Heart rate variability and ischaemia in patients with coronary heart disease and stable angina pectoris; influence of drug therapy and prognostic value. TIBBS Investigators Group. Total Ischemic Burden Bisoprolol Study.

AIMS: Determination of the influence of therapy with bisoprolol and nifedipine on the heart rate variability of patients from the Total Ischemic Burden Bisoprolol Study and examination of the prognostic value. METHODS AND RESULTS: Four hundred and twenty-two patients with stable angina were included. The heart rate variability was determined over a period of 24 h. Parameters determined: standard deviation of the mean of all corrected RR intervals, standard deviation of all 5 min mean cycle lengths, square root of the mean of the squared differences of successive corrected RR intervals. Nifedipine reduced the mean values of all heart rate variability parameters tested. Square root of the mean of the square differences of successive corrected RR intervals increased under bisoprolol. Standard deviation of the mean of all corrected RR intervals and standard deviation of all 5 min mean cycle lengths increased from low baseline values and declined from higher baseline values. The increase in heart rate variability under therapy was accompanied by a tendency towards a better prognosis. Patients with an increase in heart rate variability and simultaneous complete suppression of ischaemia under therapy displayed no serious events in the course of one year. CONCLUSIONS: The increase in the heart rate variability, which can be regarded as prognostically favourable, was predominantly observed under bisoprolol. The parameter constellation of an increase in heart rate variability and complete ischaemia suppression on the 48-h Holter ECG was associated with the greatest benefit.

Prognostic significance of transient ischemic episodes: response to treatment shows improved prognosis. Results of the Total Ischemic Burden Bisoprolol Study (TIBBs) follow-up.

OBJECTIVES: The Total Ischemic Burden Bisoprolol Study (TIBBS) follow-up examined cardiac event rates in relation to transient ischemia and its treatment. BACKGROUND: It is unclear whether transient ischemia on the ambulatory electrocardiogram has prognostic implications in stable angina and whether medical treatment can improve the prognosis. METHODS: The TIBBS trial was an 8-week, randomized, controlled comparison of the effects of bisoprolol and nifedipine on transient ischemic episodes in patients with stable angina pectoris. Of the 545 patients screened, 520 (95.4%) could be followed up. Rates of cardiac and noncardiac death, nonfatal acute myocardial infarction, hospital admission for unstable angina and need for coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty were recorded. RESULTS: A total of 145 events occurred in 120 (23.1%) of 520 patients. Patients with more than six episodes had an event rate of 32.5% compared with 25.0% for patients with two to six episodes and 13.2% for patients with less than two episodes (p < 0.001). Hard events (death, acute myocardial infarction, hospital admission for unstable angina pectoris) were more frequent in patients with two or more ischemic episodes (12.2% vs. 4.7%, p = 0.0049). Patients with a 100% response rate of transient ischemic episodes during the TIBBS trial had a 17.5% event rate at 1 year compared with 32.3% for non-100% responders (p = 0.008). Patients receiving bisoprolol during the TIBBS tria had a lower event rate (22.1%) at 1 year than patients randomized to nifedipine (33.1%, p = 0.033). CONCLUSIONS: In patients with stable angina pectoris, frequent episodes of transient ischemia are a marker for an increased event rate. A 100% response to medical treatment reduces the event rate. The greater reduction of ischemia with bisoprolol than nifedipine during the TIBBS trial translated into an improved outcome at 1 year.

Medical treatment to reduce total ischemic burden: total ischemic burden bisoprolol study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. The TIBBS Investigators.

OBJECTIVES: We compared the effects of bisoprolol on transient myocardial ischemia with those of nifedipine in patients with chronic stable angina. BACKGROUND: Both beta-adrenergic blocking agents and calcium antagonists reduce transient ischemic episodes, but comparisons of these agents have been made in only a few larger studies. METHODS: The Total Ischemic Burden Bisoprolol Study (TIBBS) was a randomized double-blind controlled study with two parallel groups; 330 patients from 30 centers in seven European countries with stable angina pectoris, a positive exercise test and more than two transient ischemic episodes during 48 h of Holter monitoring (central evaluation) were included. Of these patients 161 were randomized to receive bisoprolol and 169 to receive nifedipine slow release. There were two treatment phases of 4 weeks each, with 48-h Holter monitoring after each phase. During phase 1, patients received either 10 mg of bisoprolol daily or 2 x 20 mg of nifedipine slow release. During phase 2, they received either 20 mg of bisoprolol daily or 2 x 40 mg of nifedipine slow release. RESULTS: In phase 1 of the trial, 4 weeks of bisoprolol therapy (10 mg daily) reduced the mean [+/- SD] number of transient ischemic episodes from 8.1 +/- 0.6 to 3.2 +/- 0.4/48 h. Nifedipine (2 x 20 mg) reduced transient ischemic episodes from 8.3 +/- 0.5 to 5.9 +/- 0.4/48 h. Total duration of ischemia was reduced from 99.3 +/- 10.1 to 31.9 +/- 5.5 min/48 h with bisoprolol and from 101 +/- 9.1 to 72.6 +/- 8.1 min/48 h with nifedipine. Reductions were statistically significant for both drugs; the difference between bisoprolol and nifedipine was also significant (p < 0.0001). Bisoprolol reduced the heart rate at onset of episodes by 13.7 +/- 1.4 beats/min from a baseline value of 99.5 +/- 1.2 beats/min (p < 0.001). Heart rate was unchanged with nifedipine. Bisoprolol had significantly higher responder rates than nifedipine. Doubling of the dose in phase 2 of the trial had small additive effects. Only bisoprolol showed a marked circadian effect by reducing the morning peak of transient ischemic episodes (by 68% at peak time, 8:00 to 8:59 AM). CONCLUSIONS: Both bisoprolol and nifedipine reduced the number and duration of transient ischemic episodes in patients with chronic stable angina. Bisoprolol was significantly more effective than nifedipine in both doses tested and reduced the morning peak of ischemic activity.

Effects of therapeutic ribose levels on human lymphocyte proliferation in vitro.

Ribose has been used successfully in the treatment of ischemic heart disease and muscular enzyme deficiencies, and its administration also facilitates the diagnosis of coronary artery disease by influencing thallium-201 scintigraphy. Concerns about the safety of ribose therapy have been triggered by reports about inhibitory effects of ribose on cell proliferation in vitro. This study examines possible side effects of ribose on human lymphocytes. Unstimulated and mitogen-stimulated human lymphocytes were incubated with ribose concentrations associated with high-dose oral administration, i.e., 3.5 mM, and with two- (7 mM) and tenfold (35 mM) higher concentrations. Cell cultures with matching glucose concentrations served as controls. Incorporation of [3H]thymidine into cells was used to measure cell proliferation. No significant inhibition of human lymphocyte proliferation in vitro was observed in mitogen-stimulated cells. Unstimulated cultures showed significant inhibition only at 35 mM ribose. It is concluded that ribose plasma levels associated with high-dose oral administration do not inhibit human lymphocyte proliferation in vitro. No evidence was found that short-term ribose therapy is harmful to human lymphocytes.

Effects of ribose on exercise-induced ischaemia in stable coronary artery disease.

There is no established treatment specifically aimed at protecting or restoring cardiac energy metabolism, which is greatly impaired by ischaemia. Even after reperfusion, myocardial content of ATP remains low for more than 72 h. Long-term post-ischaemic dysfunction and irreversibility of ischaemic damage have been associated with low ATP content. Evidence that the pentose sugar ribose stimulates ATP synthesis and improves cardiac function led us to test the possibility that ribose increases tolerance to myocardial ischaemia in patients with coronary artery disease (CAD). 20 men with documented severe CAD underwent two symptom-limited treadmill exercise tests on 2 consecutive days; we postulated that the ischaemia induced might bring about changes in ATP metabolism lasting for several days. Patients whose baseline tests showed reproducibility were randomly allocated 3 days of treatment with placebo or ribose 60 g daily in four doses by mouth. Exercise testing was repeated after treatment on day 5. At that time mean (95% confidence interval) treadmill walking time until 1 mm ST-segment depression was significantly greater in the ribose than in the placebo group (276 [220-331] vs 223 [188-259] s; p = 0.002). The groups did not differ significantly in time to moderate angina. In the ribose-treated group the changes from baseline to day 5 in both time to ST depression and time to moderate angina were significant (p less than 0.005), but these changes were not significant in the placebo group. In patients with CAD, administration of ribose by mouth for 3 days improved the heart's tolerance to ischaemia. The presumed effects on cardiac energy metabolism offer new possibilities for adjunctive medical treatment of myocardial ischaemia.

[Clinical importance of silent ischemia]. / Klinische Bedeutung der stummen Ischämie.

Objective signs of myocardial ischemia without angina pectoris or its equivalents define the syndrome of silent myocardial ischemia. Its significance lies in the prevalence and prognostic implications. As a prevalence, asymptomatic coronary heart disease can be found in 2.5% of men 40 to 60 years old. Silent myocardial ischemia is frequently found in patients with unstable coronary syndromes. The Framingham Study showed 25% of all myocardial infarctions as unrecognized by patients and physicians. The prognostic implications of silent myocardial ischemia are shown in large studies on prognosis of pathologic exercise-ECG's. Asymptomatic patients with pathologic exercise-ECG have always been recognized as having a significantly increased risk of myocardial infarction and death. Recently, many studies showed a worse prognosis for patients with asymptomatic transient ischemia on Holter-ECG. This can be found in patients with stable angina pectoris, unstable angina pectoris, patients with peripheral arterial disease, and patients after myocardial infarction. It becomes clear that prognosis is not defined by the pain, but by the severity of ischemia. Silent ischemia has to be viewed together with the severity of the underlying coronary heart disease. This synopsis will define the necessary steps for further diagnosis and treatment.

Lack of association of migraine with coronary vasospasm.

Previous reports have found an association between coronary vasospasm and migraine. It has been speculated that migraine and variant angina might be manifestations of a generalized vasospastic disorder. To investigate this hypothesis, 74 patients with frequent attacks of migraine were studied using 24-h continuous ambulatory electrocardiography to identify the presence of coronary vasospasm. Control groups consisted of 19 patients with tension headaches, and 38 healthy individuals. All subjects were free of heart disease. One patient in the migraine group and one patient in the control group had symptomless episodes of ST-segment depression not indicative of coronary vasospasm. Our data do not support the hypothesis that migraine and variant angina are components of a generalized vasospastic disorder.

[The diagnosis of silent myocardial ischemia. The problems of false-positive findings in the exercise ECG and long-term ECG]. / Diagnose der stummen Myokardischämie. Problematik falsch-positiver Befunde in Belastungs- und Langzeit-EKG.

In the case of a disease that produces no complaints, such as silent myocardial ischemia, it is of particular importance not to diagnose--or even to treat--a "pseudo-disease" in a patient with false-positive findings. In assessing whether a finding is false-positive or not, there is no "gold standard" for 24-hour ECG monitoring, since no other technique is capable of detecting transient attacks of ischemia occurring at any time during the day or at night. If only the ECG finding is positive, however, a second independent method is required to confirm the diagnosis. In this it must be remembered that all causes of false positive findings known in the case of exercise ECG also apply to the 24-hour ECG, and that when patients in whom the pre-test probability in accordance with the risk profile is low, the number of false-positive findings is likely to be very high. For these reasons, the 24-hour ECG cannot be recommended as a screening procedure for the diagnosis of ischemic heart disease.

Multiple lead monitoring during and after PTCA.

We investigated whether optimized ischaemia monitoring during and after PTCA using continuous recording of standardized 12-lead ECG provides additional information regarding the presence and localization of ischaemia. We studied 50 patients undergoing PTCA who received a total of 173 balloon inflations. Chest leads showed not only significantly more frequent ischaemic changes compared with routine limb lead monitoring (116/173 (67%) vs 88/173 (51%)), but in addition, a significantly earlier appearance of changes; 15.4 +/- 6.2 s after the start of balloon inflation compared with 17.5 +/- 6.8 s in the limb leads. Anginal pain, however, first occurred at 35 +/- 14 s after vessel occlusion in 74/173 (43%) of inflations. The changes in ECG monitoring correlated well with the coronary wedge pressure; at coronary wedge pressures below 20 mmHg, 97% of inflations caused ischaemic ECG changes; at pressures greater than 40 mmHg, changes were noted in only 42% of inflations. PostPTCA, 6/36 (16.7%) patients undergoing continuous 12-lead monitoring showed ischaemic ST-segment changes (asymptomatic in five cases), which helped in decision-making regarding interventional measures. In summary, we have found standardized 12-lead monitoring both during and after PTCA to be more precise and reliable in ischaemia detection and useful for clinical decision making.

[Angiography and functional results and histologic findings following percutaneous atherectomy in patients with arterial occlusive disease]. / Angiographische und funktionelle Ergebnisse sowie histologische Befunde nach perkutaner Atherektomie bei Patienten mit arterieller Verschusskrankheit.

In this study we report on the atherectomy technique, acute and long-term data, and histological findings of excised specimens from patients with peripheral vascular disease treated with the Simpson atherectomy catheter. Forty patients with a total of 72 lesions of the iliac (n = 5), superficial femoral (n = 62), and popliteal (n = 5) arteries could be treated; five patients had rest pain and two had gangrene. The primary success rate (of all lesions, including total occlusions and longer stenoses) was over 90%. The percent of stenosis decreased from 87.2 +/- 19.9% to 16.6 +/- 15.5%; the claudication distance improved from 80.5 +/- 65.7 m to 152.8 +/- 80.3 m; the Doppler index (leg/arm) increased from 0.57 +/- 0.17 to 0.81 +/- 0.16. At 6 months the mean walking distance and Doppler index remained stable from post-atherectomy; the mean percent of stenosis had increased to 35.7 +/- 30.9%. The angiographic restenosis rate (defined as stenosis greater than 70%) was 21% with a clear difference found depending on the primary morphology of the lesion: in eccentrics 5%, concentrics 27%, and total occlusions 42%, thereby allowing categorization of the suitability of a primary lesion for atherectomy. Histologically, restenoses showed more cellular proliferation and organized thrombus as compared to their primary stenoses; further investigations (cell culture, immunohistochemistry, and electron microscopy) are underway.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of silent myocardial ischemia]. / Stellenwert der stummen Myokardischämie.

More recent long-term ECG studies in patients with coronary heart disease have resulted in a focusing of interest on silent myocardial ischemia. Diagnostically, ECG changes suspicious for ischemia should always be confirmed by a second criterion. It has been found that differences between silent myocardial ischemia and angina pectoris are to be found mainly in the origination, conduction and perception of pain, and not in the underlying ischemia. Accordingly, prognostic studies have also shown that, in common with the presence of angina pectoris, the demonstration of silent myocardial ischemia is also a prognostically unfavorable sign. In severe ischemia, the indication for therapy is based on the prognosis of the patient; however, there have so far been no studies aimed at showing whether the prognosis of the patient can be improved over the long term by drug treatment.

[Treatment of stress-induced and spontaneous myocardial ischemia in coronary disease patients with slow-release gallopamil--preliminary results of an open study]. / Therapie belastungsinduzierbarer und spontaner Myokardischämien bei Koronarpatienten mit Gallopamil retard--Vorläufige Ergebnisse einer offenen Studie.

We studied the effects of slow-release gallopamil two-times 100 mg on exercise-induced ST-segment depression, as well as on the incidence of spontaneous myocardial ischemia detected by long-term ECG monitoring for 48 h in patients with coronary artery disease and stable angina pectoris. Three out of nine patients included in this study had to be excluded (because of frequent ventricular extrasystoles, paroxysmal atrial fibrillation, and development of instable angina pectoris). In all of the remaining six patients, the substance led to a doubling of working capacity (watts X min) evaluated by bicycle ergometry, paralleled by an increase of exercise duration until the occurrence of ST-segment depression greater than or equal to 0.1 mV. The number of spontaneous episodes of myocardial ischemia during long-term ECG recording, ranging 1-13 during control, decreased in all patients, paralleled by a decrease of the mean duration of ischemic episodes. On the other hand, no significant negative chronotropic effect was observed. Therefore, these preliminary results of this open-study protocol confirm the antischemic effects of slow-release gallopamil given 100 mg two times daily; on the other hand these promising results need to be confirmed in a doubleblind, placebo-controlled trial.

Continuous bed-side monitoring of the ECG for detection of silent myocardial ischaemia.

In patients with unstable angina pectoris, transient episodes of ischaemia occur frequently and the prognostic implications of those predominantly silent episodes have been shown. The method of Holter tape recording is, however, not ideal for the care of unstable patients: (a) the results of a recording period are only available after this period is finished and subsequent evaluation has taken place; and (b) the sensitivity of monitoring may be increased by recording more than two leads. We have used a portable ECG computer, which monitors the 12-lead ECG every 20 s and records ECGs either when there is consistent ST deviation or at preset intervals (1, 3, 5 min). It stores the information on solid-state memory and displays a summarized ST-level trend on a monitoring screen. The stored information can be reviewed at any time at the bed-side and selected ECGs can be printed out on paper. We have evaluated this device in 23 patients on our CCU, with unstable angina (10), evolving myocardial infarction (4) and post PTCA (9). Forty-two consecutive trend recordings were controlled with independent visual interpretation of 2920 complete 12-lead ECGs. Deviations of the ST-level trend of less than 0.1 mV were due to artefact in over 95%. However, when the ST-level trend showed deviations of above 0.1 mV, 93% of the 12-lead ECGs showed true pathologic changes. Eighty-two per cent of the recorded episodes of transient ischaemia were silent; angina was in every case preceded by ECG changes. In four patients the on-line recorded ECG was instrumental for the decision towards acute angiography, PTCA or bypass-operation.(ABSTRACT TRUNCATED AT 250 WORDS)