Andrew Ladwiniec

Collateral Donor Artery Physiology and the Influence of a Chronic Total Occlusion on Fractional Flow Reserve

Background—The presence of a concomitant chronic total coronary occlusion (CTO) and a large collateral contribution might alter the fractional flow reserve (FFR) of an interrogated vessel, rendering the FFR unreliable at predicting ischemia should the CTO vessel be revascularized and potentially affecting the decision on optimal revascularization strategy. We tested the hypothesis that donor vessel FFR would significantly change after percutaneous coronary intervention of a concomitant CTO. Methods and Results—In consecutive patients undergoing percutaneous coronary intervention of a CTO, coronary pressure and flow velocity were measured at baseline and hyperemia in proximal and distal segments of both nontarget vessels, before and after percutaneous coronary intervention. Hemodynamics including FFR, absolute coronary flow, and the coronary flow velocity–pressure gradient relation were calculated. After successful percutaneous coronary intervention in 34 of 46 patients, FFR in the predominant donor vessel increased from 0.782 to 0.810 (difference, 0.028 [0.012 to 0.044]; P=0.001). Mean decrease in baseline donor vessel absolute flow adjusted for rate pressure product: 177.5 to 139.9 mL/min (difference −37.6 [−62.6 to −12.6]; P=0.005), mean decrease in hyperemic flow: 306.5 to 272.9 mL/min (difference, −33.5 [−58.7 to −8.3]; P=0.011). Change in predominant donor vessel FFR correlated with angiographic (%) diameter stenosis severity (r=0.44; P=0.009) and was strongly related to stenosis severity measured by the coronary flow velocity–pressure gradient relation (r=0.69; P<0.001). Conclusions—Recanalization of a CTO results in a modest increase in the FFR of the predominant collateral donor vessel associated with a reduction in coronary flow. A larger increase in FFR is associated with greater coronary stenosis severity.

Medical therapy, percutaneous coronary intervention and prognosis in patients with chronic total occlusions

Objective There is little published data reporting outcomes for those found to have a chronic total coronary occlusion (CTO) that is electively treated medically versus those treated by percutaneous coronary intervention (PCI). We sought to compare long-term clinical outcomes between patients treated by PCI and elective medical therapy in a consecutive cohort of patients with an identified CTO. Methods Patients found to have a CTO on angiography between January 2002 and December 2007 in a single tertiary centre were identified using a dedicated database. Those undergoing CTO PCI and elective medical therapy to the CTO were propensity matched to adjust for baseline clinical and angiographic differences. Results In total, 1957 patients were identified, a CTO was treated by PCI in 405 (20.7%) and medical therapy in 667 (34.1%), 885 (45.2%) patients underwent coronary artery bypass graft surgery. Of those treated by PCI or medical therapy, propensity score matching identified 294 pairs of patients, PCI was successful in 177 patients (60.2%). All-cause mortality at 5 years was 11.6% for CTO PCI and 16.7% for medical therapy HR 0.63 (0.40 to 1.00, p=0.052). The composite of 5-year death or myocardial infarction occurred in 13.9% of the CTO PCI group and 19.6% in the medical therapy group, HR 0.64 (0.42 to 0.99, p=0.043). Among the CTO PCI group, if the CTO was revascularised by any means during the study period, 5-year mortality was 10.6% compared with 18.3% in those not revascularised in the medical therapy group, HR 0.50 (0.28–0.88, p=0.016). Conclusions Revascularisation, but not necessarily PCI of a CTO, is associated with improved long-term survival relative to medical therapy alone.

The haemodynamic effects of collateral donation to a chronic total occlusion: Implications for patient management

Physiological lesion assessment in the form of Fractional Flow Reserve (FFR) is now well established for the purpose of guiding multi-vessel revascularization. Chronic total coronary occlusions are frequently associated with multi-vessel disease and the collateral dependent myocardium distal to the occlusion is often supplied by a collateral supply from another epicardial coronary artery. The haemodynamic effect of collateral donation upon collateral donor vessel flow may have important implications for the vessels FFR; rendering it unreliable at predicting ischaemia should the CTO be revascularized. As a consequence, in the setting of multi-vessel disease, optimal revascularization strategy might be altered. There is a paucity of work in the medical literature directly examining this phenomenon. We endeavoured to review the existing literature related to it, to summarise from current knowledge of coronary physiology what is known about the potential effects of CTO revascularization on both collateral flow and collateral donor vessel physiology, and to highlight where further studies might inform practice.

Diastolic Backward-Traveling Decompression (Suction) Wave Correlates With Simultaneously Acquired Indices of Diastolic Function and Is Reduced in Left Ventricular Stunning

Background—Wave intensity analysis can distinguish proximal (propulsion) and distal (suction) influences on coronary blood flow and is purported to reflect myocardial performance and microvascular function. Quantifying the amplitude of the peak, backwards expansion wave (BEW) may have clinical utility. However, simultaneously acquired wave intensity analysis and left ventricular (LV) pressure–volume loop data, confirming the origin and effect of myocardial function on the BEW in humans, have not been previously reported. Methods and Results—Patients with single-vessel left anterior descending coronary disease and normal ventricular function (n=13) were recruited prospectively. We simultaneously measured LV function with a conductance catheter and derived wave intensity analysis using a pressure–low velocity guidewire at baseline and again 30 minutes after a 1-minute coronary balloon occlusion. The peak BEW correlated with the indices of diastolic LV function: LV dP/dtmin (rs=−0.59; P=0.002) and &tgr; (rs=−0.59; P=0.002), but not with systolic function. In 12 patients with paired measurements 30 minutes post balloon occlusion, LV dP/dtmax decreased from 1437.1±163.9 to 1299.4±152.9 mm Hg/s (median difference, −110.4 [−183.3 to −70.4]; P=0.015) and &tgr; increased from 48.3±7.4 to 52.4±7.9 ms (difference, 4.1 [1.3–6.9]; P=0.01), but basal average peak coronary flow velocity was unchanged, indicating LV stunning post balloon occlusion. However, the peak BEW amplitude decreased from −9.95±5.45 W·m–2/s2×105 to −7.52±5.00 W·m–2/s2×105 (difference 2.43×105 [0.20×105 to 4.67×105; P=0.04]). Conclusions—Peak BEW assessed by coronary wave intensity analysis correlates with invasive indices of LV diastolic function and mirrors changes in LV diastolic function confirming the origin of the suction wave. This may have implications for physiological lesion assessment after percutaneous coronary intervention. Clinical Trial Registration—URL: http://www.isrctn.org. Unique identifier: ISRCTN42864201.

Change in donor artery fractional flow reserve after recanalization of a chronic total occlusion: Not as impressive as some might have us believe

We read with interest the study entitled “Reversal of Ischemia of Donor Artery Myocardium After Recanalization of a Chronic Total Occlusion” published in a recent issue of Catheterization and Cardiovascular Interventions [1]. We agree with the authors that the phenomenon they describe is important and has thus far been underinvestigated. However, an increase in fractional flow reserve (FFR) post recanalization of a chronic total occlusion (CTO) is not universal, and the change appears to be difficult to predict. If we are to make the most appropriate decision with respect to revascularisation strategy, we do not always have the luxury, as the authors suggest, of opening the CTO first and remeasuring the donor vessel FFR. If a lesion in a donor vessel is truly haemodynamically significant irrespective of the additional myocardium, the vessel subtends as a result of a CTO, the additional complexity of coronary disease as a whole may be such that coronary artery bypass graft surgery would have superior long-term outcomes to a strategy of percutaneous coronary intervention (PCI) [2]. The author’s stated aim was to define the frequency of the phenomenon of a donor vessel FFR changing from the ischaemic range (<0.80) to the nonischaemic range (>0.80). The validated value of FFR which is predictive of ischaemia is <0.75, the value of 0.80 is that used in clinical outcome studies to allow for variation in the measurement of FFR [3,4]. The FFR is a continuous estimate of hyperaemic blood flow in the presence of a coronary lesion as a proportion of flow if the epicardial coronary were to cause no resistance to flow. There is no reason to suppose that a change in FFR would be different if the initial value is >0.8, compared with if it were <0.8. Indeed, when the reported change in FFR is plotted against the reported pre-PCI FFR, there does not appear to be any relationship between the two (Fig. 1). We were therefore surprised that the mean change in FFR was not presented in the study at all. When applying the study findings to guide practice, an estimate of the change of FFR in a donor vessel and its variability when we open a CTO would seem more pertinent than the frequency that a selected cut-off is crossed in the study population. As all preand post-FFR measurements were reported in the study, we have taken the liberty of calculating the mean change in FFR using a paired t-test and STATA, version 12. Mean change in FFR was an increase of 0.04 (95% confidence interval (CI) of the difference 0.01–0.79, p1⁄4 0.02), the standard deviation of the difference was 0.062. In the article abstract, the reporting of the mean values only for the participants who had the expected large change in donor vessel FFR rather than the mean change serves only to exaggerate the magnitude of the phenomenon. In the same vein, including a patient in the study population (patient 2) who the authors have reported to have had a large change in FFR prior to the decision to conduct the study has biased the results toward a larger FFR change. The mean change in FFR and, perhaps more importantly, the standard deviation of that change would suggest that one might expect an increase in donor vessel FFR after CTO angioplasty, but that there is considerable variability to that change. There are a number of possible explanations for this including inherent variability of FFR measurement itself, differing donor vessel lesion morphology, variation in blood flow to the collateral dependent myocardium and variation in the effect of Adenosine, which can be considerable [5]. In addition, specifically applied to this study, the inclusion of three patients with 2 CTOs and the large variation in time after which FFR was measured post-PCI might have also added to the variability. With increasing evidence of a benefit in clinical outcome for the use of physiological lesion assessment to

Microvascular dysfunction in the immediate aftermath of chronic total coronary occlusion recanalization

The aim of this study was to compare microvascular resistance under both baseline and hyperemic conditions immediately after percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) with an unobstructed reference vessel in the same patient

Biomarkers of coronary endothelial health: correlation with invasive measures of collateral function, flow and resistance in chronically occluded coronary arteries and the effect of recanalization.

ObjectivesIn the presence of a chronically occluded coronary artery, the collateral circulation matures by a process of arteriogenesis; however, there is considerable variation between individuals in the functional capacity of that collateral network. This could be explained by differences in endothelial health and function. We aimed to examine the relationship between the functional extent of collateralization and levels of biomarkers that have been shown to relate to endothelial health. MethodsWe measured four potential biomarkers of endothelial health in 34 patients with mature collateral networks who underwent a successful percutaneous coronary intervention (PCI) for a chronic total coronary occlusion (CTO) before PCI and 6–8 weeks after PCI, and examined the relationship of biomarker levels with physiological measures of collateralization. ResultsWe did not find a significant change in the systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor 6–8 weeks after PCI. We did find an association between estimated retrograde collateral flow before CTO recanalization and lower levels of sICAM-1 (r=0.39, P=0.026), sE-selectin (r=0.48, P=0.005) and microparticles (r=0.38, P=0.03). ConclusionRecanalization of a CTO and resultant regression of a mature collateral circulation do not alter systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor. The identified relationship of retrograde collateral flow with sICAM-1, sE-selectin and microparticles is likely to represent an association with an ability to develop collaterals rather than their presence and extent.

107 Elective Medical Therapy Versus Angioplasty of Chronic Total Coronary Occlusions: A Propensity Matched Retrospective Cohort Study

Introduction An association between improved survival and successful PCI of chronic total coronary occlusions (CTO) when compared with failed PCI has been widely reported. However a comparison between elective medical therapy and CTO PCI is more relevant to clinical decision making. We compared long-term clinical outcomes in a cohort of patients with an identified CTO on angiography between these two treatment groups, hypothesising there would be a difference in all-cause mortality at 5 year follow-up. Methods Patients found to have a CTO on angiography between 2002 and 2008, without prior CABG or important structural heart disease in a single tertiary centre were identified using a dedicated database. Patients undergoing CTO PCI and elective medical therapy to the CTO were matched using a propensity score to adjust for baseline clinical and angiographic differences. Events at follow-up were identified using national death certification records and national registries for myocardial infarction, CABG and PCI. Results In total 1957 patients were identified, a CTO was treated by PCI in 405 (20.7%) and medical therapy in 667 (34.1%), 885 (45.2%) patients underwent CABG. Of those treated by PCI or medical therapy, propensity score matching identified 389 pairs of patients. PCI was successful in 238 patients (61.2%). There was no difference in the primary study objective of 5 year mortality between the propensity matched treatment groups (CTO PCI: 10.8%, medical therapy: 15.7%; HR 0.74; 95% CI 0.49 to 1.11; p = 0.146), or after adjustment for Syntax score: (HR 0.81; 95% CI 0.53–1.25; p = 0.336). There remained no difference if only the 238 matched pairs in which CTO PCI was successful were included (HR 0.83; 95% CI 0.48 to 1.42; p = 0.493). There was an increase in repeat revascularisation associated with CTO PCI (HR 2.18; 95% CI 1.49–3.18; p < 0.001). This difference was not present in the successful PCI matched pair subgroup (HR 0.79; 95% CI 0.45–1.37; p = 0.397). Conclusions Using an alternative approach to much of the existing literature, we have not demonstrated an associated difference in survival between patients with a CTO treated by PCI versus those in whom the CTO was treated medically. Doubt remains as to whether PCI of a CTO should be performed on grounds of prognosis. Abstract 107 Figure 1 Kaplan-Meier curve showing comparison of 5 year survival between propensity matched groups of patients with an identified CTO treated by elective medical therapy vs. CTO PCI

Response to Letter Regarding Article, “Collateral Donor Artery Physiology and the Influence of a Chronic Total Occlusion on Fractional Flow Reserve”

We appreciate the interest and comments from Dr Saito1 on our article.2 It is gratifying that some of the findings of their in vitro work have been borne out by our results. Many of their comments have already been addressed in the article.2 We agree that the mass of collateral dependent myocardium and extent of collateralization are likely to be important factors in the extent of change in donor vessel fractional flow reserve (FFR) …

72 Non-Target Vessel Haemodynamics Prior to Angioplasty of Chronic Total Coronary Occlusions, is There Really Substrate for an Important Change in Haemodynamic Lesion Severity?

Introduction Fractional flow reserve (FFR) guided angioplasty has been shown to have a beneficial effect on clinical outcome in patients with multi-vessel coronary disease. However, multi-vessel disease is frequently accompanied by a chronic total occlusion (CTO). We have limited understanding of the effect of the donation of a collateral supply to collateral dependent myocardium on the FFR. Marked changes in non-target vessel FFR post recanalisation of CTOs have been reported, but the consistency of this phenomenon remains uncertain and changes in haemodynamic indices immediately post-angioplasty might be confounded by the effect of the vessel trauma of angioplasty on the microvasculature. If the phenomenon is consistent, we might expect haemodynamics in a vessel donating collaterals to a CTO to be dependent on the extent of angiographic collateral flow originating from it. Methods Prior to CTO angioplasty in 22 patients, simultaneous pressure and flow were measured at rest and during hyperaemia in the distal and proximal segment of each non-target vessel. Absolute coronary flow, coronary flow reserve, hyperaemic microvascular resistance and fractional flow reserve were calculated. Blinded to haemodynamic measurements, the major collateral donor vessel was selected and each vessel was graded by the size of the largest collateral branch which originated from it by collateral connexion (CC) grade (0 = no continuous connexion, 1 = threadlike connexion, 2 = side branch like connexion). Haemodynamic measurements were compared between the major and minor collateral donor vessels using a paired t-test. Results All patients had right dominant coronary anatomy. The target vessel was the left anterior descending artery (LAD) in 9 patients, circumflex artery (LCx) in 2 and right coronary artery (RCA) in 11. All target vessels were filled by a modified Rentrop grade of >2 (2 n = 12, 3 n = 10). Angiographic characteristics are listed in Table 1 and haemodynamic measurements are listed in Table 2. In spite of clearly increased angiographic collateral donation, we did not identify any associated significant difference between haemodynamic indices. Abstract 72 Table 1 Minor Collateral Donorn Major Collateral Donorn CC class (0,1,2) 2 3 11 1 8 11 0 11 0 Vessel LAD 7 6 LCx 15 5 RCA 0 11 Abstract 72 Table 2 Minor Collateral Donor Mean(SD) Major Collateral Donor Mean(SD) Difference (95% CI, p-value) Donor Vessel Duke Jeopardy Score 3.27(1.91) 4.09(1.44) 0.75 (-0.61-2.11, p =. 27) Maximum diameter stenosis (%) 36.9(13.6) 32.6(14.9) -4.3 (-11.5-3.0, p =. 23) Fractional Flow Reserve 0.82(0.11) 0.80(0.10) -0.02 (-0.07-0.04, p =. 55) Hyperaemic Microvascular Resistance (mmHg/cm/s) 2.19(0.87) 2.01(0.95) -0.18 (-0.74-0.38, p =. 51) Coronary Flow Reserve 2.11(0.61) 2.13(0.78) -0.03 (-0.36-0.42, p =. 88) Hyperaemic Absolute Flow (ml/min) 168.8(97.7) 189.4(126.9) 20.6 (-30.7-72.0,p =. 41) Crude Resting Absolute Flow (ml/min) 79.5(43.0) 86.0(37.1) 6.4 (-13.6-26.5,p =. 51) Resting Absolute Flow adjustedfor Rate Pressure Product (ml/min) 105.8(61.3) 111.6(58.7) 5.8 (-21.0-32.6, p =. 66) Conclusion The mechanism for a large rise in non-target vessel FFR post CTO angioplasty must involve one or more of a fall in absolute flow, a fall in coronary flow reserve or an increase in microvascular resistance. One would expect that change to move towards the norm for a vessel donating fewer collateral branches. The absence of a difference in any of these haemodynamic indices between paired non-target vessels with differing CC grades (and therefore different extents of collateral ‘donation’) would suggest thatthe large changes in FFR which have been reported might only represent a publication biassed measurement extreme, rather than the rule.