Physical coronary arteriogenesis of cardiac and extracardiac origin

Coronary collaterals are pre-formed connections that provide an alternative route when regular antegrade blood flow to the heart muscle is compromised. In response to a coronary obstruction, coronary collaterals undergo gradual enlargement, variably compensating for impaired antegrade blood flow. As natural bypasses, sufficiently large coronary collaterals can preserve myocardial perfusion and viability in the acute and chronic phases of coronary artery disease. In chronic stable coronary artery disease, medical therapy is complemented by established interventional therapies such as percutaneous coronary intervention and surgical coronary artery bypass grafting. However, new therapeutic options are needed for patients who are not candidates for conventional revascularization due to severe and/or diffuse obstructive coronary artery disease. Promotion of coronary collaterals represents such an alternative treatment option. However, while a multitude of interventions has been shown to be effective in collateral growth promotion, the effect of current interventions is only temporary and therefore recurrent application of the arteriogenic stimulus is necessary to sustain the level of collaterals. Historically, attempts to induce durable improvement of coronary collateral flow have already been made. Experimental and clinical studies examined the efficacy of distal ligation of the internal mammary artery (IMA) to augment blood flow to the coronary circulation. The basis of these studies was the clinical structural and experimental functional documentation of pre-formed connections between the internal mammary arteries and the coronary circulation - extracardiac collaterals. With the advent of coronary artery bypass grafting, the procedure was, however, abandoned. Notably, the clinical studies were based on crude outcome measures, such as symptomatic improvement. The function and in-vivo prevalence of internal mammary-to-coronary-anastomoses was therefore investigated in a clinical study (Project I) for the first time. 120 patients referred for elective coronary angiography for suspected or established coronary artery disease (CAD) underwent 180 pairs of coronary artery balloon occlusions, the first with and the second without simultaneous distal IMA occlusion (thought to augment flow via IMA-to-coronary connections). Collateral function was assessed during coronary balloon occlusion by collateral flow index (CFI), which is the ratio of coronary occlusive to aortic (effective perfusing) pressure, accounting for the back pressure (central venous pressure). Regional myocardial ischemia was assessed by the intracoronary electrocardiogram (ECG). With simultaneous distal IMA occlusion CFI was significantly higher during left IMA with left anterior descending coronary artery (LAD) occlusion and right IMA with right coronary artery (RCA) occlusion than during LAD or RCA occlusionalone. Conversely, during contralateral IMA occlusion, ie RCA with left IMA or LAD or left circumflex coronary artery (LCX) with right IMA occlusion, CFI was not different. Concordantly, myocardial ischemia by intracoronary ECG was lower during LAD or RCA occlusion with simultaneous ipsilateral IMA occlusion nd was not different during contralateral IMA occlusion or with LCX occlusion. In conclusion, it could be demonstrated that there was functional, ischemia-reducing collateral supply from the ipsilateral IMA to the right coronary and the left anterior descending coronary artery. The effect of permanent distal right IMA on coronary collateral function was investigated or the first time in an open-label clinical trial (Project II). 50 patients with stable CAD underwent distal right IMA closure at baseline and determination of right and left coronary function (LAD or LCX) by CFI at baseline and at follow-up 6 weeks after right IMA device closure. CFI in the untreated RCA increased significantly from baseline to follow-up, while CFI in the untreated left coronary remained unchanged. Concordantly, regional myocardial ischemia determined by intracoronary ECG was reduced during a 1-minute coronary balloon occlusion in the RCA but not in the left coronary. In conclusion, permanent distal right IMA closure in this non-randomized study appeared to augment extracardiac right coronary collateral supply. With acute myocardial ischemia, the mainstay of therapy lies in the antegrade technique of prompt percutaneous revascularization. However, a reopened epicardial conduit artery does not guarantee reperfusion of myocardial tissue, which can be impaired by microvascular dysfunction. In this situation of a failed antegrade approach, retrograde treatment approach has been proposed by an intervention in the coronary venous system - intermittent coronary sinus occlusion (CSO). Although the ischemia-relieving effect of CSO is thought to depend on coronary collaterals, its role of coronary collaterals has so far not been clearly defined in humans. The role of coronary collaterals in the anti-ischemic effect of CSO was therefore investigated in a clinical study (Project III) and in a computer simulation (Project IV). In the clinical study, 35 patients with stable coronary artery disease underwent two 2-minute balloon occlusions of a major coronary artery to induce controlled ischemia. CSO was performed randomized to the first or second coronary balloon occlusion.Collateral function was assessed by CFI and regional myocardial ischemia was assessed by the ST-segment shift in the intracoronary ECG. Intermittent coronary sinus occlusion was shown to reduce myocardial ischemia depending on the extent of collateral function. With minimal collateral function, no ischemia-reducing effect of CSO was demonstrated. An anti-ischemic effect of CSO was seen with intermediate collateral function. High collateral function prevented myocardial ischemia in the first place and therefore, no additional effect of CSO was demonstrated. The computer simulation (Project IV) consisted of a lumped-parameter model of a two-branch left coronary system circuit with arterial, capillary and venous compartments. As a key point, arterial collateral connections were an integral part of the model, in contrast to prior computer models. Importantly, the salient features of coronary pressure and flow during non-ischemic and ischemic conditions, as well as during CSO could be reproduced. In particular, the proposed main mechanism of CSO - retrograde flow from the venous to the venular and capillary compartment was reproduced by the model. As a key point, the model predicted retrograde flow to be dependent on the extent of collateral blood flow and contractility. With minimal collateral function, retrograde flow to an ischemic region was low, while it progressively increased with higher collateral function. Accounting for the combination of reduced contractility during ischemia and the level of collateral function, the effect on retrograde flow was much increased. Retrograde flow was predicted to be very low at zero to minimal collateral function and concomitantly severely reduced contractility. Conversely, retrograde flow increased steeply with increasing collateral function and more preserved contractility. In essence, the mathematical model provided a reasonable explanation for the findings from the clinical study (Project III) and could, for the first time, provide an explanation for the role of collaterals in the anti-ischemic effect of CSO