Richard L. Kirkeeide

Can lifestyle changes reverse coronary heart disease?: The Lifestyle Heart Trial

In a prospective, randomised, controlled trial to determine whether comprehensive lifestyle changes affect coronary atherosclerosis after 1 year, 28 patients were assigned to an experimental group (low-fat vegetarian diet, stopping smoking, stress management training, and moderate exercise) and 20 to a usual-care control group. 195 coronary artery lesions were analysed by quantitative coronary angiography. The average percentage diameter stenosis regressed from 40.0 (SD 16.9)% to 37.8 (16.5)% in the experimental group yet progressed from 42.7 (15.5)% to 46.1 (18.5)% in the control group. When only lesions greater than 50% stenosed were analysed, the average percentage diameter stenosis regressed from 61.1 (8.8)% to 55.8 (11.0)% in the experimental group and progressed from 61.7 (9.5)% to 64.4 (16.3)% in the control group. Overall, 82% of experimental-group patients had an average change towards regression. Comprehensive lifestyle changes may be able to bring about regression of even severe coronary atherosclerosis after only 1 year, without use of lipid-lowering drugs.

Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty.

Background. Severity of coronary artery stenosis has been defined in terms of geometric dimensions, pressure gradient‐flow relations, resistance to flow and coronary flow reserve, or maximum flow capacity after maximum arteriolar vasodilation. A direct relation between coronary pressure and flow, however, may only be presumed if the resistances in the coronary circulation are constant (and minimal) as theoretically is the case during maximum arteriolar vasodilation. In that case, pressure measurements theoretically can be used to predict maximum flow and assess functional stenosis severity. Methods and Results. A theoretical model was developed for the different components of the coronary circulation, and a set of equations was derived by which the relative maximum flow or fractional flow reserve in both the stenotic epicardial artery and the myocardial vascular bed and the proportional contribution of coronary arterial and collateral flow to myocardial blood flow are calculated from measurements of arterial, distal coronary, and central venous pressures during maximum arteriolar vasodilation. To test this model, five dogs were acutely instrumented with an epicardial, coronary Doppler flow velocity transducer. Distal coronary pressures were measured by an ultrathin pressure‐monitoring guide wire (0.015 in.) with minimal influence on transstenotic pressure gradient. Fractional flow reserve was calculated from the pressure measurements and compared with relative maximum coronary artery flow measured directly by the Doppler flowmeter at three different levels of arterial pressure for each of 12 different severities of stenosis at each pressure level. Relative maximum blood flow through the stenotic artery (Qs) measured directly by the Doppler flowmeter showed an excellent correlation with the pressure‐derived values of Qs (r=0.98±0.01, intercept=0.02±0.03, slope=0.98±0.04), of the relative maximum myocardial flow (r=0.98±0.02, intercept=0.26±0.07, slope=0.73±0.08), and of the collateral blood flow (r=0.96±0.04, intercept=0.24±0.07, slope=‐0.24±0.06). Moreover, the theoretically predicted constant relation between mean arterial pressure and coronary wedge pressure, both corrected for venous pressure, was confirmed experimentally (r=0.97±0.03, intercept=9.5±13.3, slope=4.4±1.2). Conclusions. These results provide the experimental basis for determining relative maximum flow or fractional flow reserve of both the epicardial coronary artery and the myocardium, including collateral flow, from pressure measurements during maximum arteriolar vasodilation. With a suitable guide wire for reliably measuring distal coronary pressure clinically, this method may have potential applications during percutaneous transluminal coronary angioplasty for assessing changes in the functional severity of coronary artery stenoses and for estimating collateral flow achievable during occlusion of the coronary artery. (Circulation 1993;86:1354‐1367)

Coronary flow reserve as a physiologic measure of stenosis severity

PART I: Coronary flow reserve indicates functional stenosis severity, but may be altered by physiologic conditions unrelated to stenosis geometry. To assess the effects of changing physiologic conditions on coronary flow reserve, aortic pressure and heart rate-blood pressure (rate-pressure) product were altered by phenylephrine and nitroprusside in 11 dogs. There was a total of 366 measurements, 26 without and 340 with acute stenoses of the left circumflex artery by a calibrated stenoser, providing percent area stenosis with flow reserve measured by flow meter after the administration of intracoronary adenosine. Absolute coronary flow reserve (maximal flow/rest flow) with no stenosis was 5.9 +/- 1.5 (1 SD) at control study, 7.0 +/- 2.2 after phenylephrine and 4.6 +/- 2.0 after nitroprusside, ranging from 2.0 to 12.1 depending on aortic pressure and rate-pressure product. However, relative coronary flow reserve (maximal flow with stenosis/normal maximal flow without stenosis) was independent of aortic pressure and rate-pressure product. Over the range of aortic pressures and rate-pressure products, the size of 1 SD expressed as a percent of mean absolute coronary flow reserve was +/- 43% without stenosis, and for each category of stenosis severity from 0 to 100% narrowing, it averaged +/- 45% compared with +/- 17% for relative coronary flow reserve. For example, for a 65% stenosis, absolute flow reserve was 5.2 +/- 1.7 (+/- 33% variation), whereas relative flow reserve was 0.9 +/- 0.09 (+/- 10% variation), where 1.0 is normal. Therefore, absolute coronary flow reserve by flow meter was highly variable for fixed stenoses depending on aortic pressure and rate-pressure product, whereas relative flow reserve more accurately and specifically described stenosis severity independent of physiologic conditions. Together, absolute and relative coronary flow reserve provide a more complete description of physiologic stenosis severity than either does alone. PART II: Coronary flow reserve directly measured by a flow meter is altered not only by stenosis, but also by physiologic variables. Stenosis flow reserve is derived from length, percent stenosis, absolute diameters and shape by quantitative coronary arteriography using standardized physiologic conditions. To study the relative merits of absolute coronary flow reserve measured by flow meter and stenosis flow reserve determined by quantitative coronary arteriography for assessing stenosis severity, aortic pressure and rate-pressure product were altered by phenylephrine and nitroprusside in 11 dogs, with 366 stenoses of the left circumflex artery by a calibrated stenoser providing percent area stenosis as described in Part I.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessment of coronary artery disease severity by positron emission tomography. Comparison with quantitative arteriography in 193 patients.

To assess the accuracy of positron emission tomography (PET) for evaluation of coronary artery disease (CAD), cardiac PET perfusion images were obtained at rest and with dipyridamole-handgrip stress in 193 patients undergoing coronary arteriography. PET images were reviewed by two independent readers blinded to clinical data. Subjective defect severity scores were assigned to each myocardial region on a 0 (normal) to 5 (severe) scale. Results were compared with arteriographic stenosis severity expressed as stenosis flow reserve (SFR), with continuous values ranging from 0 (total occlusion) to 5 (normal), calculated from quantitative arteriographic dimensions using automated detection of the vessel borders. There were 115 patients with significant CAD (SFR less than 3), 37 patients with mild CAD (3 less than or equal to SFR less than 4), and 41 patients with essentially normal coronaries (SFR greater than or equal to 4). With increasingly severe impairment of stenosis flow reserve, subjective PET defect severity increased. Despite wide scatter, a PET score of 2 or more was highly predictive of significant flow reserve impairment (SFR less than 3). For each patient, the score of the most severe PET defect correlated with the SFR of that patients most severe stenosis (rs = 0.77 +/- 0.06). For each of 243 stenoses, PET defect score correlated with the SFR of the corresponding artery (rs = 0.63 +/- 0.08). PET defect location closely matched the region supplied by the diseased artery, and readers agreed whether the most severe PET defect was less than or more than 2 for 89% of patients.

Assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VII. Validation of coronary flow reserve as a single integrated functional measure of stenosis severity reflecting all its geometric dimensions.

The purpose of this study was to determine whether coronary flow reserve measured by flow meter correlated with or could be predicted by quantitative coronary arteriography accounting for all dimensions of a coronary artery stenosis. Five dogs were chronically instrumented with an inflatable stenosing cuff, a Doppler flow velocity meter, proximal and distal coronary artery catheters and aortic and pulmonary artery catheters. For 18 stenoses over a wide range of severity, orthogonal coronary arteriograms were analyzed quantitatively at rest to predict coronary flow reserve based on fluid dynamic equations. The X-ray-predicted coronary flow reserve correlated closely with that measured directly by implanted flowmeter with an r value of 0.91, a regression equation of X-ray-predicted coronary flow reserve = 1.08 (measured coronary flow reserve) - 0.08 and 95% confidence limits (+/- 2 SD) of 0.66. Neither percent diameter narrowing alone nor absolute stenosis diameter alone correlated well with measured coronary flow reserve. Results confirm that coronary flow reserve is a single integrated measure of coronary stenosis severity reflecting all its geometric dimensions. Flow reserve correlated closely with and was accurately predicted by quantitative coronary arteriography taking into account all stenosis dimensions. This study establishes the theoretical and experimental basis for using coronary flow reserve as a single, integrated functional measure of stenosis severity reflecting all of its geometric characteristics.

Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced Rubidium-82

The purpose of this study was to determine the clinical feasibility of diagnosing significant coronary artery disease by positron imaging of myocardial perfusion without a cyclotron, using generator-produced rubidium-82 (82Rb). Fifty patients underwent positron emission tomography of the entire heart using a multislice positron camera and intravenous 82Rb or nitrogen-13 ammonia (13NH3) before and after intravenous dipyridamole combined with handgrip stress. Images were read by two observers blinded as to clinical or arteriographic data. Automated quantitative coronary arteriography was obtained for the arteriographic determination of coronary flow reserve, previously demonstrated to be a single integrated measure of stenosis severity accounting for all its geometric dimensions of length, absolute diameter, percent narrowing and asymmetry by quantitative analysis of cine films. Significant coronary artery disease was defined as an arteriographically determined coronary flow reserve of less than 3.0 based on all stenosis dimensions. Any single geometric measure of stenosis severity alone was an inadequate reference standard for comparison with perfusion images. Sensitivity of identifying patients with coronary artery disease having an arteriographically determined coronary flow reserve of less than 3.0 was 95% by positron imaging with a specificity of 100%. The single case that was missed, studied with 13NH3, had a 43% diameter narrowing of a small ramus intermedius off the left coronary artery with no significant narrowing of the major coronary arteries. Positron emission tomography of myocardial perfusion before and after intravenous dipyridamole combined with handgrip stress utilizing generator-produced 82Rb provides sensitive and specific diagnosis of reduced coronary flow reserve due to coronary artery disease in humans.

Is discordance of coronary flow reserve and fractional flow reserve due to methodology or clinically relevant coronary pathophysiology

OBJECTIVES The purpose of this study was to determine whether observed discordance between coronary flow reserve (CFR) and fractional flow reserve (FFR) is due to methodology or reflects basic coronary pathophysiology. BACKGROUND Despite the clinical importance of coronary physiological assessment, relationships between its 2 most common tools, CFR and FFR, remain poorly defined. METHODS The worst CFR and stress relative uptake were recorded from 1,500 sequential cardiac positron emission tomography cases from our center. From the literature, we assembled all combined, invasive CFR-FFR measurements, including a subset before and after angioplasty. Both datasets were compared with a fluid dynamic model of the coronary circulation predicting relationships between CFR and FFR for variable diffuse and focal narrowing. RESULTS A modest but significant linear relationship exists between CFR and FFR both invasively (r = 0.34, p < 0.001) and using positron emission tomography (r = 0.36, p < 0.001). Most clinical patients undergoing CFR or FFR measurements have diffusely reduced CFR consistent with diffuse atherosclerosis or small-vessel disease. The theoretical model predicts linear relationships between CFR and FFR for progressive stenosis with slopes dependent on diffuse narrowing, matching observed data. Reported changes in CFR and FFR with angioplasty agree with model predictions of removing focal stenosis but leaving diffuse disease. Although CFR-FFR concordance is common, discordance is due to dominant or absent diffuse versus focal disease, reflecting basic pathophysiology. CONCLUSIONS CFR is linearly related to FFR for progressive stenosis superimposed on diffuse narrowing. The relative contributions of focal and diffuse disease define the slope and values along the linear CFR and FFR relationship. Discordant CFR and FFR values reflect divergent extremes of focal and diffuse disease, not failure of either tool. With such discordance observed by invasive and noninvasive techniques and also fitting fluid dynamic predictions, it reflects clinically relevant basic coronary pathophysiology, not methodology.

Pressure-Derived Fractional Flow Reserve to Assess Serial Epicardial Stenoses Theoretical Basis and Animal Validation

Background-Fractional flow reserve (FFR) is an index of stenosis severity validated for isolated stenoses. This study develops the theoretical basis and experimentally validates equations for predicting FFR of sequential stenoses separately. Methods and Results-For 2 stenoses in series, equations were derived to predict FFR (FFR(pred)) of each stenosis separately (ie, as if the other one were removed) from arterial pressure (P(a)), pressure between the 2 stenoses (P(m)), distal coronary pressure (P(d)), and coronary occlusive pressure (P(w)). In 5 dogs with 2 stenoses of varying severity in the left circumflex coronary artery, FFR(pred) was compared with FFR(app) (ratio of the pressure just distal to that just proximal to each stenoses) and to FFR(true) (ratio of the pressures distal to proximal to each stenosis but after removal of the other one) in case of fixed distal and varying proximal stenoses (n=15) and in case of fixed proximal and varying distal stenoses (n=20). The overestimation of FFR(true) by FFR(app) was larger than that of FFR(true) by FFR(pred) (0.070+/-0.007 versus 0.029+/-0.004, P<0.01 for fixed distal stenoses, and 0.114+/-0.01 versus 0.036+/-0. 004, P<0.01 for fixed proximal stenoses). This overestimation of FFR(true) by FFR(app) was larger for fixed proximal than for fixed distal stenoses. Conclusions-The interaction between 2 stenoses is such that FFR of each lesion separately cannot be calculated by the equation for isolated stenoses (P(d)/P(a) during hyperemia) applied to each separately but can be predicted by more complete equations taking into account P(a), P(m), P(d), and P(w).

Comparative validation of quantitative coronary angiography systems. Results and implications from a multicenter study using a standardized approach.

BACKGROUND Computerized quantitative coronary angiography (QCA) has fundamentally altered our approach to the assessment of coronary interventional techniques and strategies aimed at the prevention of recurrence and progression of stenosis. It is essential, therefore, that the performance of QCA systems, upon which much of our scientific understanding has become integrally dependent, is evaluated in an objective and uniform manner. METHODS AND RESULTS We validated 10 QCA systems at core laboratories in North America and Europe. Cine films were made of phantom stenoses of known diameter (0.5 to 1.9 mm) under four experimental conditions: in vivo (coronary arteries of pigs) calibrated at the isocenter or by use of the catheter as a scaling device and in vitro with 50% contrast and 100% contrast. The cine films were analyzed by each automated QCA system without observer interaction. Accuracy and precision were taken as the mean and SD of the signed differences between the phantom stenoses, and the measured minimal luminal diameters and the correlation coefficient (r), the SEE, the y intercept, and the slope were derived by their linear regression. Performance of the 10 QCA systems ranged widely: accuracy, +0.07 to +0.31 mm; precision, +/- 0.14 to +/- 0.24 mm; correlation (r), .96 to .89; SEE, +/- 0.11 to +/- 0.16 mm; intercept, +0.08 to +0.31 mm; and slope, 0.86 to 0.64. CONCLUSIONS There is a marked variability in performance between systems when assessed over the range of 0.5 to 1.9 mm. The range of accuracy, intercept, and slope values of this report indicates that absolute measurements of luminal diameter from different multicenter angiographic trials may not be directly comparable and additionally suggests that such absolute measurements may not be directly applicable to clinical practice using an on-line QCA system with a different edge detection algorithm. Power calculations and study design of angiographic trials should be adjusted for the precision of the QCA system used to avoid the risk of failing to detect small differences in patient populations. This study may guide the fine-tuning of algorithms incorporated within each system and facilitate the maintenance of high standards of QCA for scientific studies.

Frequency and Clinical Implications of Fluid Dynamically Significant Diffuse Coronary Artery Disease Manifest as Graded, Longitudinal, Base-to-Apex Myocardial Perfusion Abnormalities by Noninvasive Positron Emission Tomography

BACKGROUND Diffuse coronary atherosclerosis is the substrate for plaque rupture and coronary events. Therefore, in patients with mild arteriographic coronary artery disease without significant segmental dipyridamole-induced myocardial perfusion defects, we tested the hypothesis that fluid dynamically significant diffuse coronary artery narrowing is frequently manifest as a graded, longitudinal, base-to-apex myocardial perfusion abnormality by noninvasive PET. METHODS AND RESULTS In this study, 1001 patients with documented coronary artery disease by coronary arteriography showing any visible coronary artery narrowing underwent rest-dipyridamole PET perfusion imaging. Quantitative severity of dipyridamole-induced, circumscribed, segmental PET perfusion defects was objectively measured by automated software as the minimum quadrant average relative activity indicating localized flow limiting stenoses. Quantitative severity of the graded, longitudinal, base-to-apex myocardial perfusion gradient indicating fluid dynamic effects of diffuse coronary artery narrowing was objectively measured by automated software as the spatial slope of relative activity along the cardiac longitudinal axis. CONCLUSIONS In patients with mild arteriographic disease without statistically significant dipyridamole-induced segmental myocardial perfusion defects caused by flow-limiting stenoses compared with normal control subjects, there was a graded, longitudinal, base-to-apex myocardial perfusion gradient significantly different from normal control subjects (P=0. 001) that was also observed for moderate to severe dipyridamole-induced segmental perfusion defects (P=0.0001), indicating diffuse disease underlying segmental perfusion defects; 43% of patients with or without segmental perfusion defects demonstrated graded, longitudinal, base-to-apex perfusion abnormalities beyond +/-2 SD of normal control subjects, indicating diffuse coronary arterial narrowing by noninvasive PET perfusion imaging.