RNA-seq profiling reveals different pathways between remodeled vessels and myocardium in hypertrophic cardiomyopathy.

OBJECTIVE: Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM. METHODS: Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile. RESULTS: We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls. CONCLUSIONS: We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

Determinants of outcome in patients with chronic ischemic left ventricular dysfunction undergone percutaneous coronary interventions.

BACKGROUND: Percutaneous coronary interventions (PCI) in patients with ischemic systolic left ventricular dysfunction (SLVD) are routinely performed although their impact on prognosis remains unclear. METHODS: We retrospectively evaluated 385 consecutive patients (76 % male, 66 ± 9 years) with SLVD (left ventricular ejection fraction [LVEF] ≤40 %) due to chronic coronary artery disease, who underwent PCI between 1999 and 2009, and explored clinical factors associated with higher risk of death or of a composite of death and hospitalization for acute decompensated heart failure (ADHF). RESULTS: The median follow-up was 28 months (inter-quartile range 14-46 months). Death and the composite outcome of death and hospitalization for ADHF occurred in 80 (21 %) and 109 (28 %) patients respectively (8.4 and 11.5 per 100 patient-years of follow-up). Insulin-dependent diabetes mellitus (IDDM), multivessel disease, LVEF < 35 %, symptoms of heart failure (HF) emerged both as independent predictors of death (adjusted hazard ratios [HR] 2.64; 1.92, 1.88 and 1.67 respectively) and composite outcome of death and hospitalization for ADHF (adjusted HR 2.22, 1.92, 1.79 and 1.94 respectively). Furthermore advanced age (HR = 1.03) emerged as independent predictors of death and having performed a stress test before PCI correlated with reduced number of deaths and ADHF hospitalizations (HR = 0.60). Of note, PCI significantly reduced the symptom of angina from 63.2 % at baseline to 16.3 % at the last follow up (p < 0.0001). CONCLUSIONS: IDDM, symptoms of HF, multivessel disease and LVEF < 35 % appear to be associated with worse outcome patients with ischemic SLVD undergoing PCI, and may be taken into account for optimal risk stratification. On the other hand, performing a stress testing before PCI seems to be associated with a more favorable outcome.

Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque.

Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment.

Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography.

AIMS: We sought to determine whether intraplaque inflammation could be measured with positron emission tomography/computed tomography angiography (PET/CTA) using (11)C-PK11195, a selective ligand of the translocator protein (18 kDa) (TSPO) which is highly expressed by activated macrophages. METHODS AND RESULTS: Patients (n = 32; mean age 70 ± 9 years) with carotid stenoses (n = 36; 9 symptomatic and 27 asymptomatic) underwent (11)C-PK11195 PET/CTA imaging. (11)C-PK11195 uptake into carotid plaques was measured using target-to-background ratios (TBR). On CTA images, plaque composition was assessed by measuring CT attenuation of the carotid plaque. Eight patients underwent carotid endarterectomy and ultrathin contiguous sections were processed for TSPO and CD68 (using immunohistochemical staining, (3)H-PK11195 autoradiography, and confocal fluorescence microscopy). Carotid plaques associated with ipsilateral symptoms (stroke or transient ischaemic attack) had higher TBR (1.06 ± 0.20 vs. 0.86 ± 0.11, P = 0.001) and lower CT attenuation [(median, inter-quartile range) 37, 24-40 vs. 71, 56-125 HU, P = 0.01] than those without. On immunohistochemistry and confocal fluorescence microscopy, CD68 and PBR co-localized with (3)H-PK11195 uptake at autoradiography. There was a significant correlation between (11)C-PK11195 TBR and autoradiographic percentage-specific binding (r = 0.77, P = 0.025). Both TBR and CT plaque attenuation had high negative predictive values (91 and 92%, respectively) for detecting symptomatic patients. However, the best positive predictive value (100%) was achieved when TBR and CT attenuation were combined. CONCLUSION: Imaging intraplaque inflammation in vivo with (11)C-PK11195 PET/CTA is feasible and can distinguish between recently symptomatic and asymptomatic plaques. Patients with a recent ischaemic event had ipsilateral plaques with lower CT attenuation and increased (11)C-PK11195 uptake.

The coronary circulation and blood flow in left ventricular hypertrophy.

Two distinct types of left ventricular hypertrophy (LVH) have been described: the so called "physiologic" hypertrophy, which is normally found in professional athletes, and "pathologic" LVH which is found in patients with inherited heart muscle disease such as hypertrophic cardiomyopathy (HCM) or patients with cardiac and systemic diseases characterized by pressure or volume overload. Patients with pathologic LVH have often symptoms and signs suggestive of myocardial ischemia despite normal coronary angiograms. Under these circumstances ischemia is due to coronary microvascular dysfunction (CMD). The abnormalities of the coronary microcirculation may be unrelated to the degree of LVH and cause a reduction in maximum myocardial blood flow which, in the absence of epicardial stenoses, is suggestive of CMD. There is no technique that enables direct visualization of coronary microcirculation in vivo in humans. Therefore, its assessment relies on the measurement of parameters which reflect its functional status, such as myocardial blood flow and coronary flow reserve which is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. In this review article we discuss the pathophysiological mechanisms responsible for CMD in patients with primary and secondary LVH and how the recognition of this phenomenon is providing new important information on patient stratification and prognosis. Finally, we discuss how assessment of CMD may be used as a valuable surrogate marker to test the efficacy of old and new drugs. This article is part of a Special Issue entitled "Coronary Blood Flow".

Myosins and MyomiR Network in Patients with Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls). A subset of tissue-abundant myectomy samples from HCM (n = 10) and controls (n = 6) was submitted to laser-capture microdissection to isolate cardiomyocytes. We investigated the relationship among clinical phenotype, cardiac myosin proteins (MyHC6, MyHC7, and MyHC7b) measured by optimized label-free mass spectrometry, the relative genes (MYH7, MYH7B and MYLC2), and the MyomiR network (myosin-encoded microRNA (miRs) and long-noncoding RNAs (Mhrt)) measured using RNA sequencing and RT-qPCR. MyHC6 was lower in HCM vs. controls, whilst MyHC7, MyHC7b, and MyLC2 were comparable. MYH7, MYH7B, and MYLC2 were higher in HCM whilst MYH6, miR-208a, miR-208b, miR-499 were comparable in HCM and controls. These results are compatible with defective transcription by active genes in HCM. Mhrt and two miR-499-target genes, SOX6 and PTBP3, were upregulated in HCM. The presence of HCM-associated mutations correlated with PTBP3 in myectomies and with SOX6 in cardiomyocytes. Additionally, iPSC-derived cardiomyocytes, transiently transfected with either miR-208a or miR-499, demonstrated a time-dependent relationship between MyomiRs and myosin genes. The transfection end-stage pattern was at least in part similar to findings in HCM myectomies. These data support uncoupling between myosin protein/genes and a modulatory role for the myosin/MyomiR network in the HCM myocardium, possibly contributing to phenotypic diversity and providing putative therapeutic targets.

Is there evidence supporting coronary revascularization in patients with left ventricular systolic dysfunction?

The mid- and long-term outcomes of revascularization procedures in patients with chronic left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) in the presence or absence of heart failure (HF) symptoms are still uncertain. The identification of dysfunctional myocardial segments with residual viability that can improve after revascularization is pivotal for further patient management. Hibernating myocardium (ie, chronically dysfunctional but still viable tissue) can be identified by positron emission tomography (PET) and cardiac magnetic resonance (CMR) and its presence and extent can predict functional recovery after revascularization. Before ß-blockers were introduced as routine care for HF, surgical revascularization appeared to improve survival in these patients. Nowadays, novel medical treatments and devices, such as cardiac-resynchronization therapy and implantable cardioverter-defibrillators, have improved the prognosis of HF patients and their use is supported by a number of clinical trials. To adequately address the unresolved issue of the prognostic benefits of coronary revascularization in CAD patients with chronic LV dysfunction on optimal medical therapy with/without devices a randomized trial is warranted. In such a trial the presence of viability will be assessed by either PET or CMR. This is an overview of the pathophysiological mechanisms, as well as of the main clinical studies and meta-analyses that have addressed this issue in the past 4 decades.

Assessment of myocardial ischaemia and viability: role of positron emission tomography.

In developed countries, coronary artery disease (CAD) continues to be a major cause of death and disability. Over the past two decades, positron emission tomography (PET) imaging has become more widely accessible for the management of ischemic heart disease. Positron emission tomography has also emerged as an important alternative perfusion imaging modality in the context of recent shortages of molybdenum-99/technetium-99m ((99m)Tc). The clinical application of PET in ischaemic heart disease falls into two main categories: first, it is a well-established modality for evaluation of myocardial blood flow (MBF); second, it enables assessment of myocardial metabolism and viability in patients with ischaemic left ventricular dysfunction. The combined study of MBF and metabolism by PET has led to a better understanding of the pathophysiology of ischaemic heart disease. While there are potential future applications of PET for plaque and molecular imaging, as well as some clinical use in inflammatory conditions, this article provides an overview of the physical and biological principles behind PET imaging and its main clinical applications in cardiology, namely the assessment of MBF and metabolism.

Myocardial beta-adrenoceptor down-regulation early after infarction is associated with long-term incidence of congestive heart failure.

AIMS: Adverse left ventricular (LV) remodelling after myocardial infarction (MI) frequently leads to congestive heart failure (CHF). We have previously shown that myocardial beta-adrenoceptor density (beta-ARD) is reduced soon after acute MI and correlates with LV dilatation in the short term. The aim of the present study was to determine whether myocardial beta-ARD measured early after MI was associated with progression to CHF in the long term. METHODS AND RESULTS: We prospectively included 61 consecutive patients (mean age, 52 +/- 11 years, 10 female) in whom MI was the first manifestation of coronary artery disease. Two to 4 weeks after MI, patients underwent positron emission tomography with S-[(11)C]CGP 12177 to measure beta-ARD and (15)O-labelled water to measure myocardial blood flow and coronary flow reserve. Patients were followed-up for a median of 12.7 years (interquartile range, 6.5-13.7 years) and incidence of CHF was recorded. Eleven patients (18%) developed CHF during follow-up. They had lower beta-ARD compared with those who did not (5.35 vs. 6.49 pmol/g, P < 0.001). In patients with myocardial beta-ARD < or =5.57 pmol/g, 10-year CHF incidence rates were higher than in patients with beta-ARD >5.57 pmol/g (57% vs. 9%, P < 0.001). In a Cox regression model, only whole-heart beta-ARD [hazard ratio (HR) 0.29; 95% confidence interval (CI), 0.15-0.58, P < 0.001] and beta-ARD in remote myocardium (HR 0.32; 95% CI, 0.16-0.61, P = 0.001) were significantly associated with the incidence of CHF at follow-up. CONCLUSION: Reduced myocardial beta-ARD early after MI is associated with the incidence of CHF on long-term follow-up.

Mitochondrial Energetics and Ca2+-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca2+-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca2+-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca2+-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here.

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.

Extent and characteristics of carotid plaques and brain parenchymal loss in asymptomatic patients with no indication for revascularization.

BACKGROUND AND AIMS: Extent of subclinical atherosclerosis has been associated with brain parenchymal loss in community-dwelling aged subjects. Identification of patient-related and plaque-related markers could identify subjects at higher risk of brain atrophy, independent of cerebrovascular accidents. Aim of the study was to investigate the relation between extent and characteristics of carotid plaques and brain atrophy in asymptomatic patients with no indication for revascularization. METHODS AND RESULTS: Sixty-four patients (aged 69 ± 8 years, 45% females) with carotid stenosis <70% based on Doppler flow velocity were enrolled in the study. Potential causes of cerebral damage other than atherosclerosis, including history of atrial fibrillation, heart failure, previous cardiac or neurosurgery and neurological disorders were excluded. All subjects underwent carotid computed tomography angiography, contrast enhanced ultrasound for assessment of plaque neovascularization and brain magnetic resonance imaging for measuring brain volumes. On multivariate regression analysis, age and fibrocalcific plaques were independently associated with lower total brain volumes (ß = -3.13 and ß = -30.7, both p < 0.05). Fibrocalcific plaques were also independently associated with lower gray matter (GM) volumes (ß = -28.6, p = 0.003). On the other hand, age and extent of carotid atherosclerosis were independent predictors of lower white matter (WM) volumes. CONCLUSIONS: WM and GM have different susceptibility to processes involved in parenchymal loss. Contrary to common belief, our results show that presence of fibrocalcific plaques is associated with brain atrophy.

Myocardial stunning is associated with impaired calcium uptake by sarcoplasmic reticulum.

Myocardial stunning (temporary post-ischaemic contractile dysfunction) may be caused by oxidative stress and/or impaired myocyte calcium homeostasis. Regional myocardial stunning was induced in open-chest pigs (segment shortening reduced to 68.3+/-4.7% of baseline) by repetitive brief circumflex coronary occlusion (I/R). Reduced glutathione was depleted in stunned myocardium (1.34+/-0.06 vs. 1.77+/-0.11 nmol/mg, p=0.02 vs. remote myocardium) indicating regional oxidant stress, but no regional differences were observed in protein-bound 3-nitrotyrosine or S-nitrosothiol content. Repetitive I/R did not affect myocardial quantities of the sarcolemmal sodium-calcium exchanger, L-type channel, SR calcium ATPase and phospholamban, or the kinetics of ligand binding to L-type channels and SR calcium release channels. However, initial rates of oxalate-supported (45)Ca uptake by SR were impaired in stunned myocardium (41.3+/-13.5 vs. 73.0+/-15.6 nmol/min/mg protein, p=0.03). The ability of SR calcium ATPase to sequester cytosolic calcium is impaired in stunned myocardium. This is a potential mechanism underlying contractile dysfunction.

The clinical value of myocardial blood flow measurement.

PET provides robust and reproducible measurements of regional myocardial blood flow in milliliters per minute per gram of tissue, providing unique pathophysiologic and diagnostic information on the function of the coronary macro- and microcirculation. There is compelling evidence to suggest that in many instances abnormalities of global myocardial perfusion are demonstrated in individuals with either coronary risk factors for coronary artery disease or different myocardial diseases in the absence of angiographically demonstrable stenosis of the epicardial coronary arteries. In this context, measurement of myocardial blood flow gives unique diagnostic information regarding the function of the coronary microcirculation and provides a quantitative surrogate endpoint against which the efficacy of treatments can be established.

Impairment of coronary flow reserve in aortic stenosis.

Coronary flow reserve (CFR) is markedly reduced in patients with severe aortic valve stenosis (AS), but the exact mechanisms underlying this impairment of CFR in AS remain unclear. Reduced CFR is the key mechanism leading to myocardial ischemia symptoms and adverse outcomes in AS patients. The objective of this study was to develop an explicit mathematical model formulated with a limited number of parameters that describes the effect of AS on left coronary inflow patterns and CFR. We combined the mathematical V(3) (ventricular-valvular-vascular) model with a new lumped-parameter model of coronary inflow. One thousand Monte-Carlo computational simulations with AS graded from mild up to very severe were performed within a wide range of physiological conditions. There was a good agreement between the CFR values computed with this new model and those measured in 24 patients with isolated AS (r = 0.77, P < 10(-4)). A global sensitivity analysis showed that the valve effective orifice area (EOA) was the major physiological determinant of CFR (total sensitivity index = 0.87). CFR was markedly reduced when AS became severe, i.e., when EOA was <1.0 cm(2), and was generally exhausted when the EOA was <0.5-0.6 cm(2). The reduction of CFR that is associated with AS can be explained by the concomitance of 1) reduced myocardial supply as a result of decreased coronary perfusion pressure, and 2) increased myocardial metabolic demand as a result of increased left ventricular workload.

Progression of brain white matter hyperintensities in asymptomatic patients with carotid atherosclerotic plaques and no indication for revascularization.

BACKGROUND AND AIMS: Brain white matter hyperintensities (WMHs) have been associated with an increased risk of ischemic stroke and considered as markers of brain ischemia. Progression of WMHs in asymptomatic patients with non-hemodynamically significant carotid plaque could represent a putative marker of plaque vulnerability. We prospectively evaluate progression and determinants of WMHs in this population. METHODS: This prospective study included 51 asymptomatic patients with carotid stenosis <70% that underwent brain magnetic resonance imaging scans at baseline and after a median follow up of 595 days (interquartile range 553-641 days). Patients (mean age of 69 years and 45% females) underwent baseline carotid computed tomography angiography, contrast-enhanced ultrasound for carotid plaque characterization and analysis of subsets of circulating lymphocytes and monocytes by flow cytometry. RESULTS: Seventeen subjects (33.3%) had carotid stenoses of 50-70% (Doppler flow velocity) while the rest had stenoses of <50%. In 25 (49.0%) patients, new WMHs, with 5 new lesions on average and a median volume of 134 mm3, were detected at follow-up. None of the plaque characteristics or of the circulating cellular biomarkers investigated were associated with the global and ipsilateral occurrence of new WMHs whereas, at multivariate analysis, female sex, hypercholesterolemia, and lower glomerular filtration rate (GFR) emerged as independent variables associated with new WMHs. CONCLUSIONS: Half of the patients with carotid plaques of intermediate severity had evidence of WMH progression at follow up. Female gender and systemic factors such as hypercholesterolemia, and lower GFR, but not plaque characteristics or circulating cellular biomarkers, are associated with WMH progression.

Carotid artery plaque uptake of 11C-PK11195 inversely correlates with circulating monocytes and classical CD14++CD16- monocytes expressing HLA-DR.

BACKGROUND: We explored the relation between blood concentrations of monocyte/lymphocyte subsets and carotid artery plaque macrophage content, measured by positron emission tomography (PET) with 11C-PK11195. METHODS AND RESULTS: In 9 patients with carotid plaques we performed 11C-PK11195-PET/computed tomography angiography imaging and measurement of absolute concentrations and frequencies of circulating monocytes and T-cell subsets. Plaque standardized uptake value (SUV) for 11C-PK11195 was negatively correlated with concentrations of total monocytes (r = -0.58, p = 0.05) and CD14++CD16-HLA-DR+ classical subset (r = -0.82, p = 0.005). These correlations hold true also in relation to plaque target to background ratio. No correlation was observed between plaque SUV and CD3+T lymphocytes, CD4+T lymphocytes nor with activated CD3+CD4+T cells expressing HLA-DR. CONCLUSIONS: We first demonstrated a reduction in the absolute concentration of monocytes and particularly in classical monocytes expressing HLA-DR in the presence of an increased uptake of 11C-PK11195 in carotid plaques. The present work, despite being a pilot study comprising only a small number of subjects provides new insights in the search for specific cellular biomarkers with potential diagnostic and prognostic value in patients with a known carotid plaque.

Relation between characteristics of carotid atherosclerotic plaques and brain white matter hyperintensities in asymptomatic patients.

White matter hyperintensities (WMH) can be incidentally found in patients with carotid atherosclerosis on brain magnetic resonance imaging (MRI). We investigated the relationship between WMH and characteristics of carotid plaques in asymptomatic patients without indication for carotid revascularization. We prospectively screened 235 consecutive patients with carotid stenosis <70%. After excluding patients with confounding causes of cerebral damage, 67 asymptomatic patients underwent carotid computed tomography angiography (CTA), contrast-enhanced ultrasound and brain MRI. Number and quantitative measurement of volume of WMH were associated with history of resistant hypertension, degree of stenosis (Doppler) and presence of an ulcerated plaque at CTA (p < 0.05). At multivariate regression analysis, resistant hypertension was independently associated with both number and volume of WMH, presence of an ulcer with number of WMH and degree of stenosis with WMH volume (p < 0.05), although WMH were equally distributed in both hemispheres irrespectively of plaque side. In conclusion, in asymptomatic patients with carotid plaques <70%, a higher burden of WMHs is associated with history of resistant hypertension that could be the expression of microvascular damage. Stenosis severity and presence of plaque ulceration are also associated with WMH burden although their causative relation is not supported by the bilateral distribution of WMH.