinician's attention to the coronoid process site while evaluating the aetiology of the restriction of mandibular opening, four cases are illustrated. These cases represent a diversity of causes hampering the free rotational movement of the coronoid process in space during jaw function. Case 1 is an example of unilateral hyperplastic coronoid process and osteochondroma; case 2 shows unusually shaped short and divergent coronoid processes combined with a bucally displaced maxillary third molar on one side; cases 3 and 4 represent an anatomical variation of an extremely narrow vestibular space due to the close proximity of the medial aspect of the coronoid process to the distal molar. It is suggested that each clinical examination include the width of the buccal vestibular space while performing mandibular movements.

Bruxism secondary to antipsychotic drug exposure: a positive response to propranolol.

We present two cases of acute nocturnal bruxism occurring as an early side effect of antipsychotic drug treatment. The development of bruxism was coupled with the appearance of neuroleptic-induced akathisia. Both complications were relieved after the beta-adrenergic blocker propranolol was added, suggesting the involvement of the adrenergic and serotonergic central nervous systems, besides the dopaminergic system, in the pathogenesis of bruxism. The positive response of iatrogenic bruxism to propranolol implies that propranolol also deserves a trial for the treatment of noniatrogenic nocturnal bruxism.

Comparison between metoprolol orally osmotic once daily and metoprolol two or three times daily in suppressing exercise-induced and daily myocardial ischemia.

Metoprolol is a widely used anti-ischemic drug with a relatively short half-life. To improve patient' compliance and to provide 24-hour coverage, its once daily ORally OSmotic (OROS) formulation was developed. In this multicenter double-blind study, the anti-ischemic effects of metoprolol OROS given once daily at doses of 190 and 285 mg were compared to the regular metoprolol formulation of 100 mg 2 or 3 times daily. Sixty-five patients with stable coronary artery disease, positive exercise tests, and ischemic episodes during daily activity as recorded by ambulatory electrocardiographic monitoring (AEM) were included. In the OROS group, 23 patients completed all 3 treatment periods. In these patients, the number of myocardial ischemic episodes decreased from 239 on placebo to 128 during the 190 mg/day dose (p < 0.0001) and to 86 during the 285 mg/day treatment period (p < 0.0001). In the metoprolol group, there were 204 episodes at baseline and 142 and 140 during the 100 mg 2 or 3 times daily treatment periods (p < 0.0001 for both). During exercise testing, time to 1-mm ST depression increased significantly in the OROS group from 6.3 minutes at baseline to 7.1 and 9.6 minutes during 190- and 285-mg treatment periods. In the metoprolol group, it increased from 5.8 to 7.2 and 8.2 minutes, respectively. Both formulations of metoprolol were well tolerated. The OROS formulation was highly effective in suppressing daily and exercise-induced ischemia and exerted its effect throughout the 24-hour period.

Effects of transdermal nicotine patches on ambulatory ECG monitoring findings: a double-blind study in healthy smokers.

The cardiovascular effects and safety of transdermal nicotine patches were assessed in 50 healthy smokers using repeated 48 hour ambulatory electrocardiographic monitoring as a part of a smoking cessation program. Following baseline measurements, subjects were randomized to active (n = 25) or placebo (n = 25) treatment groups for a period of 2 weeks. Twenty-two patients in each group completed the trial. During the treatment period, subjects also received behavioral supportive therapy. Heart rate and blood pressure were significantly reduced relative to baseline both groups. In the active treatment group, mean values at baseline and after 2 weeks of double-blind treatments were as follows: heart rates, 74.0 and 71.3 beats/min, respectively; systolic blood pressure, 108.9 and 106.9 mmHg; and diastolic blood pressure, 69.7 and 68.2 mmHg, respectively. Values for the placebo group were as follows: heart rate, 73.2 and 69.6 beats/min; systolic blood pressure, 110.6 and 105.3 mmHg; diastolic blood pressure, 71.4 and 70.5 mmHg. The confidence intervals of the mean for the differences between the groups are as follows: heart rate, -4.0 +8.2; systolic blood pressure, -6.7, +10.1; diastolic blood pressure, -7.9, +3.9. There were no changes in the frequency of atrial or ventricular arrhythmia as documented by repeated 48 hour ambulatory ECG recordings from baseline period before stopping smoking compared with the treatment period in the active as well as in the placebo groups. No ischemic events were detected in any of the volunteers during either the baseline or treatment periods. As a measure of smoking abstinence, we assessed the level of carbon monoxide in expired air; in the active group, the mean levels fell from 14.2 to 4.4 ppm after smoking cessation and in the placebo group from 13.2 to 4.2 ppm. The mean urine cotinine level fell from 8.18 mmol/l at baseline to 5.74 mmol/l after 2 weeks of treatment in the active group and from 8.78 to 3.93 mmol/l in the placebo group. The number of cigarettes smoked per week in both treatment groups was significantly reduced: from 175.2 to 8.4 for the active group and from 136 to 8.6 for the placebo group. Eleven out of 22 subjects in each group quit smoking completely. Smoking withdrawal symptoms during the first week of treatment were more severe in the placebo group than in those on active treatment. There were no significant side effects in either the placebo or the active treatment groups. These results indicate that nicotine delivered by transdermal system is free of cardiac adverse effects in healthy volunteers.

Ischemic threshold during two exercise testing protocols and during ambulatory electrocardiographic monitoring.

OBJECTIVES: The aim of this study was to examine the dependence of the ischemic threshold during exercise testing on the exercise protocol employed and to determine the relation between the ischemic thresholds observed during exercise and during daily activity. BACKGROUND: The ischemic threshold (heart rate at 1-mm ST segment depression) during daily activity has been reported to be lower than that observed during exercise testing. Recent reports have hypothesized that this difference is probably dependent on the exercise protocol employed. METHODS: Twenty-two patients with known coronary artery disease, not receiving antianginal medications, were evaluated by repeated exercise testing according to the Bruce and the modified Davidson protocols and by 48-h ambulatory electrocardiographic monitoring. RESULTS: Although the heart rate at 1-mm ST segment depression was somewhat lower with the Davidson than with the Bruce protocol (112 +/- 14 vs. 115 +/- 14 beats/min), the rate-pressure product at 1-mm ST segment depression was similar during the two protocols (16,900 +/- 4,000 vs. 17,700 +/- 3,600). The mean heart rate (100 + 12 beats/min) at 1-mm ST segment depression during ambulatory ischemic episodes (n = 137) was significantly lower than that observed during both exercise protocols (p < 0.001 for both comparisons). CONCLUSIONS: Exercise-induced ischemia occurs at a relatively fixed threshold that is mainly dependent on myocardial oxygen demand and is independent of the exercise protocol employed. Ischemia on ambulatory monitoring, however, occurs at a much more variable threshold that is commonly lower than that observed during exercise and is therefore dependent on other factors in addition to increased demand.

Circadian variations in ischemic threshold and their relation to the occurrence of ischemic episodes.

BACKGROUND: The occurrence of ischemic episodes during daily activity has been reported to exhibit a bimodal circadian distribution, yet its relation to the ischemic threshold (heart rate at 1-mm ST segment depression) has not been explored. METHODS AND RESULTS: To determine whether the ischemic threshold during daily activity exhibits a circadian pattern that might relate to the frequency of occurrence of ischemic episodes, we studied the time of occurrence and the heart rate at onset of ischemia in 1,371 ischemic episodes recorded in 41 patients with stable coronary disease, positive exercise testing, and repeated ischemic episodes during ambulatory ECG monitoring (AEM). All patients had 7 days of AEM; 23 were off any anti-ischemic therapy, while 18 were on low dose of beta-blockers. The occurrence of ischemic episodes exhibited the typical bimodal circadian distribution with a prominent peak between 7:00 and 11:00 AM and a second less prominent peak between 6:00 and 9:00 PM. The threshold of myocardial ischemia exhibited a different single-peaked circadian distribution; it was lowest between 1:00 and 3:00 AM and highest between 10 AM and 1 PM. Time series analyses indicated a strong hour-by-hour trend of each of the two circadian distributions, whereas the two series cross-correlated maximally at a lag of zero hours (p < 0.01), indicating a complex interplay between myocardial oxygen demand and supply in determining the occurrence of ischemic episodes during daily activity. The morning increase in the frequency of ischemic episodes could not be attributed to a reduced threshold but rather to an increase in demand. The low threshold at night-time might probably indicate that the mechanism of ischemia during these hours is reduced coronary flow due to increased coronary tone. Secondary analyses for several predefined patients' subsets gave similar results. Patients who received low-dose beta-blockers maintained the bimodal circadian distribution of the occurrence of ischemic episodes, whereas the ischemic threshold exhibited a constant pattern with no circadian changes. CONCLUSIONS: Our results demonstrate that myocardial oxygen demand is a major determinant of daily ischemia, yet changes in the ischemic threshold that probably reflect dynamic changes in coronary tone play also an important role. The relative contribution of increased demand and decreased threshold to the genesis of ischemic episodes during daily activity can be assessed by AEM and may help to optimize medical therapy.

Effect of benazepril on myocardial ischaemia in patients with chronic stable angina pectoris.

The anti-ischaemic properties of benazepril, a non-sulfhydryl inhibitor of angiotensin-converting enzyme, were assessed in 20 patients with chronic stable angina pectoris, by repeated exercise tests and repeated 72-h ambulatory electrocardiographic monitoring. The study was a double-blind, placebo-controlled cross-over; 11 patients received benazepril 10 mg b.i.d. and nine received 20 mg b.i.d. All patients had a positive treadmill stress test and at least three ischaemic episodes during 24 h of ambulatory electrocardiographic monitoring. Benazepril at a dose of 10 mg b.i.d. did not improve the exercise duration, the time taken to reach 1 mm ST depression. Similar findings were observed during treatment with 20 mg b.i.d. Benazepril at a dose of 10 mg b.i.d. was ineffective in improving ischaemic parameters during daily activities. However, among the nine patients who received 20 mg b.i.d. the number of ischaemic episodes was reduced from 142 to 103, and the total duration of ischaemic was reduced from 1099 to 531 min. The number of weekly anginal attacks was reduced from 58 to 33, and the weekly sublingual nitroglycerin tablets consumption was reduced from 31 to 14. When the two doses (10 mg and 20 mg) were combined (N = 20), the number of ischaemic episodes was reduced from 314 to 260 (P = 0.074), and the duration of ischaemic was reduced from 3453 to 2514 min (P = 0.072).