Ranil de Silva

Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation.

OBJECTIVES The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease. BACKGROUND Intravascular optical coherence tomography (IVOCT) is a catheter-based modality that acquires images at a resolution of ~10 μm, enabling visualization of blood vessel wall microstructure in vivo at an unprecedented level of detail. IVOCT devices are now commercially available worldwide, there is an active user base, and the interest in using this technology is growing. Incorporation of IVOCT in research and daily clinical practice can be facilitated by the development of uniform terminology and consensus-based standards on use of the technology, interpretation of the images, and reporting of IVOCT results. METHODS The IWG-IVOCT, comprising more than 260 academic and industry members from Asia, Europe, and the United States, formed in 2008 and convened on the topic of IVOCT standardization through a series of 9 national and international meetings. RESULTS Knowledge and recommendations from this group on key areas within the IVOCT field were assembled to generate this consensus document, authored by the Writing Committee, composed of academicians who have participated in meetings and/or writing of the text. CONCLUSIONS This document may be broadly used as a standard reference regarding the current state of the IVOCT imaging modality, intended for researchers and clinicians who use IVOCT and analyze IVOCT data.

Reduced Coronary Vasodilator Function in Infarcted and Normal Myocardium after Myocardial Infarction

BACKGROUND The ability of the coronary vascular bed to dilate and thus increase blood flow to the myocardium may be impaired in coronary artery disease, even in regions of myocardium supplied by an angiographically normal coronary artery. If this kind of vasomotor dysfunction was present or accentuated after acute myocardial infarction, it might influence the extent of ischemia and necrosis in areas not directly injured by the infarction. METHODS We studied 13 patients (mean [+/- SD] age, 62 +/- 11 years) with single-vessel coronary artery disease after they had received thrombolytic therapy for myocardial infarction. Using positron-emission tomography (PET) with oxygen-15-labeled water, we measured regional myocardial blood flow under basal conditions and after the intravenous administration of dipyridamole (0.5 mg per kg of body weight over a period of four minutes) 8 +/- 3 days after infarction in all 13 patients (1-week study) and 6 +/- 2 months after infarction in 9 of the 13 (6-month study). On both occasions we measured blood flow both in the infarcted region and in a region of myocardium that was remote from the infarcted region and supplied by a normal artery. RESULTS At the one-week PET study, the coronary vasodilator response (the ratio of the myocardial blood flow after the administration of dipyridamole to basal blood flow) was 1.12 +/- 0.50 in the infarct-related artery and 1.53 +/- 0.36 in the remote region (P = 0.015). At the six-month study, the coronary vasodilator response was 1.42 +/- 0.37 in the infarcted region and 2.19 +/- 0.69 in the remote region (P = 0.004 for the comparison with the infarcted region; P = 0.011 for the comparison with the remote region at the one-week study). The value in remote myocardium remained lower than that in similar regions in 10 control patients, who had single-vessel coronary artery disease but no evidence of myocardial infarction (3.17 +/- 0.72; P = 0.009). CONCLUSIONS After acute myocardial infarction, there is a severe vasodilator abnormality involving not only resistance vessels in infarcted myocardium, but also those in myocardium perfused by normal coronary vessels. This dysfunction may affect the extent of myocardial ischemia and necrosis after coronary occlusion.

Genetic variation in SCN10A influences cardiac conduction

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 × 10−15) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10−5 to 10−20). SCN10A encodes NaV1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a−/− mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.

Genetic loci influencing kidney function and chronic kidney disease.

Using genome-wide association, we identify common variants at 2p12–p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10−10 to 10−15). Of these, rs10206899 (near NAT8, 2p12–p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10−5 and P = 3.6 × 10−4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

Pathophysiological Mechanisms of Chronic Reversible Left Ventricular Dysfunction due to Coronary Artery Disease (Hibernating Myocardium)

The long-term consequences of CAD remain a prominent clinical problem. Particularly with new therapeutic strategies that reduce the mortality associated with acute coronary syndromes, more patients suffer from the long-term sequelae of this condition. In this setting, the identification of those segments of myocardium that appear dysfunctional distal to coronary stenoses and that can improve after coronary revascularization is of considerable clinical importance. Although the diagnostic and therapeutic aspects of this problem are clearly defined, the pathophysiological mechanisms underlying the dysfunctional myocardium are controversial. It was demonstrated more than 20 years ago1 2 that resting wall-motion abnormalities in patients with CAD can improve after administration of an inotropic agent or after coronary bypass. An article published in 1978 by Diamond et al3 presaged the concept of hibernating myocardium: “Reports of sometimes dramatic improvement in segmental left ventricular function following coronary bypass surgery, although not universal, leaves the clear implication that ischemic non-infarcted myocardium can exist in a state of function hibernation.” Rahimtoola, in an article published in 1985,4 popularized this concept and later suggested that “hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand.”5 Since the introduction of the term “hibernation,”3 4 5 6 the clinical importance of reversible left ventricular dysfunction has been widely accepted. The concept of an adaptive process that decreases myocardial oxygen consumption in the presence of either chronically or intermittently reduced oxygen delivery has generated considerable clinical and experimental interest. Accordingly, our aims were to (1) review the current criteria of the definition of hibernating myocardium, (2) summarize recent clinical as well as experimental data pertaining to this subject, …

In vivo diffusion tensor MRI of the human heart: reproducibility of breath-hold and navigator-based approaches.

The aim of this study was to implement a quantitative in vivo cardiac diffusion tensor imaging (DTI) technique that was robust, reproducible, and feasible to perform in patients with cardiovascular disease. A stimulated‐echo single‐shot echo‐planar imaging (EPI) sequence with zonal excitation and parallel imaging was implemented, together with a novel modification of the prospective navigator (NAV) technique combined with a biofeedback mechanism. Ten volunteers were scanned on two different days, each time with both multiple breath‐hold (MBH) and NAV multislice protocols. Fractional anisotropy (FA), mean diffusivity (MD), and helix angle (HA) fiber maps were created. Comparison of initial and repeat scans showed good reproducibility for both MBH and NAV techniques for FA (P > 0.22), MD (P > 0.15), and HA (P > 0.28). Comparison of MBH and NAV FA (FAMBHday1 = 0.60 ± 0.04, FANAVday1 = 0.60 ± 0.03, P = 0.57) and MD (MDMBHday1 = 0.8 ± 0.2 × 10−3 mm2/s, MDNAVday1 = 0.9 ± 0.2 × 10−3 mm2/s, P = 0.07) values showed no significant differences, while HA values (HAMBHday1Endo = 22 ± 10°, HAMBHday1Mid‐Endo = 20 ± 6°, HAMBHday1Mid‐Epi = −1 ± 6°, HAMBHday1Epi = −17 ± 6°, HANAVday1Endo = 7 ± 7°, HANAVday1Mid‐Endo = 13 ± 8°, HANAVday1Mid‐Epi = −2 ± 7°, HANAVday1Epi = −14 ± 6°) were significantly different. The scan duration was 20% longer with the NAV approach. Currently, the MBH approach is the more robust in normal volunteers. While the NAV technique still requires resolution of some bulk motion sensitivity issues, these preliminary experiments show its potential for in vivo clinical cardiac diffusion tensor imaging and for delivering high‐resolution in vivo 3D DTI tractography of the heart. Magn Reson Med 70:454–465, 2013.

Diffuse reduction of myocardial beta-adrenoceptors in hypertrophic cardiomyopathy: A study with positron emission tomography

OBJECTIVES This study was conducted to determine the myocardial beta-adrenoceptor density as a marker of sympathetic function in patients with hypertrophic cardiomyopathy and normal control subjects. BACKGROUND Although some cases of hypertrophic cardiomyopathy are familial with an autosomal dominant pattern of inheritance, there remains a substantial proportion of cases in which neither a family history nor genetic abnormalities can be demonstrated. Additional abnormalities, both genetic and acquired, may be important in the phenotypic expression of this condition. Clinical features of the disease and metabolic studies suggest an increased activity of the sympathetic nervous system. METHODS Eleven patients with hypertrophic cardiomyopathy, none of whom had previously received beta-blocking drugs, and eight normal control subjects underwent positron emission tomography to evaluate regional left ventricular beta-adrenoceptor density and myocardial blood flow using carbon-11-labeled CGP 12177 and oxygen-15-labeled water as tracers. Plasma catecholamines were also measured. RESULTS Mean (+/- SD) myocardial beta-adrenoceptor density was significantly less in the hypertrophic cardiomyopathy group than in the control group (7.70 +/- 1.86 vs. 11.50 +/- 2.18 pmol/g tissue, p < 0.001). Myocardial blood flow was similar in both groups (0.91 +/- 0.22 vs. 0.91 +/- 0.21 ml/min per g, p = NS). The distribution of beta-adrenoceptor density was uniform throughout the left ventricle in both groups. In the hypertrophic cardiomyopathy group, there was no correlation between regional wall thickness and myocardial beta-adrenoceptor density. There were no significant differences in either plasma norepinephrine or epinephrine concentrations between the two groups. CONCLUSIONS There is a diffuse reduction in myocardial beta-adrenoceptor density in patients with hypertrophic cardiomyopathy in the absence of significantly elevated circulating catecholamine concentrations. This most likely reflects downregulation of myocardial beta-adrenoceptors secondary to increased myocardial concentrations of norepinephrine and is consistent with the hypothesis that cardiac sympathetic drive is increased in this condition.

X-Ray Fused With Magnetic Resonance Imaging (XFM) to Target Endomyocardial Injections: Validation in a Swine Model of Myocardial Infarction

Background— Magnetic resonance imaging (MRI) permits 3-dimensional (3D) cardiac imaging with high soft tissue contrast. X-ray fluoroscopy provides high-resolution, 2-dimensional (2D) projection imaging. We have developed real-time x-ray fused with MRI (XFM) to guide invasive procedures that combines the best features of both imaging modalities. We tested the accuracy of XFM using external fiducial markers to guide endomyocardial cell injections in infarcted swine hearts. Methods and Results— Endomyocardial injections of iron-labeled mesenchymal stromal cells admixed with tissue dye were performed in previously infarcted hearts of 12 Yucatan miniswine (weight, 33 to 67 kg). Features from cardiac MRI were displayed combined with x-ray in real time to guide injections. During 130 injections, operators were provided with 3D surfaces of endocardium, epicardium, myocardial wall thickness (range, 2.6 to 17.7 mm), and infarct registered with live x-ray images to facilitate device navigation and choice of injection location. XFM-guided injections were compared with postinjection MRI and with necropsy specimens obtained 24 hours later. Visual inspection of the pattern of dye staining on 2,3,5-triphenyltetrazolium chloride–stained heart slices agreed (&kgr;=0.69) with XFM-derived injection locations mapped onto delayed hyperenhancement MRI and the susceptibility artifacts seen on the postinjection T2*-weighted gradient echo MRI. The distance between the predicted and actual injection locations in vivo was 3.2±2.6 mm (n=64), and 75% of injections were within 4.1 mm of the predicted location. Conclusions— Three-dimensional to two-dimensional registration of x-ray and MR images with the use of external fiducial markers accurately targets endomyocardial injection in a swine model of myocardial infarction.

Efficacy of a Device to Narrow the Coronary Sinus in Refractory Angina

BACKGROUND Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium. METHODS We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months. RESULTS A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction. CONCLUSIONS In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).

Technology Preview: X-Ray Fused With Magnetic Resonance During Invasive Cardiovascular Procedures

We have developed and validated a system for real‐time X‐ray fused with magnetic resonance imaging, MRI (XFM), to guide catheter procedures with high spatial precision. Our implementation overlays roadmaps—MRI‐derived soft‐tissue features of interest—onto conventional X‐ray fluoroscopy. We report our initial clinical experience applying XFM, using external fiducial markers, electrocardiogram (ECG)‐ gating, and automated real‐time correction for gantry and table movement.