**2. Clinical perspective**

assessing it has proven to be difficult due to the unclear lines between ischemic regions, normal circulation, and collateral growth. The hypotheses regarding the causative factor(s) for collateral growth are not mutually exclusive as there are likely many mechanisms that are the principal driver, which vary at various points of the process. For example, even if one maintains that ischemia is the initiating mechanism for collateral growth, it is likely that other stimuli continue the growth of the vessel after the ischemic stimulus has waned. To provide perspective for this chapter, we refer to **Figure 1**, which summarizes four factors that exert important effects in this adaptive process. The bulk of this chapter will focus on the collateral growth from a clinical perspective, the role of stem cells, and chemical factors involved in this process. We will not extensively review the role that shear stress in coronary collateral growth as this has been reviewed ample times in the past. We also will not review the genetic aspects because the bulk of this information has been derived from studies of collateral growth in vascular beds other than the heart, e.g., skeletal muscle and brain [7, 8], although there is some preliminary information about genetic links to collateral growth in patients [9]. **Figure 1** also shows the anatomical structure of a collateral; namely, an arterial-arterial anastomosis that connect large coronary perfusion territories. Collateral growth, also known as arteriogenesis, in the heart involves the abluminal expansion of a preexisting arterial-arterial anastomosis [10]. The degree of expansion is profound—the caliber of collateral vessels can increase over an order of magnitude [10]. This degree of expansion would greatly reduce vascular resistance of these vessels, thereby increasing flow in the area of risk. This increase in flow is the reason why the collateral circulation exerts beneficial effects through the reduction in infarct size (following a coronary occlusive event) and reduction in the incidence of sudden cardiac death.

134 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

We also would like to point out an obvious distinction between the growth of collateral vessels (arteriogenesis) and angiogenesis. These processes are often confused as the same, but

 **Figure 1.** An image of the human coronary circulation depicting large collateral vessels that connect perfusion territories

of major arteries and some factors that regulate their development.

Heart disease is extremely prevalent in the United States, where it accounts for every one in four deaths and almost 735,000 Americans suffer a heart attack each year (Centers for Disease Control, USA). However, there are numerous differences between these individuals in terms of response to treatment, future adverse events, and long-term survival rates. One explanation for these differences involves the presence of good collateral growth in certain individuals. A 5-year study called Osaka Acute Coronary Insufficiency Study (OACIS) assessed both acute and long-term survival in patients and came to three important conclusions: (1) patients with a Rentrop collateral score (RCS) of one or two showed the most promising 5-year survival rates, (2) RCS of three was associated with a worse 5-year survival rate, (3) RCS of three was associated with the best survival rates in a specific subgroup of patients with single vessel disease without previous myocardial infarction (MI) [12]. These first two conclusions can be explained due to the fact a higher baseline RCS can be indicative of a worse background of clinical characteristics such as previous MI or angina pectoris resulting in increased mortality rates, whereas an RCS of one or two was developed in the acute setting negating any adverse effects of chronic ischemia [12]. The third conclusion states RCS of three is more beneficial in the setting of single vessel occlusion and without previous MI, which would liken it to individuals who have RCS of one or two, but without any previous adverse events. In this subgroup, patients are having increased collateral flow, but without the chronic angina pectoris or previous MI improving survival rates [12]. This information leads to an important conclusion where the increased number of collaterals does not equate to decreased mortality rates, but rather is dependent upon a multitude of factors.

## **2.1. Methods**

The literature is replete with the salubrious effects of a well-developed coronary collateral circulation and the potential benefit of a therapeutic process aimed at stimulating coronary collateral growth [13–19]. One patient study focused on coronary collateral growth in patients that had stable coronary artery disease. Specifically, the Möbius-Winkler et al. study looked at the impact of exercise on coronary collateral growth [20]. The patients were put into groups of usual care, moderate intensity exercise, and high-intensity exercise. The main findings of this study were that moderate and high-intensity exercise increased the coronary collateral blood flow. Scientists in this study postulated the cause of the coronary collateral growth. They questioned whether ischemia triggers collateral growth, since a percutaneous coronary intervention was performed before the study began; however, there is a large body of literature suggesting the PCI procedures may not completely resolve myocardial ischemia. The authors further speculated that the cause could be this increased blood flow and could have been from either increasing work done by preexisting blood vessels or an "improvement in endothelial function of small intramyocardial vessels." There was a CFI increase of 39% in the group of patients that did high-intensity exercise and a 41% CFI increase in the group that did moderate intensity exercise, which emphasized that exercise increased the coronary collateral blood flow in patients with coronary artery disease [20].

There has been much discussion for stimulating arteriogenesis in patients in order to give them proper blood perfusion to ischemic areas. Collaterals have been found to give patients many benefits over individuals who do not have collaterals, with a long-term mortality reduction, reduced myocardial infarct size, a greater postinfarction ejection fraction, and a reduced risk for rupture of the papillary muscle, myocardial free wall, or interventricular septum [21]. A reduction in infarct size was noted by the decreased peak creatinine levels as the number of collaterals increased depicting a cardioprotective effect [12]. Additionally, specific benefits have been noted between the presence of collaterals and sudden cardiac death and myocardial infarction.

There are three prevalent assessment methods of collateral growth circulation: the Rentrop score, collateral flow index (CFI), and intracoronary electrocardiogram. The Rentrop score can be most easily assessed when using coronary angiography as a visual assessment method. Circulation is then categorized into four different grades: Grade 0, Grade 1, Grade 2, and Grade 3. These categories range from no filling of the coronary collaterals to complete filling of collaterals, respectively. Although successful, the Rentrop method has some limitations due to being easily influenced by blood pressure changes and the force of injections during imaging procedures. Currently, the method considered to be the most accurate is the collateral flow index measurement. This method centers around utilizing a Doppler sensor tipped guide wire to quantify flow velocity in an occluded vessel compared with a normal vessel. Briefly mentioned was the intracoronary electrocardiogram, which is regarded as "simpler, cheaper, and very accurate" [22].

#### **2.2. Benefits of coronary collaterals**

Although many in the preclinical models have been employed in the study of coronary collateral growth, there is a relative paucity of clinical studies that have attempted to elucidate mechanisms of growth. One of the first studies done was in 1971 and was published in the *New England Journal of Medicine* [23]. This study only had three successful trials that demonstrated collaterals alleviating cardiovascular mortality. The inconsistency, according to Meier et al., could be rooted in the method by which they measured coronary collateral growth. The 1971 study "qualified" collaterals visually using coronary angiography, but Meier et al. postulates that had a better measurement method such as CFI been used, results could have been more promising [22].

One successful clinical study was performed by Seiler et al., which found that there is a direct correlation between collateral function and atherosclerotic lesions [24]. Patients with chronic total coronary occlusions had higher CFI values than those patients who did not have this condition. A CFI shift was quantified that patients with coronary occlusions had a CFI of 0.365 ± 0.190 versus 0.180 ± 0.105 of that of patients without occlusions. This study directly demonstrated that "collateral function is a direct indicator of CAD severity." The clinical importance of these findings suggests that human coronary collaterals can act as a "marker of poor outcome" in diseases such as acute coronary syndromes.

ture suggesting the PCI procedures may not completely resolve myocardial ischemia. The authors further speculated that the cause could be this increased blood flow and could have been from either increasing work done by preexisting blood vessels or an "improvement in endothelial function of small intramyocardial vessels." There was a CFI increase of 39% in the group of patients that did high-intensity exercise and a 41% CFI increase in the group that did moderate intensity exercise, which emphasized that exercise increased the coronary collateral

There has been much discussion for stimulating arteriogenesis in patients in order to give them proper blood perfusion to ischemic areas. Collaterals have been found to give patients many benefits over individuals who do not have collaterals, with a long-term mortality reduction, reduced myocardial infarct size, a greater postinfarction ejection fraction, and a reduced risk for rupture of the papillary muscle, myocardial free wall, or interventricular septum [21]. A reduction in infarct size was noted by the decreased peak creatinine levels as the number of collaterals increased depicting a cardioprotective effect [12]. Additionally, specific benefits have been noted between the presence of collaterals and sudden cardiac death and myocardial

There are three prevalent assessment methods of collateral growth circulation: the Rentrop score, collateral flow index (CFI), and intracoronary electrocardiogram. The Rentrop score can be most easily assessed when using coronary angiography as a visual assessment method. Circulation is then categorized into four different grades: Grade 0, Grade 1, Grade 2, and Grade 3. These categories range from no filling of the coronary collaterals to complete filling of collaterals, respectively. Although successful, the Rentrop method has some limitations due to being easily influenced by blood pressure changes and the force of injections during imaging procedures. Currently, the method considered to be the most accurate is the collateral flow index measurement. This method centers around utilizing a Doppler sensor tipped guide wire to quantify flow velocity in an occluded vessel compared with a normal vessel. Briefly mentioned was the intracoronary electrocardiogram, which is regarded as "simpler,

Although many in the preclinical models have been employed in the study of coronary collateral growth, there is a relative paucity of clinical studies that have attempted to elucidate mechanisms of growth. One of the first studies done was in 1971 and was published in the *New England Journal of Medicine* [23]. This study only had three successful trials that demonstrated collaterals alleviating cardiovascular mortality. The inconsistency, according to Meier et al., could be rooted in the method by which they measured coronary collateral growth. The 1971 study "qualified" collaterals visually using coronary angiography, but Meier et al. postulates that had a better measurement method such as CFI been used, results could have

One successful clinical study was performed by Seiler et al., which found that there is a direct correlation between collateral function and atherosclerotic lesions [24]. Patients with chronic

blood flow in patients with coronary artery disease [20].

136 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

infarction.

cheaper, and very accurate" [22].

been more promising [22].

**2.2. Benefits of coronary collaterals**

Sudden cardiac death (SCD) has several causes including electrical instability of the heart, specifically QRS complex variabilities can be used as markers for SCD and at times even trigger SCD [25]. The Oregon Sudden Unexpected Death Study (Ore-SUDS) has shown that prolongation of the QRS complex is associated with a large increase of SCD due to both known and unknown causes; therefore, methods to reduce this adverse event in the presence of myocardial ischemia can reduce mortality [26]. Additionally, fragmented QRS (fQRS), which are various RSR patterns in two continuous leads, have a well-established relationship with cardiac fibrosis caused by previous myocardial infarction or ischemia [27]. fQRS patterns have also been associated with increased morbidity and mortality, SCD, and repeat cardiovascular (CV) events and were found more often in individuals with poor collateral growth [27]. The presence of a well-developed collateral network has been shown to reduce QRS prolongation in left coronary artery occlusion and occurrence of fQRS in patients with chronic total occlusion [25, 27]. With this information, it can be concluded that with an increased number of coronary collaterals, patients can avoid QRS complex abnormalities thereby decreasing the chances of sudden cardiac death.

Additionally, the presence of collaterals has shown an increased time from symptom-onsetto-perfusion (>6 hours in good collateral versus poor collateral). This enables patients to increase the amount of time before onset of detrimental cardiac damage [28]. During an acute MI, the presence of a well-developed collateral circulation was seen in infarcted tissue that did not undergo cell necrosis, proving that increased collaterals will increase the chances of myocardial viability [29–31].

Overall, the presence of a well-developed collateral circulation in conjunction with healthy baseline characteristics (absence of repeat MI or angina pectoris) will be protective in patients who may suffer SCD, MI, or bouts of ischemia. Working to induce this collateral growth in patients both mechanically and chemically will prove to be very beneficial in decreasing mortality rates of patients with heart disease and perhaps ameliorate the possibility of recurrent cardiac events.
