Michael Stoller

The human coronary collateral circulation: development and clinical importance

Coronary collaterals are an alternative source of blood supply to myocardium jeopardized by ischaemia. In comparison with other species, the human coronary collateral circulation is very well developed. Among individuals without coronary artery disease (CAD), there are preformed collateral arteries preventing myocardial ischaemia during a brief vascular occlusion in 20-25%. Determinants of such anastomoses are low heart rate and the absence of systemic arterial hypertension. In patients with CAD, collateral arteries preventing myocardial ischaemia during a brief occlusion are present in every third individual. Collateral flow sufficient to prevent myocardial ischaemia during coronary occlusion amounts to one-fifth to one-fourth the normal flow through the open vessel. Myocardial infarct size, the most important prognostic determinant after such an event, is the product of coronary artery occlusion time, area at risk for infarction, and the inverse of collateral supply. Well-developed coronary collateral arteries in patients with CAD mitigate myocardial infarcts and improve survival. Approximately one-fifth of patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting. Therapeutic promotion of collateral growth is a valuable treatment strategy in those patients. It should aim at growth of large conductive collateral arteries (arteriogenesis). Potential arteriogenic approaches include the treatment with granulocyte colony-stimulating factor, physical exercise training, and external counterpulsation.

The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease

Objective To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD). Methods This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. Results During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by –8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to −0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113). Conclusions Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD. ClinicalTrials.gov Identifier: NCT01039389.

Direct quantitative assessment of the peripheral artery collateral circulation in patients undergoing angiography.

Background— Despite the fact that numerous studies have pursued the strategy of improving collateral function in patients with peripheral artery disease, there is currently no method available to quantify collateral arterial function of the lower limb. Methods and Results— Pressure-derived collateral flow index (CFIp, calculated as (occlusive pressure−central venous pressure)/(aortic pressure−central venous pressure); pressure values in mm Hg) of the left superficial femoral artery was obtained in patients undergoing elective coronary angiography using a combined pressure/Doppler wire (n=30). Distal occlusive pressure and toe oxygen saturation (SaO2) were measured for 5 minutes under resting conditions, followed by an exercise protocol (repetitive plantar-flexion movements in supine position; n=28). In all patients, balloon occlusion of the superficial femoral artery over 5 minutes was painless under resting conditions. CFIp increased during the first 3 minutes from 0.451±0.168 to 0.551±0.172 (P=0.0003), whereas SaO2 decreased from 98±2% to 93±7% (P=0.004). Maximal changes of SaO2 were inversely related to maximal CFIp (r2=0.33, P=0.003). During exercise, CFIp declined within 1 minute from 0.560±0.178 to 0.393±0.168 (P<0.0001) and reached its minimum after 2 minutes of exercise (0.347±0.176), whereas SaO2 declined to a minimum of 86±6% (P=0.002). Twenty-five patients (89%) experienced pain or cramps/tired muscles, whereas 3 (11%) remained symptom-free for an occlusion time of 10 minutes. CFIp values were positively related to the pain-free time span (r2=0.50, P=0.002). Conclusions— Quantitatively assessed collateral arterial function at rest determined in the nonstenotic superficial femoral artery is sufficient to prevent ischemic symptoms during a total occlusion of 5 minutes. During exercise, there is a decline in CFIp that indicates a supply-demand mismatch via collaterals or, alternatively, a steal phenomenon. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01742455.

Prognostic relevance of coronary collateral function: confounded or causal relationship?

Objective To expand the limited information on the prognostic impact of quantitatively obtained collateral function in patients with coronary artery disease (CAD) and to estimate causality of such a relation. Design Prospective cohort study with long-term observation of clinical outcome. Setting University Hospital. Patients One thousand one hundred and eighty-one patients with chronic stable CAD undergoing 1771 quantitative, coronary pressure-derived collateral flow index measurements, as obtained during a 1-min coronary balloon occlusion (CFI is the ratio between mean distal coronary occlusive pressure and mean aortic pressure both subtracted by central venous pressure). Subgroup of 152 patients included in randomised trials on the longitudinal effect of different arteriogenic protocols on CFI. Interventions Collection of long-term follow-up information on clinical outcome. Main outcome measures All-cause mortality and major adverse cardiac events. Results Cumulative 15-year survival rate was 48% in patients with CFI<0.25 and 65% in the group with CFI≥0.25 (p=0.0057). Cumulative 10-year survival rate was 75% in patients without arteriogenic therapy and 88% (p=0.0482) in the group with arteriogenic therapy and showing a significant increase in CFI at follow-up. By proportional hazard analysis, the following variables predicted increased all-cause mortality: age, low CFI, left ventricular end-diastolic pressure and number of vessels with CAD. Conclusions A well-functioning coronary collateral circulation independently predicts lowered mortality in patients with chronic CAD. This relation appears to be causal, because augmented collateral function by arteriogenic therapy is associated with prolonged survival.

Function of Natural Internal Mammary–to–Coronary Artery Bypasses and Its Effect on Myocardial Ischemia

Background— The function of naturally existing internal mammary (IMA)–to–coronary artery bypasses and their quantitative effect on myocardial ischemia are unknown. Methods and Results— The primary end point of this study was collateral flow index (CFI) obtained during two 1-minute coronary artery balloon occlusions, the first with and the second without simultaneous distal IMA occlusion. The secondary study end point was the quantitatively determined intracoronary ECG ST-segment elevation. CFI is the ratio of simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. A total of 180 pairs of CFI measurements were performed among 120 patients. With and without IMA occlusion, CFI was 0.110±0.074 and 0.096±0.072, respectively (P<0.0001). The difference of CFI obtained in the presence minus CFI obtained in the absence of IMA occlusion was highest and most consistently positive during left IMA with left anterior descending artery occlusion and during right IMA with right coronary artery occlusion (ipsilateral occlusions): 0.033±0.044 and 0.025±0.027, respectively. This CFI difference was absent during right IMA with left anterior descending artery occlusion and during left IMA with right coronary artery occlusion (contralateral occlusions): −0.007±0.034 and 0.001±0.023, respectively (P=0.0002 versus ipsilateral occlusions). The respective CFI differences during either IMA with left circumflex artery occlusion were inconsistently positive. Intracoronary ECG ST-segment elevations were significantly reduced during ipsilateral IMA occlusions but not during contralateral or left circumflex artery occlusions. Conclusion— There is a functional, ischemia-reducing extracardiac coronary artery supply via ipsilateral but not via contralateral natural IMA bypasses. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCTO1676207.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function

Objective This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. Design Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. Setting University Hospital. Patients 35 patients with chronic stable coronary artery disease. Intervention 2-min iCSO. Main outcome measures Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. Results I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r2=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05–0.20, whereas in the low and high CFI range the effect of iCSO was absent. Conclusions ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place. ClinicalTrials.gov Identifier NCT01625832.

Pathophysiology of Coronary Collaterals

While the existence of structural adaptation of coronary anastomoses is undisputed, the potential of coronary collaterals to be capable of functional adaptation has been questioned. For many years, collateral vessels were thought to be rigid tubes allowing only limited blood flow governed by the pressure gradient across them. This concept was consistent with the notion that although collaterals could provide adequate blood flow to maintain resting levels, they would be unable to increase blood flow sufficiently in situations of increased myocardial oxygen demand. However, more recent studies have demonstrated the capability of the collateral circulation to deliver sufficient blood flow even during exertion or pharmacologic stress. Moreover, it has been shown that increases in collateral flow could be attributed directly to collateral vasomotion. This review summarizes the pathophysiology of the coronary collateral circulation, ie the functional adapation of coronary collaterals to acute alterations in the coronary circulation.

Electrocardiographic ST-segment monitoring during controlled occlusion of coronary arteries ☆ ☆☆

BACKGROUND Ischemia monitoring cannot always be performed by 12-lead ECG. Hence, the individual performance of the ECG leads is crucial. No experimental data on the ECGs specificity for transient ischemia exist. METHODS In 45 patients a 19-lead ECG was registered during a 1-minute balloon occlusion of a coronary artery (left anterior descending artery [LAD], right coronary artery [RCA] or left circumflex artery [LCX]). ST-segment shifts and sensitivity/specificity of the leads were measured. RESULTS During LAD occlusion, V3 showed maximal ST-segment elevation (0.26mV [IQR 0.16-0.33mV], p=0.001) and sensitivity/specificity (88% and 80%). During RCA occlusion, III showed maximal ST-elevation (0.2mV [IQR 0.09-0.26mV], p=0.004), aVF had the best sensitivity/specificity (85% and 68%). During LCX occlusion, V6 showed maximal ST-segment elevation (0.04mV [IQR 0.02-0.14mV], p=0.005), and sensitivity/specificity was (31%/92%) but could be improved (63%/72%) using an optimized cut-off for ischemia. CONCLUSION V3, aVF and V6 show the best performance to detect transient ischemia.

Effect of Permanent Right Internal Mammary Artery Closure on Coronary Collateral Function and Myocardial Ischemia

Background— The objective of this study is to test the effect of permanent right internal mammary artery device closure on coronary collateral function and myocardial ischemia. Methods and Results— This was a prospective, open-label clinical trial in 50 patients with coronary artery disease. The primary study end point was coronary collateral flow index as obtained during a 1-minute proximal right coronary artery (RCA) and left coronary artery balloon occlusion at baseline before and at follow-up examination 6 weeks after distal right internal mammary artery device closure. Collateral flow index is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure, both subtracted by central venous pressure. Secondary study end points were fractional flow reserve during vessel patency, the quantitative intracoronary ECG ST-segment elevation, and angina pectoris during the same 1-minute coronary occlusion. Collateral flow index in the untreated RCA and left coronary artery changed from 0.071±0.082 at baseline to 0.132±0.117 (P<0.0001) at follow-up examination and from 0.106±0.092 to 0.081±0.079 (P=0.29), respectively. RCA fractional flow reserve increased significantly (P=0.0029) from baseline to follow-up examination, despite deferral of coronary intervention in all patients. There was a decrease in intracoronary ECG ST-elevation during RCA occlusion from baseline to follow-up examination (P=0.0015); it did not change in the left coronary artery. Angina pectoris during RCA occlusion tended to occur in fewer patients at follow-up versus baseline examination (P=0.06). Conclusions— Permanent right internal mammary artery device closure seems to augment extracardiac ipsilateral coronary supply to the effect of reducing ischemia in the dependent myocardial region. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02475408.

Reactive myocardial hyperaemia for functional assessment of coronary stenosis severity

AIMS Our aim was to compare functional assessment of coronary stenosis severity by fractional flow reserve (FFR) measurement, as induced by systemic adenosine, and by regional reactive myocardial hyperaemia. METHODS AND RESULTS The primary study endpoints were coronary pressure-derived FFR values in response to intravenous adenosine infusion (140 µg/min/kg), and to a one-minute proximal coronary artery balloon occlusion (reactive hyperaemia) for the same stenosis of interest. The secondary study endpoint was coronary collateral flow index (CFI) during the same occlusion. CFI is the ratio between simultaneous mean arterial occlusive pressure and mean aortic pressure, both subtracted by central venous pressure. As a reference, coronary artery stenoses were assessed quantitatively as percent diameter reduction (%S). One hundred and twenty-five patients with coronary artery disease were included in the study. There was an inverse association between quantitatively determined structural stenosis severity and adenosine-induced FFR as well as post-ischaemic reactive hyperaemia FFR (%S=1-0.004 FFR; both at p<0.0001). Sensitivity and specificity for detecting a stenosis of ≥50% at an FFR threshold of 0.80 was 0.891 and 0.605 (adenosine-induced FFR), and 0.817 and 0.684 (post-ischaemic FFR), respectively. The FFR difference for a given stenosis (post-ischaemic minus adenosine-induced FFR) was directly related to CFI. CONCLUSIONS Regional reactive hyperaemia FFR is not inferior to systemic adenosine FFR in detecting structurally relevant coronary stenosis. Depending on the absence or presence of functional collaterals, systemic adenosine-induced FFR may underestimate or overestimate stenosis severity, respectively.