Clinical Features

Although the angiographic features of the CSFP are of interest, it is the associated clinical features that are of key importance and warrant the condition being considered as a new coronary microvascular disorder. The clinical presentation prompting coronary angiography, the subsequent clinical progress, and markers of myocardial ischemia in patients with the CSFP are discussed next.

Initial Presentation

Syndrome X is clinically characterized as exertional angina that precipitates referral to a physician. An exercise

*significant difference compared with control group (p < 0.05) #significant difference compared with initial angiogram (p < 0.05)

Figure 1 Serial angiographic studies in patients with CSFP. Number of cardiac cycles to opacify the LAD, Cx, and RCA in 12 patients with the CSFP who underwent a repeat angiogram (median interval = 7 months) and 47 control patients who did not exhibit this phenomenon. Although there was a trend toward improvement in the repeat study (significant for the LAD only), both studies showed delayed opacification as compared with controls.

stress test is then usually performed and angiography undertaken that reveals no obstructive epicardial coronary artery disease. Patients with CSFP have a different presentation scenario. These patients usually present with an acute coronary syndrome to the emergency department and are admitted to the coronary care unit for further observation. When the case is reviewed by a cardiologist, angiography is undertaken because of the apparent unstable nature of the clinical syndrome. Hence, these patients are clinically (and angio-graphically) different from patients with syndrome X.

The data for the preceding clinical description is derived from observational and case-control studies. In an observational study of 65 patients with CSFP, review of their clinical records revealed that all except one patient underwent coronary angiography for the investigation of chest pain. The exceptional patient was diabetic and underwent angiog-raphy following a presentation with ventricular tachycardia requiring electrical cardioversion. Further evaluation of the remaining patients revealed that 75 percent underwent angiography following an acute coronary syndrome presentation, with most fulfilling Braunwald Class IIIB criteria.

The findings of this study prompted a more detailed case-control study to further characterize the clinical features associated with this angiographic phenomenon. Forty-seven consecutive patients with the CSFP who had smooth epicar-dial vessels on angiography were compared with 47 patients who also had smooth epicardial vessels on angiography but

Table I Clinical Characteristics of the CSFP.a

Characteristic Control Coronary

Coronary risk factor

Characteristic Control Coronary

Coronary risk factor

Age

55 ± 11

years

50 ± 10

years4

Males

21

45%

32

68%b

Current smoker

4

9%

15

32%b

Hypertension

22

47%

18

38%

Diabetes

3

6%

5

11%

Positive family history

19

41%

19

41%

Hypercholesterolemia

8

20%

15

37%

Chest pain features

Recent onset (<1 month)

15

32%

29

62%b

Predominantly rest pain

28

59%

40

85%b

Pain prompting urgent admission

10

21%

35

74%b

CCU admission

8

17%

31

66%b

Urgent angiography

10

21%

33

70%b

Acute myocardial infarction

0

0%

3

6%

ECG findings

ST/T wave changes on resting ECG

8

17%

17

36%b

Positive stress test'

11

39%

6

19%

a Clinical characteristics of patients with chest pain, smooth epicardial vessels on angiography, and absence (control) or presence (cases) of CSFP. (From Beltrame et al., 2002, Cardiology 97, 197-202, with permission.)

b Significant difference between controls and coronary slow flow patients (chi-square or unpaired f-test, p < 0.05).

c Data available for each 47 control and coronary slow flow patients except for hypercholesterolemia (39 versus 41, respectively) and stress test (28 versus 32, respectively).

a Clinical characteristics of patients with chest pain, smooth epicardial vessels on angiography, and absence (control) or presence (cases) of CSFP. (From Beltrame et al., 2002, Cardiology 97, 197-202, with permission.)

b Significant difference between controls and coronary slow flow patients (chi-square or unpaired f-test, p < 0.05).

c Data available for each 47 control and coronary slow flow patients except for hypercholesterolemia (39 versus 41, respectively) and stress test (28 versus 32, respectively).

who did not have TIMI-2 flow in any vessels. The comparative findings are summarized in Table I. Compared with controls, the patients with CSFP were more often younger, male, and smokers and presented with recent onset, rest pain prompting admission to the coronary care unit and thereafter angiography. Of note, 6 percent of the CSFP patients had elevated cardiac markers consistent with myocardial infarction. However, only 19 percent had a subsequent positive stress test and, hence, the majority would not fulfill standard criteria for syndrome X.

These findings have been supported by case reports and small observational studies, in particular in the TIMI-IIIA study where angiography was undertaken in 391 patients presenting with unstable angina/non-ST elevation myocar-dial infarction. Of these patients, 14 percent had no significant epicardial coronary artery disease with one-third exhibiting the CSFP [3].

Clinical Progress

Follow-up of 64 patients with CSFP during a median period of 21 months (range 1 to 126 months) found that 84 percent experienced recurrent chest pain with 33 percent representing to the emergency department with severe rest pain and 19 percent readmitted to the coronary care unit for intravenous nitrate therapy. Although many studies of

*significant difference compared with control group (p < 0.05) #significant difference compared with initial angiogram (p < 0.05)

patients with chest pain and normal angiography demonstrate recurrent chest pain, those with the CSFP appear to be particularly susceptible. Voelker and colleagues followed 88 patients with angina and normal angiography for a mean period of 9 years (range: 6 to 11 years) and examined factors that were predictive for ongoing chest pain. The best predictor of continuing chest pain at follow-up was the demonstration of CSFP on the initial angiogram.

Although CSFP is associated with recurrent chest pain and frequent hospital readmissions, the risk of a subsequent cardiac event is low. None of the 64 patients just described endured a subsequent documented myocardial infarct, although one patient experienced a fatal cardiac arrest at home following an episode of chest pain. This latter finding is of concern since ventricular tachycardia has been documented in a number of patients with CSFP. Furthermore a recent investigation has demonstrated a higher corrected QT dispersion among patients with CSFP, suggesting a predisposition to ventricular arrhythmias [4]. Further investigation is required into the relationship between CSFP and ventricular arrhythmias.

Myocardial Ischemia in the Coronary Slow Flow Phenomenon

The presence of myocardial ischemia in patients with syndrome X is controversial with studies demonstrating disparate results. The same appears to be so for CSFP, with some investigators finding a poor association with ischemic markers while others claim that the delayed contrast opaci-fication may be considered "a marker for ischemia."

Clinical Markers of Ischemia

Table II summarizes the findings from exercise stress testing and myocardial perfusion scintigraphy in patients with the CSFP. In both investigations there is considerable heterogeneity in the findings. This may be attributable to (a) different definitions for the CSFP, (b) different exclusion criteria, and (c) variable definitions as to what constitutes a positive result. In relation to exercise stress testing, significant ST depression has been reported between 0-71 percent amongst the various studies. Five of the 7 studies (Table II) report positive stress test findings in less than 20 percent of patients suggesting that there is seldom evidence of ischemia on standard exercise stress testing in the CSFP. Myocardial perfusion scintigraphic studies are more often positive for ischemia with approximately a third demonstrating a reversible perfusion defect (Table II).

Biochemical Markers of Ischemia

Myocardial lactate production is the gold standard marker of ischemia, and two studies have evaluated its presence in the CSFP. Yaymaci and others undertook rapid atrial pacing in 34 patients with the CSFP and demonstrated ischemic lactate production in only six patients (18%). In an independent study by Beltrame and colleagues, 12 patients with documented CSFP failed to demonstrate net lactate production during rapid atrial pacing, cold pressor stimulation, or acetylcholine provocation despite many patients experiencing chest pain. Thus, consistent with the clinical markers, most patients with CSFP do not have objective evidence of ischemia on metabolic criteria. Whether this is due to an absence of myocardial ischemia or inability to detect it is open to speculation.

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