Ronald D. Wuttke

Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon

BACKGROUND The coronary slow flow phenomenon (CSFP) is an angiographic finding characterized by Thrombolysis in Myocardial Infarction (TIMI)-2 flow in the absence of significant large vessel coronary disease. Although clinical and pathological features have been previously described, the underlying pathophysiology has not been fully elucidated. This study investigates the persistence of the phenomenon on serial angiographic studies, coronary hemodynamic findings at rest and during provocative stimuli, and biochemical evidence of inducible myocardial ischemia. METHODS Twelve patients with CSFP underwent repeat angiography and coronary sinus canulation that allowed for the assessment of coronary blood flow, transmyocardial lactate, and oxygen extraction. Parameters were assessed at rest and during rapid atrial pacing, cold pressor stimulation, and acetylcholine infusion. Angiographic and coronary hemodynamic findings were compared with 47 patients who underwent angiography and 8 patients who were hemodynamic control subjects, respectively. RESULTS Persistent TIMI-2 flow was demonstrated with repeat angiography in only 4 of the patients. However, the corrected TIMI frame count remained delayed compared with that in control subjects. Furthermore, resting coronary sinus oxygen saturation was low compared with control subjects (23% +/- 4% vs 31% +/- 4%; P <.01), reflecting an increased basal coronary vasomotor tone. The coronary vasodilatory response to atrial pacing was similar to that in control subjects; however, several patients exhibited abnormal vasomotor responsiveness to cold pressor and acetylcholine stimuli. There was no evidence of nett myocardial lactate production with atrial pacing. CONCLUSION The CSFP is associated with a chronically elevated resting coronary microvascular tone, even when symptoms are relatively quiescent.

Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets

OBJECTIVES The study examined possible clinical determinants of platelet resistance to nitric oxide (NO) donors in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS), relative to nonischemic patients and normal subjects. BACKGROUND We have shown previously that platelets from patients with SAP are resistant to the antiaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP). METHODS Extent of adenosine diphosphate (1 micromol/liter)-induced platelet aggregation (impedance aggregometry in whole blood) and inhibition of aggregation by NTG (100 micromol/liter) and SNP (10 micromol/liter) were compared in normal subjects (n = 43), nonischemic patients (those with chest pain but no fixed coronary disease, (n = 35) and patients with SAP (n = 82) or ACS (n = 153). Association of NO resistance with coronary risk factors, coronary artery disease (CAD), intensity of angina and current medication was examined by univariate and multivariate analyses. RESULTS In patients with SAP and ACS as distinct from nonischemic patients and normal subjects, platelet aggregability was increased (both p < 0.01), and inhibition of aggregation by NTG and SNP was decreased (both p < 0.01). Multivariate analysis revealed that NO resistance occurred significantly more frequently with ACS than with SAP (odds ratio [OR] 2.3:1), and was less common among patients treated with perhexiline (OR 0.3:1) or statins (OR 0.45:1). Therapy with other antianginal drugs, extent of CAD, intensity of angina and coronary risk factors were not associated with variability in platelet responsiveness to NO donor. CONCLUSIONS Patients with symptomatic ischemic heart disease, especially ACS, exhibit increased platelet aggregability and decreased platelet responsiveness to the antiaggregatory effects of NO donors. The extent of NO resistance in platelets is not correlated with coronary risk factors. Pharmacotherapy with perhexiline and/or statins may improve platelet responsiveness to NO.

Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations

Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin‐converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.

Acute heart failure: determinants of outcome

We prospectively studied 69 consecutive patients hospitalized with a primary diagnosis of acute left ventricular failure so as to assess the impact of vasodilators on incidence and morbidity of acute symptomatic left ventricular failure. The determinants of duration of hospitalization, in-hospital mortality and symptomatic status 2 months after discharge were examined. There were 9 in-hospital deaths (13%), and survival at 60 days was 77%. Median duration of hospitalization was 9 days, and 33% of the surviving patients remained in New York Heart Association functional class III-IV 60 days subsequent to discharge. Of the patients, 49 (76%) had previously received treatment for left ventricular failure: 30 (61%) of these had received vasodilators, most commonly angiotensin converting enzyme inhibitors and nitrates. Ischaemic chest pain was present in 34 (49%) of the patients. Acute utilization of vasodilators (45% of patients) was largely limited to nitrate therapy associated with ischaemic chest pain (P less than 0.01). Multiple logistic regression revealed previous left ventricular failure, advanced age and hypokalaemia as significant correlates of prolonged hospitalization (greater than 9 days). Previous left ventricular failure was also predictive of persistent severe disability two months subsequent to discharge. No factor was a significant predictor of in-hospital death. Although preceding treatment with digoxin and incremental angiotensin converting enzyme inhibitor therapy tended to predict brief hospitalization, the parameter of acute ischaemia, other biochemical anomalies and modes of acute or chronic therapy were not significant correlates of any end point. We conclude that preceding disability, rather than mode of treatment, predicts an adverse outcome in acute left ventricular failure.

Relation Between Acute Myocardial Uptake and Hemodynamic and Electrocardiograpic Effects of Metoprolol in Humans

Summary We studied myocardial disposition of metoprolol after a 4-mg intravenous (i.v.) bolus in 12 patients undergoing cardiac catheterization for investigation of chest pain, using a paired transcoronary sampling technique with simultaneous determination of coronary sinus blood flow (CSF). Myocardial metoprolol content (MMC) was then correlated with concomitant effects on hemodynamic and ECG parameters. Peak myocardial metoprolol content (1.89 ± 0.40% of injected dose) was attained rapidly (2.67 ± 0.38 min), but time to peak content was significantly delayed in the presence of extensive coronary artery disease. Residual MMC 17.5 min after injection was 49.1 ± 8.7% of maximal MMC. Extent of coronary artery disease or variability in left ventricular (LV) systolic function did not influence peak MMC. Metoprolol induced slowing of spontaneous heart rate (HR, p < 0.05), reduction in LV +dP/dt (p < 0.0005), and prolongation of PR intervals (p < 0.05) with maximal changes 5+10 min after injection. Thus, time of peak hemodynamic effects of metoprolol was consistently delayed relative to time of peak MMC. We conclude that after i.v. injection, myocardial metoprolol accumulation in humans is rapid, with marked hysteresis between peak MMC and subsequent hemodynamic effects.

Incidence of adverse events during treatment with verapamil for suspected acute myocardial infarction

Abstract The potential clinical role of non-dihydropyridine calcium antagonists, such as verapamil and diltiazem, in the management of patients during and subsequent to acute myocardial infarction (AMI) is an area of considerable and changing controversy.1 Recent investigations suggest that both verapamil1,2 and diltiazem1,2,4 exert beneficial effects after AMI, largely, if not entirely mediated by reduction in the incidence of reinfarction. However, there is considerable concern about the use of these negatively inotropic calcium antagonists in patients with significantly impaired left ventricular systolic function.1,2,4 Although diltiazem may be beneficial in the periinfarct period3 and verapamil may exert beneficial effects on both ischemia5 and infarct size6 in this setting, the results of the only large randomized study conducted to date concerning the early use of verapamil — Danish Verapamil Infarction Trial-I (DAVIT-I)1— discouraged initiation of verapamil therapy in the first week, representing the period of maximal risk for reinfarction. Specifically, in DAVIT-I the incidence of death due to cardiogenic shock or pulmonary edema, or both, complicating infarction was 5.3%, somewhat higher than in the placebo-treated patients (3.2%). These results of DAVIT-I may have been influenced by the use of large intravenous doses of the drug and by the absence of thrombolytic therapy, which would be expected to both reduce the potential risk of the development of cardiogenic shock and increase the risk of reinfarction. Therefore, there is a need to reevaluate this area of therapeutics. We prospectively examined the incidence of potential drug-associated adverse events in consecutive patients treated with intravenous or oral verapamil, or both, in the early management of suspected AMI. We also sought to determine potential clinical parameters predisposing to the occurrence of such adverse outcomes. End points included death, significant bradyarrhythmia requiring treatment due to hemodynamic compromise and symptomatic left ventricular failure. Frequency of these outcomes was expressed as a percentage with 95% confidence intervals (CI). Correlates between 12 prospectively chosen clinical variables and individual end points were determined using multiple logistic regression.

The positive inotropic effects of milrinone but not of digoxin are attenuated at short cycle lengths.

The effects of inotropically active agents on the left ventricular force-interval relation are a potential determinant of their clinical utility and safety. However, little information is available concerning the effects of noncatecholamine positive inotropic agents on this relation. Therefore this study compared the short-term effects of digoxin and milrinone on resting hemodynamics, frequency potentiation (FP), and mechanical restitution (MR) in patients undergoing nonemergency cardiac catheterization. Both digoxin and milrinone produced similar increases in LV + dP/dt at rest (12.2 +/- 1.3%, p < 0.000001 and 11.4 +/- 3.2%, p < 0.01, respectively). The positive inotropic effects of digoxin were marginally attenuated during FP (by 8.5 +/- 4.2% and 4.6 +/- 2.9% at 10 and 60 s, respectively, both p = NS compared with baseline). Similarly, on MRC analysis, the parameter c (a measure of sensitivity of contractile performance to reductions in cycle length) increased by 3.6 +/- 3.7% (p = NS). Whereas the positive inotropic effects of milrinone were not significantly attenuated during FP, they were abolished and possibly reversed at short cycle lengths on MR curve construction (6.8 +/- 5.9% negative inotropic effect at 60% of resting cycle length; p = NS; p < 0.05 vs. resting cycle length). In conclusion, in patients with well-preserved left ventricular systolic function, the positive inotropic effects of milrinone but not of digoxin are markedly dependent on heart rate. These properties may influence both relative safety and efficacy of both agents.

Early Treatment with Verapamil or Diltiazem in Patients with Acute Myocardial Infarction: Safety and Possible Beneficial Effects

While dihydropyridine calcium antagonists may be harmful in the immediate peri-infarction period, the effect of verapamil or diltiazem in these circumstances in uncertain. We utilized the GUSTO-1 formula to calculate the predicted 30-day mortality risk in a cohort of 352 patients with acute myocardial infarction presenting <6 hours after onset of symptoms, with ECG changes consistent with eligibility for thrombolysis. All patients were treated with an intravenous bolus dose of verapamil followed by oral verapamil (240–360mg/day) or diltiazem (180–360mg/day), in the absence of specific contraindications. Predicted 30-day mortality risk was then compared with the actual 30-day mortality rate of the cohort.The actual 30-day mortality of the cohort was 3.7% (95%CI:2.0,6.3); this was significantly lower than that predicted by the GUSTO-1 formula (7%). A similarly significantly lower mortality (7.5% vs 19.3%) was observed in a “high risk” subset of patients. Of the 13 patients who died, only 4 developed cardiogenic shock.It is concluded that verapamil and diltiazem can be administered safely in a selected patients with evolving acute transmural myocardial infarction. While the current data suggest that this form of treatment may be beneficial, definitive conclusions in this regard should await further randomized studies.

The Prevalence of ST-Segment Depression on Ambulatory Electrocardiographic Monitoring During Daily Life in High-Risk Asymptomatic Police Officers

Background: In individuals with no known ischaemic heart disease, the prevalence and significance of ST-segment depression on ambulatory electrocardiographic monitoring is unclear. We therefore determined the prevalence of ST-segment depression among middle-aged male police officers, an occupational group in whom an increased risk of ischaemic heart disease has been reported, who also had multiple individual coronary risk factors but no known ischaemic heart disease. Methods: Full-time male police officers aged 45 years or more with at least two coronary risk factors but no known ischaemic heart disease performed a 24 h ambulatory electrocardiographic monitor, timed to include a shift of work. The number and duration of episodes of ST-segment depression were determined. In those in whom ST-segment depression was detected, exercise thallium scintigraphy and repeat 24 h ambulatory electrocardiographic monitoring were performed. Results: The prevalence of ST-segment depression on 24 h ambulatory electrocardiographic monitoring, including an 8h period of normal work, was 3.4% (95% confidence interval 1.3–8.3%). Exercise thallium scintigraphy was carried out in those in whom ST-segment depression had been detected. Despite two participants developing ST-segment depression during exercise, no evidence of myocardial ischaemia was observed on the perfusion scan. Therefore, the prevalence of ST-segment depression on ambulatory electrocardiographic monitoring in this asymptomatic but high-risk population was low and, when it did occur, no exercise-induced myocardial ischaemia was observed. Conclusion: These results suggest that ST-segment depression on ambulatory electrocardiographic monitoring in asymptomatic subjects may not represent myocardial ischaemia. The use of this parameter to screen asymptomatic populations for ischaemic heart disease is therefore highly questionable.