Nikant Sabharwal

Relationship Between Left Ventricular Structural and Metabolic Remodeling in Type 2 Diabetes

Concentric left ventricular (LV) remodeling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodeling in diabetes per se is unclear, but it may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship between myocardial metabolic changes and LV remodeling in T2DM. Forty-six nonhypertensive patients with T2DM and 20 matched control subjects underwent cardiovascular magnetic resonance to assess LV remodeling (LV mass–to–LV end diastolic volume ratio), function, tissue characterization before and after contrast using T1 mapping, and 1H and 31P magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine-to-ATP ratio, respectively. When compared with BMI- and blood pressure–matched control subjects, subjects with diabetes were associated with concentric LV remodeling, higher MTG, impaired myocardial energetics, and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodeling and systolic strain. Extracellular volume fraction was unchanged, indicating the absence of fibrosis. In conclusion, cardiac steatosis may contribute to concentric remodeling and contractile dysfunction of the LV in diabetes. Because cardiac steatosis is modifiable, strategies aimed at reducing MTG may be beneficial in reversing concentric remodeling and improving contractile function in the hearts of patients with diabetes.

Ectopic and Visceral Fat Deposition in Lean and Obese Patients With Type 2 Diabetes

Background Type 2 diabetes (T2D) and obesity are associated with nonalcoholic fatty liver disease, cardiomyopathy, and cardiovascular mortality. Both show stronger links between ectopic and visceral fat deposition, and an increased cardiometabolic risk compared with subcutaneous fat. Objectives This study investigated whether lean patients (Ln) with T2D exhibit increased ectopic and visceral fat deposition and whether these are linked to cardiac and hepatic changes. Methods Twenty-seven obese patients (Ob) with T2D, 15 Ln-T2D, and 12 normal-weight control subjects were studied. Subjects underwent cardiac computed tomography, cardiac magnetic resonance imaging (MRI), proton and phosphorus MR spectroscopy, and multiparametric liver MR, including hepatic proton MRS, T1- and T2*-mapping yielding “iron-corrected T1” [cT1]. Results Diabetes, with or without obesity, was associated with increased myocardial triglyceride content (p = 0.01), increased hepatic triglyceride content (p = 0.04), and impaired myocardial energetics (p = 0.04). Although cardiac structural changes, steatosis, and energetics were similar between the T2D groups, epicardial fat (p = 0.04), hepatic triglyceride (p = 0.01), and insulin resistance (p = 0.03) were higher in Ob-T2D. Epicardial fat, hepatic triglyceride, and insulin resistance correlated negatively with systolic strain and diastolic strain rates, which were only significantly impaired in Ob-T2D (p < 0.001 and p = 0.006, respectively). Fibroinflammatory liver disease (elevated cT1) was only evident in Ob-T2D patients. cT1 correlated with hepatic and epicardial fat (p < 0.001 and p = 0.01, respectively). Conclusions Irrespective of body mass index, diabetes is related to significant abnormalities in cardiac structure, energetics, and cardiac and hepatic steatosis. Obese patients with T2D show a greater propensity for ectopic and visceral fat deposition.

Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus

Aims Patients with type 2 diabetes mellitus (T2DM) are known to have impaired resting myocardial energetics and impaired myocardial perfusion reserve, even in the absence of obstructive epicardial coronary artery disease (CAD). Whether or not the pre-existing energetic deficit is exacerbated by exercise, and whether the impaired myocardial perfusion causes deoxygenation and further energetic derangement during exercise stress, is uncertain. Methods and results Thirty-one T2DM patients, on oral antidiabetic therapies with a mean HBA1c of 7.4 ± 1.3%, and 17 matched controls underwent adenosine stress cardiovascular magnetic resonance for assessment of perfusion [myocardial perfusion reserve index (MPRI)] and oxygenation [blood-oxygen level-dependent (BOLD) signal intensity change (SIΔ)]. Cardiac phosphorus-MR spectroscopy was performed at rest and during leg exercise. Significant CAD (>50% coronary stenosis) was excluded in all patients by coronary computed tomographic angiography. Resting phosphocreatine to ATP (PCr/ATP) was reduced by 17% in patients (1.74 ± 0.26, P = 0.001), compared with controls (2.07 ± 0.35); during exercise, there was a further 12% reduction in PCr/ATP (P = 0.005) in T2DM patients, but no change in controls. Myocardial perfusion and oxygenation were decreased in T2DM (MPRI 1.61 ± 0.43 vs. 2.11 ± 0.68 in controls, P = 0.002; BOLD SIΔ 7.3 ± 7.8 vs. 17.1 ± 7.2% in controls, P < 0.001). Exercise PCr/ATP correlated with MPRI (r = 0.50, P = 0.001) and BOLD SIΔ (r = 0.32, P = 0.025), but there were no correlations between rest PCr/ATP and MPRI or BOLD SIΔ. Conclusion The pre-existing energetic deficit in diabetic cardiomyopathy is exacerbated by exercise; stress PCr/ATP correlates with impaired perfusion and oxygenation. Our findings suggest that, in diabetes, coronary microvascular dysfunction exacerbates derangement of cardiac energetics under conditions of increased workload.

Detecting human coronary inflammation by imaging perivascular fat

Adipocyte size and lipid content in perivascular adipose tissue are inversely associated with coronary inflammation and atherosclerotic plaque burden in human patients. Picturing plaques and imaging inflammation To determine risk of future coronary artery disease, calcium content in vascular plaques is typically evaluated by coronary calcium scoring, which uses computerized tomography (CT) imaging. To detect inflammation and subclinical coronary artery disease (soft, noncalcified plaques), Antonopoulos et al. developed an alternative metric called the perivascular CT fat attenuation index (FAI). The perivascular FAI uses CT imaging of adipose tissue surrounding the coronary arteries to assess adipocyte size and lipid content. Larger, more mature adipocytes exhibit greater lipid accumulation, which is inversely associated with the FAI. Inflammation reduces lipid accumulation and slows preadipocyte differentiation. Imaging pericoronary fat in human patients after myocardial infarction revealed that unstable plaques had larger perivascular FAIs than stable plaques and that the FAI was greatest directly adjacent to the inflamed coronary artery. The perivascular FAI may be a useful, noninvasive method for monitoring vascular inflammation and the development of coronary artery disease. Early detection of vascular inflammation would allow deployment of targeted strategies for the prevention or treatment of multiple disease states. Because vascular inflammation is not detectable with commonly used imaging modalities, we hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation could be quantified using a new computerized tomography (CT) angiography methodology. We show that inflamed human vessels release cytokines that prevent lipid accumulation in PVAT-derived preadipocytes in vitro, ex vivo, and in vivo. We developed a three-dimensional PVAT analysis method and studied CT images of human adipose tissue explants from 453 patients undergoing cardiac surgery, relating the ex vivo images with in vivo CT scan information on the biology of the explants. We developed an imaging metric, the CT fat attenuation index (FAI), that describes adipocyte lipid content and size. The FAI has excellent sensitivity and specificity for detecting tissue inflammation as assessed by tissue uptake of 18F-fluorodeoxyglucose in positron emission tomography. In a validation cohort of 273 subjects, the FAI gradient around human coronary arteries identified early subclinical coronary artery disease in vivo, as well as detected dynamic changes of PVAT in response to variations of vascular inflammation, and inflamed, vulnerable atherosclerotic plaques during acute coronary syndromes. Our study revealed that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can be monitored using a CT imaging approach. This methodology can be implemented in clinical practice to noninvasively detect plaque instability in the human coronary vasculature.

Mycotic aneurysm of the superior mesenteric artery and other sequelae of prosthetic valve endocarditis on 18F-FDG PET/CT

A 61-year-old man with an implantable cardioverter defibrillator (ICD) and treated tissue aortic valve Staphylococcus epidermidis endocarditis, re-presented with fevers. Echocardiography confirmed recurrent valvular vegetations and blood cultures grew S. epidermidis. F-FDG PET/CT was performed to exclude infection associated with the ICD or elsewhere. This demonstrated a markedly FDG-avid (SUVmax 12.9) dilated proximal superior mesenteric artery (a) surrounded by fat stranding (b), a curvilinear moderately FDG-avid (SUVmax 6.2) normal calibre distal splenic artery (c), confirmed as mycotic thrombus on subsequent CT angiography, and photopenic splenic infarcts (d). There was mild–moderate FDG uptake associated with the prosthetic valve (e) attributed to the vegetations, with no abnormal FDG uptake relating to the ICD. This case illustrates the utility of PET/CT to delineate extracardiac sites of septic embolism and their sequelae [1], and to investigate cardiac device infection (specificities of 85 – 100 %) [2, 3]. The negative finding practically excluded ICD infection and informed decisions on device removal.

Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data.

Summary Background Coronary artery inflammation inhibits adipogenesis in adjacent perivascular fat. A novel imaging biomarker—the perivascular fat attenuation index (FAI)—captures coronary inflammation by mapping spatial changes of perivascular fat attenuation on coronary computed tomography angiography (CTA). However, the ability of the perivascular FAI to predict clinical outcomes is unknown. Methods In the Cardiovascular RISk Prediction using Computed Tomography (CRISP-CT) study, we did a post-hoc analysis of outcome data gathered prospectively from two independent cohorts of consecutive patients undergoing coronary CTA in Erlangen, Germany (derivation cohort) and Cleveland, OH, USA (validation cohort). Perivascular fat attenuation mapping was done around the three major coronary arteries—the proximal right coronary artery, the left anterior descending artery, and the left circumflex artery. We assessed the prognostic value of perivascular fat attenuation mapping for all-cause and cardiac mortality in Cox regression models, adjusted for age, sex, cardiovascular risk factors, tube voltage, modified Duke coronary artery disease index, and number of coronary CTA-derived high-risk plaque features. Findings Between 2005 and 2009, 1872 participants in the derivation cohort underwent coronary CTA (median age 62 years [range 17–89]). Between 2008 and 2016, 2040 patients in the validation cohort had coronary CTA (median age 53 years [range 19–87]). Median follow-up was 72 months (range 51–109) in the derivation cohort and 54 months (range 4–105) in the validation cohort. In both cohorts, high perivascular FAI values around the proximal right coronary artery and left anterior descending artery (but not around the left circumflex artery) were predictive of all-cause and cardiac mortality and correlated strongly with each other. Therefore, the perivascular FAI measured around the right coronary artery was used as a representative biomarker of global coronary inflammation (for prediction of cardiac mortality, hazard ratio [HR] 2·15, 95% CI 1·33–3·48; p=0·0017 in the derivation cohort, and 2·06, 1·50–2·83; p<0·0001 in the validation cohort). The optimum cutoff for the perivascular FAI, above which there is a steep increase in cardiac mortality, was ascertained as −70·1 Hounsfield units (HU) or higher in the derivation cohort (HR 9·04, 95% CI 3·35–24·40; p<0·0001 for cardiac mortality; 2·55, 1·65–3·92; p<0·0001 for all-cause mortality). This cutoff was confirmed in the validation cohort (HR 5·62, 95% CI 2·90–10·88; p<0·0001 for cardiac mortality; 3·69, 2·26–6·02; p<0·0001 for all-cause mortality). Perivascular FAI improved risk discrimination in both cohorts, leading to significant reclassification for all-cause and cardiac mortality. Interpretation The perivascular FAI enhances cardiac risk prediction and restratification over and above current state-of-the-art assessment in coronary CTA by providing a quantitative measure of coronary inflammation. High perivascular FAI values (cutoff ≥–70·1 HU) are an indicator of increased cardiac mortality and, therefore, could guide early targeted primary prevention and intensive secondary prevention in patients. Funding British Heart Foundation, and the National Institute of Health Research Oxford Biomedical Research Centre.

Severe vasospastic angina complicated by multiple pulseless electrical activity arrests.

In May, 2012, a 46year-old woman reported chest pain before having an out-of-hospital cardiac arrest. Para medics successfully resuscitated her. The pre-arrest rhythm strip showed a sinus tachycardia only. A 12-h troponin I was raised at 5·9 μg/L (normal values 0–0·04 μg/L) A year earlier, she had been admitted with a similar history of chest pain, which had developed after taking sumatriptan for a migraine. A 12-lead electrocardiograph (ECG) showed transient inferior and lateral ST elevation. A 12-h troponin was negative. At this time, coronary angiography showed a normal left coronary system and a dominant right coronary artery, with minor ostial spasm and slow fl ow. A bubble study was negative for right to left shunting. She was diagnosed with vasospastic angina and started oral diltiazem. On advice, she stopped smoking and sumatriptan was discontinued. She continued to have occasional episodes of chest pain responsive to sublingual glycerol trinitrate. At the time of her cardiac arrest, her regular medications were oral diltiazem, nicorandil, lansoprazole, and a beclometasone inhaler. In the 48 h after the cardiac arrest she had fi ve additional pulseless electrical activity (PEA) arrests while intubated and ventilated in the intensive care unit. These were characterised by transient ST elevation (fi gure) and progressive hypotension, cul minating in loss of car diac output. Each episode responded to about 15–25 min of resuscitation. In between episodes, left ven tricular size and function was normal on echocardi ography. Electro cardiography was unremarkable. Repeat coronary angi ography showed normal coronary arteries, though of smaller luminal diameter than a year earlier. An intra-aortic balloon pump and a temporary tunnelled dual cham ber pacemaker were placed, which permitted potent vaso dilator therapy (intra venous glyceryl trinitrate and verapa mil, with nifedipine via a nasogastric tube) to be estab lished without the need for prolonged use of ino tropes. During this time, one episode of ST elevation and brady cardia was ter minated with a bolus of intravenous verapamil. The patient had a full neurological recovery; however it was complicated by the development of compartment syndrome in her left leg which necessitated removal of the intra-aortic balloon pump and a fasciotomy. She was converted to oral medications and underwent a cardiac magnetic resonance scan which was normal. At review in July, 2013, she remains entirely well. Although ventricular arrhythmia is recognised as the main cause of cardiac arrest in these patients, isolated cases of PEA have been reported. However, only one case has been described fully and did not feature the type of aggressive disease, with recurrent PEA arrests, detailed here. Patients with vasospastic angina are at higher risk of cardiac arrest than the background population. In a recent study of 1429 patients with vaso spastic angina, 35 (2·4%) had an out-of-hospital arrest and were younger (mean age 58 years) and more likely to have spasm of the left anterior descending coronary artery than were patients who had not had cardiac arrest. Since predicting which patients will have recurrent events is diffi cult, one suggestion is that all patients with vasospastic angina and a history of life-threatening arrhyth mia could benefi t from an automated implantable cardioverter-defi brillator alongside calcium channel blockers. In the absence of ventricular arrhythmias in our patient, an implantable cardioverter-defi brillator was not felt to be benefi cial. That this patient developed compart ment syndrome with no history of peripheral vascular disease is note worthy. We postulated that this was directly related to vasospasm provoked by the intra-aortic balloon pump. This case also highlights the value of intravenous calcium channel blockade to abort ST elevation and progression to PEA arrest. Our patient has been reminded to treat any further chest pain promptly with sublingual glyceryl trinitrate and seek immediate medical attention. Maintenance of vasodilator therapy has been strongly recommended.

Multi-vessel disease and CZT SPECT. Comparison with coronary angiography

The thorny issue of multi-vessel balanced ischemia raises it head again. One of the greatest fears in Nuclear Cardiology is the fact that we might miss a ‘‘balanced’’ multi-vessel ischemia situation and call the perfusion scan normal. Underidentification and treatment of these patients is an ongoing problem. Conversely, underdiagnosing the extent of coronary lesions with SPECT once a patient has already been referred to angiography, due to the severity of identified ischemia, is forgivable. If we identify single-vessel disease but the patient has two separate coronary lesions, then the principle of ‘‘no harm’’ can be ascribed apart from possibly underdetecting the total ischemic burden. The problem of globally reduced relative perfusion has generated a whole raft of indices that help the reporter to identify a ‘‘normal’’ scan from a homogenously hypo-perfused but balanced ischemic myocardium. Transient ischemic dilatation, a drop in stress LVEF, RV prominence, lung uptake with thallium 201 and more recently coronary calcification have all been proposed as potential indicators of multi-vessel ischemia. The frequency of missed balanced multi-vessel ischemia is possibly lower than what we realize when an experienced reader is reporting the scans. The greatest assumption is that the invasive luminogram (aka invasive coronary angiogram) is the ‘‘gold standard’’. As a result, anatomical-based investigations will then tend to be more ‘‘accurate’’ that functional tests. The discussion regarding perfusion versus anatomical assessment is advanced and mature. It is well recognized that diffuse CAD can produce ischemic defects in the absence of discrete stenosis. For this reason, FFR evaluation of ‘‘moderate’’ CAD is considered reasonable in all but the most obviously stenosed vessel. Ideally, we should be moving away from the anatomy/perfusion debate and looking at patient-focussed events such as improvement in symptoms and cardiac event rates. However, in the ‘‘real world’’ the practicalities of providing medical care can sometimes be very different to the published clinical trial literature. The authors of this paper should be congratulated on taking on this task with a defined set of parameters that apply a ‘‘real world’’ situation. Patients with chest pain and either an intermediate likelihood of IHD or known CAD were subjected to both Tc-tetrofosmin CZT SPECT and coronary angiography (invasive or CT). Bicycle stress was the predominant stress method employed. A low-dose one-day stress-rest protocol was utilized. Results are stratified according to semi-quantitative SSS and SDS evaluation of perfusion by two experienced reporters. The results confirm that on a per-patient basis, a SSS [7 ([10% of LV myocardium) showed a sensitivity of 74% (95% CI 70% to 79%) and a specificity of 83% (95% CI 80% to 89%) in detecting [70% coronary stenosis lesions on quantitative angiographic criteria. In 16% of patients, MPI did not show significant perfusion abnormalities despite the presence of angiographic CAD, while in 6% it was positive in the absence of obstructive coronary lesions (more frequent in diabetics and those with multi-vessel disease). The false positive results occurred in older patients and those with Reprint requests: Nikant Sabharwal, BSc, BM BCh, DM, FRCP, Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom; nikant.sabharwal@ouh.nhs.uk J Nucl Cardiol 2017;24:696–7. 1071-3581/

State of the art in nuclear cardiology

34.00 Copyright 2016 American Society of Nuclear Cardiology.

Three-dimensional transoesophageal echocardiography of an aberrant chordae tendinae causing aortic valvular regurgitation

### Learning objectives Nuclear Cardiology is the most frequently used functional imaging test in the UK and throughout the world. It was the first test used to localise and quantify myocardial ischaemia. The wealth of evidence related to diagnosis and long-term prognosis in varying subgroups is unparalleled.1 Radionuclide ventriculography (RNV) provides a geometrically independent assessment of ventricular function which remains the gold standard. Nuclear techniques can be used in patients with renal dysfunction, obesity, dysrhythmias and claustrophobia. Up until a few years ago, gamma camera hardware relied on the inexpensive technology of the 1960s, which has only recently undergone a revolution in response to improvements to complementary modalities. Radiation doses continue to fall. Exciting developments in positron emission tomography (PET) and hybrid imaging are promising a bright future with a potential resurgence in popularity for this ‘workhorse’. The mainstay of Nuclear Cardiology, myocardial perfusion scintigraphy (MPS), is performed using single photon emission computed tomography (SPECT) via a gamma camera. Worldwide, there is significant interest and investment in the role of PET in the assessment of myocardial disease. Gamma cameras have used the scintillation properties of sodium iodide (NaI) since the 1960s. Solid-state detectors using cadmium zinc telluride (CZT) are available on modern systems which allow for a significant improvement in sensitivity, additional radiation dose reductions or reduced scanning time.2 On a new CZT system, a scan time of 4–6 min is achievable with a much lower injected dose than that used for a NaI gamma camera. Iterative reconstruction with resolution recovery software is available for …