Michael Sturek

The evidence on atherosclerosis imaging with ¹⁸F-sodium-fluoride (NaF) positron emission tomography (PET) is hotly debated because of the different patient characteristics, methodology, vascular beds, etc. in reported studies. This review is a continuation of a previous review on this topic, which covered the period 2010–2018. The purpose was to examine whether some of the most important questions that the previous review had left open had been elucidated by the most recent literature. Using principles of a systematic review, we ended analyzing 25 articles dealing with the carotids, coronary arteries, aorta, femoral, intracranial, renal, and penile arteries. The knowledge thus far can be summarized as follows: by targeting active arterial microcalcification, NaF uptake is considered a marker of early stage atherosclerosis, is age-dependent, and consistently associated with cardiovascular risk. Longitudinal studies on NaF uptake, conducted in the abdominal aorta only, showed unchanged uptake in postmenopausal women for nearly four years and varying uptake in prostate cancer patients over 1.5 years, despite constant or increasing calcium volume detected by computed tomography (CT). Thus, uncertainty remains about the transition from active arterial wall calcification marked by increased NaF uptake to less active or consolidated calcification detected by CT. The question of whether early-phase atherosclerosis and calcification can be modified remains also unanswered due to lack of intervention studies.

Intravascular photoacoustic/ultrasound (IVPA/US) is an emerging hybrid imaging modality that provides specific lipid detection and localization, while maintaining co‐registered artery morphology, for diagnosis of vulnerable plaque in cardiovascular disease. However, current IVPA/US approaches based on a single‐element transducer exhibit compromised performance for lipid detection due to the relatively low contrast of lipid absorption and conflicting detection bands for photoacoustic and ultrasound signals. Here, we present a dual‐frequency IVPA/US catheter for highly sensitive detection and precision localization of lipids. The low‐frequency transducer provides enhanced photoacoustic sensitivity, while the high‐frequency transducer maintains state‐of‐the‐art spatial resolution for ultrasound imaging. The boosted capability of IVPA/US imaging enables a multi‐scale analysis of lipid distribution in swine with coronary atherosclerosis. The dual‐frequency IVPA/US catheter has a diameter of 1 mm and flexibility to easily adapt to current catheterization procedures and is a significant step toward clinical diagnosis of vulnerable plaque.

With a quasi-collinear imaging catheter and functional sheath material, we successfully implemented intravascular photoacoustic tomography for in vivo imaging of rabbit aorta, with localization and quantification analysis of lipid distribution in arterial walls.

Intravascular photoacoustic-ultrasound (IVPA-US) imaging is an emerging hybrid modality for the detection of lipidladen plaques by providing simultaneous morphological and lipid-specific chemical information of an artery wall. The clinical utility of IVPA-US technology requires real-time imaging and display at speed of video-rate level. Here, we demonstrate a compact and portable IVPA-US system capable of imaging at up to 25 frames per second in real-time display mode. This unprecedented imaging speed was achieved by concurrent innovations in excitation laser source, rotary joint assembly, 1 mm IVPA-US catheter, differentiated A-line strategy, and real-time image processing and display algorithms. By imaging pulsatile motion at different imaging speeds, 16 frames per second was deemed to be adequate to suppress motion artifacts from cardiac pulsation for in vivo applications. Our lateral resolution results further verified the number of A-lines used for a cross-sectional IVPA image reconstruction. The translational capability of this system for the detection of lipid-laden plaques was validated by ex vivo imaging of an atherosclerotic human coronary artery at 16 frames per second, which showed strong correlation to gold-standard histopathology. © (2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

A highly sensitive catheter probe is critical to catheter-based intravascular photoacoustic imaging. Here, we present a photoacoustic catheter probe design on the basis of collinear alignment of the incident optical wave and the photoacoustically generated sound wave within a miniature catheter housing for the first time. Such collinear catheter design with an outer diameter of 1.6 mm provided highly efficient overlap between optical and acoustic waves over an imaging depth of >6 mm in D₂O medium. Intravascular photoacoustic imaging of lipid-laden atherosclerotic plaque and perivascular fat was demonstrated, where a lab-built 500 Hz optical parametric oscillator outputting nanosecond optical pulses at a wavelength of 1.7 μm was used for overtone excitation of C-H bonds. In addition to intravascular imaging, the presented catheter design will benefit other photoacoustic applications such as needle-based intramuscular imaging.

Chronic exercise attenuates coronary artery disease (CAD) in humans largely independent of reductions in risk factors; thus major protective mechanisms of exercise are directly within the coronary vasculature. Further, tight control of diabetes, e.g., blood glucose, can be detrimental. Accordingly, knowledge of mechanisms by which exercise attenuates diabetic CAD could catalyze development of molecular therapies. Exercise attenuates CAD (atherosclerosis) and restenosis in miniature swine models, which enable precise control of exercise parameters (intensity, duration, and frequency) and characterization of the metabolic syndrome (MetS) and diabetic milieu. Intracellular Ca²⁺ is a pivotal second messenger for coronary smooth muscle (CSM) excitation-contraction and excitation-transcription coupling that modulates CSM proliferation, migration, and calcification. CSM of diabetic dyslipidemic Yucatan swine have impaired Ca²⁺ extrusion via the plasmalemma Ca²⁺ ATPase (PMCA), downregulation of L-type voltage-gated Ca²⁺ channels (VGCC), increased Ca²⁺ sequestration by the sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA), increased nuclear Ca²⁺ localization, and greater activation of K channels by Ca²⁺ release from the SR. Endurance exercise training prevents Ca²⁺ transport changes with virtually no effect on the diabetic milieu (glucose, lipids). In MetS Ossabaw swine transient receptor potential canonical (TRPC) channels are upregulated and exercise training reverses expression and TRPC-mediated Ca²⁺ influx with almost no change in the MetS milieu. Overall, exercise effects on Ca²⁺ signaling modulate CSM phenotype. Future studies should 1) selectively target key Ca²⁺ transporters to determine definitively their causal role in atherosclerosis and 2) combine mechanistic studies with clinical outcomes, e.g., reduction of myocardial infarction.

We demonstrate for the first time the applicability of multimodal nonlinear optical (NLO) microscopy to the interrogation of stented coronary arteries under different diet and stent deployment conditions. Bare metal stents and Taxus drug-eluting stents (DES) were placed in coronary arteries of Ossabaw pigs of control and atherogenic diet groups. Multimodal NLO imaging was performed to inspect changes in arterial structures and compositions after stenting. Sum frequency generation, one of the multimodalities, was used for the quantitative analysis of collagen content in the peristent and in-stent artery segments of both pig groups. Atherogenic diet increased lipid and collagen in peristent segments. In-stent segments showed decreased collagen expression in neointima compared to media. Deployment of DES in atheromatous arteries inhibited collagen expression in the arterial media.

Adenosine clearly regulates coronary blood flow (CBF); however, contributions of specific adenosine receptor (AR) subtypes (A₁, A_2A, A_2B, A₃) to CBF in swine have not been determined. ARs generally decrease (A₁, A₃) or increase (A_2A, A_2B) cyclic adenosine monophosphate, a major mediator of vasodilation. We hypothesized that A₁ antagonism potentiates coronary vasodilation and coronary stent deployment in dyslipidemic Ossabaw swine elicits impaired vasodilation to adenosine that is associated with increased A₁/A_2A expression. The left main coronary artery was accessed with a guiding catheter allowing intracoronary infusions. After placement of a flow wire into the left circumflex coronary artery the responses to bolus infusions of adenosine were obtained. Steady-state infusion of AR-specific agents was achieved by using a small catheter fed over the flow wire in control pigs. CBF was increased by the A₂-nonselective agonist 2-phenylaminoadenosine (CV1808) in a dose-dependent manner. Baseline CBF was increased by the highly A₁-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), but not changed by other AR-specific agents. The nonselective A₂ antagonist 3,7-dimethyl-1-propargylxanthine and A_2A-selective antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) abolished adenosine-induced CBF, whereas A_2B and A₃ antagonism had no effect. Dyslipidemia and stenting decreased adenosine-induced CBF ∼70%, whereas A₁, A_2A, and A_2B mRNA were up-regulated in dyslipidemic versus control >5-fold and there was no change in the ratio of A₁/A_2A protein in microvessels distal to the stent. In control Ossabaw swine A₁ antagonism by DPCPX positively regulated basal CBF. Impaired adenosine-induced CBF after stenting in dyslipidemia is most likely caused by the altered balance between A₁ and A_2A signaling, not receptor expression.