Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET.

PURPOSE: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF). METHODS: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). RESULTS: Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI. CONCLUSIONS: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Data on the gut and saliva microbiota from a cohort of atherosclerosis patients determined by 16S rRNA gene sequencing.

This work was conducted to characterize the 16S rRNA gene profile of a cohort of patients with traditional risk factors for developing atherosclerosis. The patients in the cohort were divided into two extremes; those predicted to develop extreme atherosclerosis who did not (Protected), and those predicted not to develop atherosclerosis who did (Unexplained). Bacterial DNA was isolated from stool and saliva and this was used to determine the V4 variable region of the 16S rRNA gene sequence composition of the samples in triplicate.

Mediterranean Diet Score: Associations with Metabolic Products of the Intestinal Microbiome, Carotid Plaque Burden, and Renal Function.

Metabolic products of the intestinal microbiome such as trimethylamine N-oxide (TMAO) that accumulate in renal failure (gut-derived uremic toxins, GDUTs) affect atherosclerosis and increase cardiovascular risk. We hypothesized that patients on a Mediterranean diet and those consuming lower amounts of dietary precursors would have lower levels of GDUTs. Patients attending vascular prevention clinics completed a Harvard Food Frequency Questionnaire (FFQ) and had plasma levels of TMAO, p-cresylsulfate, hippuric acid, indoxyl sulfate, p-cresyl glucuronide, phenyl acetyl glutamine, and phenyl sulfate measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Carotid plaque burden was measured by ultrasound; CKD-Epi equations were used to estimate the glomerular filtration rate. In total, 276 patients completed the study. Even moderate renal function significantly increased plasma GDUTs, which were significantly associated with higher carotid plaque burden. There was no significant difference in plasma levels of any GDUT associated with a Mediterranean diet score or with intake of dietary precursors. In omnivorous patients with vascular disease, the intake of dietary precursors of intestinal metabolites or adherence to a Mediterranean diet did not change plasma GDUT. Approaches other than diet, such as probiotics and repopulation of the intestinal microbiome, may be required to mitigate the adverse effects of GDUTs.

Metabolic products of the intestinal microbiome and extremes of atherosclerosis.

BACKGROUND AND AIMS: There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area. METHODS: Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <-2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure - gut-derived uremic toxins (GDUT) - were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden. CONCLUSIONS: The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.

Repeatable and reproducible measurements of myocardial oxidative metabolism, blood flow and external efficiency using 11C-acetate PET.

BACKGROUND: Non-invasive approaches to investigate myocardial efficiency can help track the progression of heart failure (HF). This study evaluates the repeatability and reproducibility of 11C-acetate positron emission tomography (PET) imaging of oxidative metabolism. METHODS AND RESULTS: Dynamic 11C-acetate PET scans were performed at baseline and followup (47 ± 22 days apart) in 20 patients with stable HF with reduced ejection fraction. Two observers blinded to patients' clinical data used FlowQuant® to evaluate test-retest repeatability, as well as intra- and inter-observer reproducibility of 11C-acetate tracer uptake and clearance rates, for the measurement of myocardial oxygen consumption (MVO2), myocardial external efficiency (MEE), work metabolic index (WMI), and myocardial blood flow. Reproducibility and repeatability were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient-of-repeatability (CR). Test-retest correlations and repeatability were better for MEE and WMI compared to MVO2. All intra- and inter-observer correlations were excellent (ICC = 0.95-0.99) and the reproducibility values (CR = 3%-6%) were significantly lower than the test-retest repeatability values (22%-54%, P < 0.001). Repeatability was improved for all parameters using a newer PET-computed tomography (CT) scanner compared to older PET-only instrumentation. CONCLUSION: 11C-acetate PET measurements of WMI and MEE exhibited excellent test-retest repeatability and operator reproducibility. Newer PET-CT scanners may be preferred for longitudinal tracking of cardiac efficiency.

Factors Determining Periprocedural and Long-term Complications of High Risk Carotid Artery Stenting.

BACKGROUND AND PURPOSE: Carotid artery stenting (CAS) has been, historically, an alternative to open endarterectomy (CEA) for stroke prevention in high risk patients with carotid atherosclerosis. We sought to determine the rates of periprocedural and long-term stroke or death and the risk factors for complications after CAS in our high risk patient population. METHODS: Clinical and treatment variables of consecutive CAS procedures performed between 2002 and 2011 were analyzed. Using univariate and multivariate logistic regression analyses we examined how patient characteristics influenced outcomes and changes in modified Rankin Score (mRS). RESULTS: In 152 patients, the composite total of periprocedural death, stroke, transient ischemic attack (TIA) and myocardial infarction (MI) rate was 3.95% (6/152). Chronic kidney disease (CKD) was strongly associated with periprocedural complications (p<0.001). Coronary artery disease/peripheral vascular disease (CAD/PVD) (p=0.03), dyslipidemia (p=0.02), CKD (p=0.01), and contralateral internal carotid artery stenosis (p=0.02) were non-modifiable risk factors for mRS increase. There were 25 deaths, 8 strokes, 11 TIAs, and 1 MI (mean follow-up 38.4 months, range 0-116 months). The presence of CAD/PVD (p=0.009) and dyslipidemia (p=0.002) were significantly associated with long-term complications. CONCLUSION: CAS was performed with low periprocedural complications in high-risk patients. Our rates compare very favorably to large-scale trials that have ideal patients. This data encourages the consideration of CAS in patients considered high risk for CEA and provides possible patient characteristics (CKD) to help with periprocedural risk stratification.