Paul F. Teunissen

Doppler-Derived Intracoronary Physiology Indices Predict the Occurrence of Microvascular Injury and Microvascular Perfusion Deficits After Angiographically Successful Primary Percutaneous Coronary Intervention

Background—A total of 40% to 50% of patients with ST-segment–elevation myocardial infarction develop microvascular injury (MVI) despite angiographically successful primary percutaneous coronary intervention (PCI). We investigated whether hyperemic microvascular resistance (HMR) immediately after angiographically successful PCI predicts MVI at cardiovascular magnetic resonance and reduced myocardial blood flow at positron emission tomography (PET). Methods and Results—Sixty patients with ST-segment–elevation myocardial infarction were included in this prospective study. Immediately after successful PCI, intracoronary pressure–flow measurements were performed and analyzed off-line to calculate HMR and indices derived from the pressure–velocity loops, including pressure at zero flow. Cardiovascular magnetic resonance and H215O PET imaging were performed 4 to 6 days after PCI. Using cardiovascular magnetic resonance, MVI was defined as a subendocardial recess of myocardium with low signal intensity within a gadolinium-enhanced area. Myocardial perfusion was quantified using H215O PET. Reference HMR values were obtained in 16 stable patients undergoing coronary angiography. Complete data sets were available in 48 patients of which 24 developed MVI. Adequate pressure–velocity loops were obtained in 29 patients. HMR in the culprit artery in patients with MVI was significantly higher than in patients without MVI (MVI, 3.33±1.50 mm Hg/cm per second versus no MVI, 2.41±1.26 mm Hg/cm per second; P=0.03). MVI was associated with higher pressure at zero flow (45.68±13.16 versus 32.01±14.98 mm Hg; P=0.015). Multivariable analysis showed HMR to independently predict MVI (P=0.04). The optimal cutoff value for HMR was 2.5 mm Hg/cm per second. High HMR was associated with decreased myocardial blood flow on PET (myocardial perfusion reserve <2.0, 3.18±1.42 mm Hg/cm per second versus myocardial perfusion reserve ≥2.0, 2.24±1.19 mm Hg/cm per second; P=0.04). Conclusions—Doppler-flow–derived physiological indices of coronary resistance (HMR) and extravascular compression (pressure at zero flow) obtained immediately after successful primary PCI predict MVI and decreased PET myocardial blood flow. Clinical Trial Registration—URL: http://www.trialregister.nl. Unique identifier: NTR3164.

Changes in Coronary Blood Flow After Acute Myocardial Infarction: Insights From a Patient Study and an Experimental Porcine Model.

OBJECTIVES The aim of this study was to determine the effects of an acute myocardial infarction (AMI) on baseline and hyperemic flow in both culprit and nonculprit arteries. BACKGROUND An impaired coronary flow reserve (CFR) after AMI is related to worse outcomes. The individual contribution of resting and hyperemic flow to the reduction of CFR is unknown. Furthermore, it is unclear whether currently used experimental models of AMI resemble the clinical situation with respect to coronary flow parameters. METHODS Intracoronary Doppler flow velocity measurements were obtained in culprit and nonculprit arteries immediately after successfully revascularized ST-segment elevation myocardial infarction (n = 40). Stable patients without obstructive coronary artery disease served as control subjects and were selected by propensity-score matching (n = 40). Similar measurements in an AMI porcine model were taken both before and immediately after 75-min balloon occlusion of the left circumflex artery (n = 11). RESULTS In the culprit artery, CFR was 36% lower than in matched control subjects (Δ = -0.9; 1.8 ± 0.9 vs. 2.8 ± 0.7; p < 0.001) with consistent observations in swine (Δ = -0.9; 1.5 ± 0.4 vs. 2.4 ± 0.9 for after and before AMI, respectively; p = 0.04). An increased baseline and a decreased hyperemic flow contributed to the reduction in CFR in both patients (baseline flow: Δ = +5 and hyperemic flow: Δ = -7 cm/s) and swine (baseline flow: Δ = +8 and hyperemic flow: Δ = -6 cm/s). Similar changes were observed in nonculprit arteries (CFR: 2.8 ± 0.7 vs. 2.0 ± 0.7 for STEMI patients and control subjects; p < 0.001). CFR significantly correlated with infarct size as a percentage of the left ventricle in both patients (r = -0.48; p = 0.001) and swine (r = -0.61; p = 0.047). CONCLUSIONS CFR in both culprit and nonculprit coronary arteries decreases after AMI with contributions from both an increased baseline flow and a decreased hyperemic flow. The decreased CFR after AMI in culprit and nonculprit vessels is not a result of pre-existing microvascular dysfunction, but represents a combination of post-occlusive hyperemia, myocardial necrosis, hemorrhagic microvascular injury, compensatory hyperkinesis, and neurohumoral vasoconstriction.

Invasive measurement of coronary microvascular resistance in patients with acute myocardial infarction treated by primary PCI

Up to 40% of patients with acute myocardial infarction develop microvascular obstruction (MVO) despite successful treatment with primary percutaneous coronary intervention (PCI). The presence of MVO is linked to negative remodelling and left ventricular dysfunction, leading to decreased long-term survival, increased morbidity and reduced quality of life. The acute obstruction and dysfunction of the microvasculature can potentially be reversed by pharmacological treatment in addition to the standard PCI treatment. Identifying patients with post-PCI occurrence of MVO is essential in assessing which patients could benefit from additional treatment. However, at present there is no validated method to identify these patients. Angiographic parameters like myocardial blush grade or corrected Thrombolysis In Myocardial Infarction (TIMI) flow do not accurately predict the occurrence of MVO as visualised by MRI in the days after the acute event. Theoretically, acute MVO can be detected by intracoronary measurements of flow and resistance directly following the PCI procedure. In MVO the microvasculature is obstructed or destructed and will therefore display a higher coronary microvascular resistance (CMVR). The methods for intracoronary assessment of CMVR are based on either thermodilution or Doppler-flow measurements. The aim of this review is to present an overview of the currently available methods and parameters for assessing CMVR, with special attention given to their use in clinical practice and information provided by clinical studies performed in patients with acute myocardial infarction.

MAb therapy against the IFN-α/β receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden

AIMS IFN-beta (IFNβ) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNβ hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNβ treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNβ signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis. METHODS AND RESULTS In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-α/β receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNβ were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice. CONCLUSION Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.

The emerging role of galectins in cardiovascular disease.

Galectins are an ancient family of β-galactoside-specific lectins and consist of 15 different types, each with a specific function. They play a role in the immune system, inflammation, wound healing and carcinogenesis. In particular the role of galectin in cancer is widely studied. Lately, the role of galectins in the development of cardiovascular disease has gained attention. Worldwide cardiovascular disease is still the leading cause of death. In ischemic heart disease, atherosclerosis limits adequate blood flow. Angiogenesis and arteriogenesis are highly important mechanisms relieving ischemia by restoring perfusion to the post-stenotic myocardial area. Galectins act ambiguous, both relieving ischemia and accelerating atherosclerosis. Atherosclerosis can ultimately lead to myocardial infarction or ischemic stroke, which are both associated with galectins. There is also a role for galectins in the development of myocarditis by their influence on inflammatory processes. Moreover, galectin acts as a biomarker for the severity of myocardial ischemia and heart failure. This review summarizes the association between galectins and the development of multiple cardiovascular diseases such as myocarditis, ischemic stroke, myocardial infarction, heart failure and atrial fibrillation. Furthermore it focuses on the association between galectin and more general mechanisms such as angiogenesis, arteriogenesis and atherosclerosis.

Monoclonal antibody therapy against the Interferon-alpha/beta receptor subunit 1 stimulates arteriogenesis in a murine hindlimb-ischemia model without enhancing atherosclerotic burden

AIMS IFN-beta (IFNβ) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNβ hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNβ treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNβ signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis. METHODS AND RESULTS In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-α/β receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNβ were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice. CONCLUSION Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.

Hyperaemic microvascular resistance predicts clinical outcome and microvascular injury after myocardial infarction

Objectives Early detection of microvascular dysfunction after acute myocardial infarction (AMI) could identify patients at high risk of adverse clinical outcome, who may benefit from adjunctive treatment. Our objective was to compare invasively measured coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR) for their predictive power of long-term clinical outcome and cardiac magnetic resonance (CMR)-defined microvascular injury (MVI). Methods Simultaneous intracoronary Doppler flow velocity and pressure measurements acquired immediately after revascularisation for AMI from five centres were pooled. Clinical follow-up was completed for 176 patients (mean age 60±10 years; 140(80%) male; ST-elevation myocardial infarction (STEMI) 130(74%) and non-ST-segment elevation myocardial infarction 46(26%)) with median follow-up time of 3.2 years. In 110 patients with STEMI, additional CMR was performed. Results The composite end point of death and hospitalisation for heart failure occurred in 17 patients (10%). Optimal cut-off values to predict the composite end point were 1.5 for CFR and 3.0 mm Hg cm−1•s for HMR. CFR <1.5 was predictive for the composite end point (HR 3.5;95% CI 1.1 to 10.8), but not for its individual components. HMR ≥3.0 mm Hg cm−1 s was predictive for the composite end point (HR 7.0;95% CI 1.5 to 33.7) as well as both individual components. HMR had significantly greater area under the receiver operating characteristic curve for MVI than CFR. HMR remained an independent predictor of adverse clinical outcome and MVI, whereas CFR did not. Conclusions HMR measured immediately following percutaneous coronary intervention for AMI with a cut-off value of 3.0 mm Hg cm−1 s, identifies patients with MVI who are at high risk of adverse clinical outcome. For this purpose, HMR is superior to CFR.

Doppler Versus Thermodilution-Derived Coronary Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients With Acute Myocardial Infarction or Stable Angina Pectoris

Coronary microvascular resistance is increasingly measured as a predictor of clinical outcomes, but there is no accepted gold-standard measurement. We compared the diagnostic accuracy of 2 invasive indices of microvascular resistance, Doppler-derived hyperemic microvascular resistance (hMR) and thermodilution-derived index of microcirculatory resistance (IMR), at predicting microvascular dysfunction. A total of 54 patients (61 ± 10 years) who underwent cardiac catheterization for stable coronary artery disease (n = 10) or acute myocardial infarction (n = 44) had simultaneous intracoronary pressure, Doppler flow velocity and thermodilution flow data acquired from 74 unobstructed vessels, at rest and during hyperemia. Three independent measurements of microvascular function were assessed, using predefined dichotomous thresholds: (1) coronary flow reserve (CFR), the average value of Doppler- and thermodilution-derived CFR; (2) cardiovascular magnetic resonance (CMR) derived myocardial perfusion reserve index; and (3) CMR-derived microvascular obstruction. hMR correlated with IMR (rho = 0.41, p <0.0001). hMR had better diagnostic accuracy than IMR to predict CFR (area under curve [AUC] 0.82 vs 0.58, p <0.001, sensitivity and specificity 77% and 77% vs 51% and 71%) and myocardial perfusion reserve index (AUC 0.85 vs 0.72, p = 0.19, sensitivity and specificity 82% and 80% vs 64% and 75%). In patients with acute myocardial infarction, the AUCs of hMR and IMR at predicting extensive microvascular obstruction were 0.83 and 0.72, respectively (p = 0.22, sensitivity and specificity 78% and 74% vs 44% and 91%). We conclude that these 2 invasive indices of coronary microvascular resistance only correlate modestly and so cannot be considered equivalent. In our study, the correlation between independent invasive and noninvasive measurements of microvascular function was better with hMR than with IMR.

Kinetics of coagulation in ST-elevation myocardial infarction following successful primary percutaneous coronary intervention.

INTRODUCTION ST-elevated myocardial infarction (STEMI) is most frequently caused by coronary occlusion due to formation of an intracoronary thrombus in reaction to rupture of atherosclerotic plaques. Little is known about kinetics of coagulation markers after STEMI in patients treated according to current guidelines. We aimed to investigate kinetics of important coagulation markers in percutaneous coronary intervention (PCI)-treated STEMI patients. MATERIALS AND METHODS 60 consecutive PCI-treated STEMI patients were prospectively included. Blood samples were collected immediately after as well as 1, 4 and 7 days following PCI. Samples collected 90 days after PCI served as baseline values. ADAMTS13 activity, VWF (von Willebrand factor) activity, VWF antigen, VWF propeptide, fibrinogen antigen, D-dimer, alpha2-antiplasmin (α2AP), plasmin-alpha2-antiplasmin complex (PAP), prothrombin fragment F1+2 (F1+2), prothrombin time (PT), activated partial thromboplastin time (aPTT), and anti-factor Xa (anti-Xa) were measured. Cardiac magnetic resonance (CMR) was performed at 4-6 and 90 days after PCI in 49 patients and left ventricular ejection fraction (LVEF), infarct size and microvascular injury (MVI) were determined. RESULTS Immediately after PCI, ADAMTS13 activity, fibrinogen antigen and α2AP levels were significantly decreased and VWF activity, VWF antigen and VWF propeptide levels were significantly elevated, compared to baseline. Individual coagulation markers and different combinations thereof were not related to LVEF or infarct size at 90 days, or the occurrence of MVI at 4-6 days after PCI. CONCLUSION Coagulation parameters show a very dynamic profile in the early days after STEMI. However, individual coagulation parameters or combinations thereof do not predict CMR-defined LVEF, infarct size or MVI.

Coronary vasomotor function in infarcted and remote myocardium after primary percutaneous coronary intervention

Objective In patients with acute myocardial infarction (AMI), coronary vasomotor function is impaired in the myocardial territory supplied by the culprit artery and in remote myocardium supplied by angiographically normal vessels. The aim was to investigate the temporal evolution of coronary vasodilatory reserve in patients with AMI by use of [15O]H2O positron emission tomography, after successful percutaneous coronary intervention. Methods 44 patients with AMI and successful revascularisation by percutaneous coronary intervention were included. Subjects were examined 1 week and 3 months after AMI with [15O]H2O positron emission tomography to assess the coronary flow reserve (CFR). CFR was defined as the ratio of myocardial blood flow (MBF) during hyperaemia and rest. Additionally, 45 age-matched and sex-matched subjects underwent similar scanning procedures and served as controls. Results At baseline, CFR averaged 1.81±0.66 in infarcted myocardium versus 2.51±0.81 in remote myocardium (p<0.01). In comparison, CFR in the control group averaged 4.16±1.45 (p=0.001 vs both). During follow-up, the CFR increased to 2.74±0.85 in infarcted myocardium (p<0.01), and to 2.85±0.70 in remote myocardium (p<0.01). This was predominantly due to an increase in hyperaemic MBF, from 1.62±0.54 mL/min/g to 2.19±0.68 mL/min/g in infarcted myocardium (p<0.001), and 2.17±0.54 mL/min/g to 2.60±0.65 mL/min/g in remote myocardium (p<0.001). Conclusions CFR in infarcted and remote myocardium is impaired 1 week after AMI. After 3 months vasomotor function partially recovers. However, as compared with control patients, MBF remains impaired in culprit and reference territories in patients with AMI. Clinical trial registration NTR3164.