Circulation Topic Review

Circulation Editors’ Picks

Most Read Articles in Cardiovascular Imaging

The Editors
https://doi.org/10.1161/CIRCULATIONAHA.113.004366
Circulation. 2013;128:e32-e38
Originally published July 15, 2013

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Computed Tomography Coronary Angiography in Patients With Acute Myocardial Infarction Without Significant Coronary Stenosis

Summary—Almost 10% of patients with acute myocardial infarction have normal or nonsignificant coronary stenosis at coronary angiography. The absence of critical stenosis may challenge the diagnosis, however atherosclerosis may be present also in angiographically normal coronary arteries attributable to outward remodeling and acute myocardial infarction may result from disruption of nonobstructive atherosclerotic plaques. In this study, we enrolled 50 consecutive patients with acute myocardial infarction confirmed by late gadolinium–enhanced cardiac magnetic resonance without obstructive coronary stenosis at coronary angiography. In this population, coronary computed tomography angiography showed a significant number of angiographically invisible atherosclerotic plaques. Moreover, coronary plaques located on infarct-related arteries were more frequently mixed or noncalcified with higher mean plaque area and remodeling index, compatible with vulnerable plaques. These findings may support the use of optimal secondary prevention therapy to reduce the risk of recurrent events.

Conclusions—Computed tomography conorary angiography detects coronary plaques in nonstenotic coronary arteries that are underestimated by coronary angiography, and identifies a different distribution of plaque types in infarct-related arteries and non-infarct-related arteries. It may therefore be valuable for diagnosing coronary atherosclerosis in acute myocardial infarction patients without significant coronary stenosis.1

Impact of a High Loading Dose of Atorvastatin on Contrast-Induced Acute Kidney Injury

Summary—Patients with chronic kidney disease were randomly assigned to (1) the atorvastatin group (atorvastatin loading dose [80 mg] within 24 hours before contrast media exposure; n=202) or (2) the control group (n=208). All patients received a high dose of N-acetylcysteine and sodium bicarbonate solution. Contrast-induced acute kidney injury (defined as an increase >10% of serum cystatin C) occurred in 9 of 202 patients in the atorvastatin group (4.5%) and in 37 of 208 patients in the control group (17.8%) (P=0.005; odds ratio=0.22; 95% confidence interval, 0.07–0.69). In the in vitro model, pretreatment with atorvastatin (1) prevented contrast media–induced renal cell apoptosis by reducing activation of stress kinases and (2) restored survival signals (mediated by Akt and ERK pathways). The present study demonstrates that a single high loading dose of atorvastatin administered within 24 hours before contrast media exposure (on top of conventional strategies) is effective in reducing the rate of contrast-induced acute kidney injury by preventing contrast media–induced epithelial tubular renal cell apoptosis and increasing survival signaling pathways.

Conclusions—A single high loading dose of atorvastatin administered within 24 hours before contrast media exposure is effective in reducing the rate of contrast-induced acute kidney injury. This beneficial effect is observed only in patients at low to medium risk.2

Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

Summary—Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. In this study, we have demonstrated that patients with rheumatoid arthritis have increased inflammation along the entire length of the aorta in comparison with age-matched patients who have cardiovascular disease and that antitumor necrosis factor-α therapy leads to a reduction of inflammation in the whole aorta and in the most diseased segment, as well, and to a decrease in aortic stiffness. Our data suggest that vascular inflammation could underpin the mechanism of increased cardiovascular disease seen in rheumatoid arthritis and propose that effective control of inflammation may reduce cardiovascular disease risk in patients with rheumatoid arthritis. Furthermore, our study demonstrates that positron emission tomography/computed tomography scanning could be a useful tool for cardiovascular disease risk stratification and for monitoring risk reduction of anti-inflammatory therapies in patients with chronic inflammatory diseases.

Conclusions—This study demonstrates that rheumatoid arthritis (RA) patients have increased aortic18F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.3

Age, Sex, and Hypertension-Related Remodeling Influences Left Ventricular Torsion Assessed by Tagged Cardiac Magnetic Resonance in Asymptomatic Individuals: The Multi-Ethnic Study of Atherosclerosis

Summary—Left ventricular (LV) systolic torsion limits myocardial energy consumption and minimizes transmural fiber stress gradients and oxygen demand, resulting in a more efficient contraction in the mathematical model. According to the lever-arm theory, a greater radius difference between the endocardium and the epicardium such as concentric hypertrophy would result in increased torsion. In addition, reduced subendocardial function would result in less opposition to the dominant epicardium and finally enhanced torsion because helical contraction of subendocardial and subepicardial muscle layers would counteract one another. However, the influence of LV remodeling associated with age, sex, and hypertension on LV torsion is not well understood. Therefore, we used cardiac MRI to examine LV structure and function among 1478 participants of the Multi-Ethnic Study of Atherosclerosis who had no cardiovascular disease at baseline. In multivariable regression models, older age was associated with lower LV volumes, higher relative wall thickness, and a significant fall in stoke volume, along with lower myocardial shortening. However, torsion was greater with old age (0.14°/cm per decade; P<0.001). The smaller LV and higher contraction of women’s hearts were accompanied by the greater torsion (0.37°/cm versus men; P<0.001). Finally, although hypertension is associated with concentric hypertrophy and lower circumferential shortening, torsion is greater in hypertensive individuals independently of age and sex (0.17°/cm versus nonhypertension; P<0.05). These findings suggest that torsion represents a compensatory mechanism that maintains an adequate stroke volume and cardiac output in the face of progressively reduced LV volumes and myocardial shortening associated with ageing and/or hypertension.

Conclusions—Older age is associated with lower LV volumes and greater relative wall thickness and is accompanied by lower circumferential myocardial shortening, whereas torsion is greater with older age. Hypertensive individuals have greater LV volumes and relative wall thickness and lower circumferential shortening. Torsion, however, is greater in hypertension independently of age and sex. Torsion may therefore represent a compensatory mechanism to maintain an adequate stroke volume and cardiac output in the face of the progressively reduced LV volumes and myocardial shortening associated with hypertension and aging.4

Association Between Coronary Vascular Dysfunction and Cardiac Mortality in Patients With and Without Diabetes Mellitus

Summary—Patients with diabetes mellitus are at increased risk of adverse cardiac events even in the absence of overt myocardial ischemia or scar compared with patients without diabetes mellitus. Coronary flow reserve (CFR) is a quantitative measure of coronary vascular dysfunction, which is an early manifestation of coronary artery disease. CFR can be measured noninvasively with positron emission tomography. The present study establishes that CFR is associated with increased rates of cardiac mortality among both diabetics and nondiabetics and results in similar improvement in risk discrimination and reclassification for both cohorts. In both cases, ≈1 in 3 patients has a clinically relevant change in assessed risk based on CFR, even after accounting for clinical risk factors and traditional stress imaging findings. Intriguingly, diabetic patients without known coronary artery disease with visually normal stress tests but impaired CFR experience a 2.8%/y cardiac mortality rate, comparable to that for patients with known coronary artery disease (2.0%/y). Conversely, diabetic patients without known coronary artery disease and visually normal stress tests who have preserved CFR experience cardiac mortality rates comparable to those of nondiabetic patients free of coronary artery disease with normal stress imaging findings (0.3%/y versus 0.5%/y, respectively). These findings offer important insights into the mechanism of increased cardiac risk among diabetics and the classification of diabetes mellitus as a cardiac risk equivalent.

Conclusions—Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and nondiabetics and provides meaningful incremental risk stratification. Among diabetic patients without coronary artery disease, those with impaired CFR have event rates comparable to those of patients with prior coronary artery disease, whereas those with preserved CFR have event rates comparable to those of nondiabetics.5

Echocardiographic Predictors of Outcome in Eisenmenger Syndrome

Summary—Although echocardiography provides accurate information on cardiac anatomy and physiology, as well as prognosis data in patients with idiopathic pulmonary arterial hypertension, only few data exist on the prognostic power of echocardiographic parameters in adults with Eisenmenger syndrome, which was the subject of this study. Our data from a single center on a large contemporary cohort of adults with Eisenmenger syndrome showed that echocardiographic indices of right ventricular function (tricuspid annular plane systolic excursion, ratio of right ventricular effective systolic to diastolic duration) and right atrial area are predictive of mortality, assessed either alone or even more so in a composite score. Because the assessment of functional class remains difficult, especially in patients with congenital heart disease, we believe that this score may be used in the risk stratification of Eisenmenger patients and could influence the decision to initiate or escalate therapy.

Conclusions—Echocardiographic parameters of right ventricular function and right atrial area predict mortality in Eisenmenger patients. A new composite echocardiographic score, described herewith, may be incorporated into the noninvasive, periodic assessment of these patients.6

Aortic Regurgitation Quantification Using Cardiovascular Magnetic Resonance: Association With Clinical Outcome

Summary—Timing surgery in patients with significant aortic regurgitation (AR) can be difficult. Currently, surgery is advised for severe regurgitation once symptoms, excess left ventricular (LV) dilation or dysfunction, occur. However, prognosis is already reduced by this stage, and earlier identification of patients suitable for surgery might be beneficial. Accurate quantification of the regurgitation may help, but is difficult with echocardiography. Cardiovascular magnetic resonance can accurately quantify AR and also provides highly accurate measurements of LV volume, but the clinical utility of this has not been established. Our study examined whether quantification of AR and LV volumes with cardiovascular magnetic resonance was associated with the future development of symptoms or other indications for surgery in an initially asymptomatic group with moderate to severe AR. We showed that both severity of AR and LV volumes had significant associations with outcome over the subsequent few years. AR quantification showed a stronger association than LV end-diastolic volume, but the combination of these 2 parameters was better still. Cardiovascular magnetic resonance measurements of AR and LV volumes might enable the identification of potential candidates for early surgery, and this should be tested in a large-scale clinical trial.

Conclusions—High degrees of cardiovascular magnetic resonance (CMR)-quantified AR were associated with the development of symptoms or other indications for surgery. Quantifying AR showed slightly better discriminatory ability than “gold standard” CMR ventricular volume assessment. This could provide a new paradigm for the timing of surgical intervention but requires confirmation in a clinical trial.7

Association Between Extracellular Matrix Expansion Quantified by Cardiovascular Magnetic Resonance and Short-Term Mortality

Summary—Extracellular matrix expansion may be ubiquitous in chronically diseased viable myocardium as shown by histopathologic studies in humans and animals. It is associated with mechanical, vasomotor, and electric dysfunction and is treatable, but the relationship with outcomes has remained poorly understood. Historically, there has not been a robust noninvasive method to quantify the extent of extracellular matrix expansion in myocardium, which is often diffuse and not detectable by conventional late gadolinium enhancement imaging. Thus, the presence and extent of extracellular matrix expansion has mostly been invisible to clinicians. We used novel cardiovascular magnetic resonance techniques to quantify extracellular matrix expansion by measuring the extracellular volume fraction in myocardium without myocardial infarction in a consecutive cohort of individuals referred for cardiovascular magnetic resonance. These techniques require: i) robust blood pool and myocardial T1 measurement before and after gadolinium contrast, and ii) hematocrit measurement. Extracellular volume fraction measures of the interstitial space can be embedded in clinical protocols easily and correlate highly with the collagen volume fraction in viable myocardium in most settings. In our study, extracellular matrix expansion appeared prevalent, and the extracellular volume fraction predicted both mortality and the composite end point of death/cardiac transplant/left ventricular assist device implantation even after adjusting for age, ejection fraction and myocardial infarction size. The apparent statistical independence of the extracellular volume fraction measure suggests a potential to improve risk stratification in patients. Further work is needed to advance our understanding of the causes, consequences, and treatment of extracellular matrix expansion and myocardial fibrosis.

Conclusions—Extracellular volume measures of extracellular matrix expansion may predict mortality as well as other composite end points (death/cardiac transplant/left ventricular assist device implantation).8

Prognostic Value of High-Dose Dipyridamole Stress Myocardial Contrast Perfusion Echocardiography

Summary—Dipyridamole real-time contrast echocardiography (DipRCE) has considerable advantages over other imaging stress-tests, including no irradiation, spatial and temporal resolution, short test duration, immediate availability of results at the bedside, and the ability to perform stress and rest images in the same setting. The addition of myocardial perfusion (MP) imaging over standard wall motion (WM) analysis during DipRCE improves the sensitivity to detect coronary artery disease (CAD), but its risk reclassification potential to predict hard cardiac events in large numbers of patients with known or suspected CAD remains unknown. We studied 1252 patients with DipRCE and followed them for a median of 25 months. A total of 59 hard events (4.7%) occurred during the follow up (24 deaths, 35 myocardial infarctions). Reversible MP defects added incremental prognostic value and risk reclassification benefit to predict hard events, after adjustment for clinical data, ejection fraction, and WM analysis. A normal MP response during DipRCE identified a low-risk patient group (close to 1% yearly hard event rate) with a better outcome than patients with a normal WM but abnormal MP response. An ischemic WM response, which was always accompanied by MP defects, predicted the highest risk of hard events. Patients with a normal MP response can be reassured regarding their low risk of future 1 or 2-year hard events, regardless of their clinical risk factors or previous CAD history. MP should not simply substitute WM analysis during DipRCE, but the 2 variables are complementary and may have different clinical implications for the cardiologist.

Conclusions—MP imaging using real-time perfusion echocardiography during dipyridamole real-time contrast echocardiography provides independent, incremental prognostic information regarding hard cardiac events in patients with known or suspected coronary artery disease. Patients with normal MP responses have better outcome than patients with normal WM; patients with both reversible WM and MP abnormalities have the worst outcome.9

Noninvasive MRI Evaluation of Endothelial Permeability in Murine Atherosclerosis Using an Albumin-Binding Contrast Agent

Summary—Despite the systemic and multifactorial nature of atherosclerosis, lesion development is focal and occurs at particular regions of the vasculature including the branches, the inner curvature, and the outer wall of bifurcations, where focal hemodynamic factors exert major damage on the vascular endothelium. Although several imaging modalities are now available for imaging of atherosclerosis, most of the work has focused on identifying anatomic changes associated with disease progression and risk, which have shown low predictive value. Conversely, the combination of imaging structural and functional properties of the vessel wall may allow investigation of the manner in which the extent of local artery disease is related to the degree of local abnormal endothelial function. Therefore, noninvasive physiological imaging of endothelial permeability and function may offer a comprehensive methodology for monitoring focal atherosclerotic progression in both early and later stages, as well as plaque instability, and testing the effectiveness of treatment interventions targeting vascular endothelium integrity and function.

Conclusions—We demonstrate the noninvasive assessment of endothelial permeability and function with the use of an albumin-binding magnetic resonance contrast agent. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim to restore the endothelium.10

Transplantation and Tracking of Human-Induced Pluripotent Stem Cells in a Pig Model of Myocardial Infarction: Assessment of Cell Survival, Engraftment, and Distribution by Hybrid Single Photon Emission Computed Tomography/Computed Tomography of Sodium Iodide Symporter Transgene Expression

Summary—Cardiac cell replacement therapies may significantly extend current therapeutic options for various cardiac diseases. The recently developed induced pluripotent stem cells are considered a major breakthrough with respect to the development of novel regenerative therapies and combine the advantages of adult and embryonic stem cells, namely, the availability of an autologous, ethically nonproblematic cell source with high potential for proliferation and differentiation into all cell lineages of interest. However, evaluation of novel cellular therapies in preclinical large-animal models and patients is currently hampered by the lack of suitable imaging approaches that allow long-term monitoring of viable transplanted cells. The present study was therefore designed to evaluate sodium iodide symporter transgene imaging as a novel approach to follow human induced pluripotent stem cell derivatives in a pig model of myocardial infarction. For the first time, our study demonstrates the usefulness of a sodium iodide symporter transgene for longitudinal in vivo tracking of survival, engraftment, and distribution of cellular grafts in a large-animal model with the use of single photon emission tomographic/computed tomographic imaging. Moreover, for the first time we demonstrate long-term survival and differentiation of human induced pluripotent stem cells in a preclinical pig model of myocardial infarction. The applied 3-dimensional hybrid imaging protocol enables combined assessment of cardiac anatomy and myocardial perfusion and monitoring of donor cell survival, proliferation, and distribution within 1 imaging modality. The developed approach will contribute to further optimization of novel cardiovascular cell–based treatment strategies and is of utmost importance for careful in vivo monitoring of associated risks such as potential tumor or teratoma formation.

Conclusions—This study describes for the first time the feasibility of repeated long-term in vivo imaging of viability and tissue distribution of cellular grafts in large animals. Moreover, this is the first report demonstrating vascular differentiation and long-term engraftment of hiPSCs in a large-animal model of myocardial infarction. NISpos-hiPSCs represent a valuable tool to monitor and improve current cellular treatment strategies in clinically relevant animal models.11

Ischemic Preconditioning for Prevention of Contrast Medium–Induced Nephropathy: Randomized Pilot RenPro Trial (Renal Protection Trial)

Summary—The prevention of contrast medium–induced acute kidney injury is a major challenge for interventional cardiologists. Several patient and procedure-associated risk factors were identified in previous studies. Only a few contrast medium–induced acute kidney injury prevention strategies exist. Ischemic preconditioning has been shown in the RenPro (Renal Protection) Trial to be an effective, safe, and economic method for prevention of contrast medium–induced acute kidney injury in high-risk patients. The broad application of this method in daily clinical settings may remarkably influence the cardiovascular outcome in high-risk patients.

Conclusions—Remote ischemic preconditioning before contrast medium use prevents contrast medium–induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes.12

Long-Term Outcome of Aortic Dissection With Patent False Lumen: Predictive Role of Entry Tear Size and Location

Summary—Persistent patent false lumen in descending aorta after acute aortic dissection is common in type A and type B dissections and has been associated with poor prognosis. However, to date, no study has shown that elective surgical or endovascular treatment in subacute phase of aortic dissection reduces mortality. Therefore, identification of clinical and imaging predictors of poor prognosis seems mandatory. We studied 184 patients, 108 surgically treated type A and 76 medically treated type B dissections, discharged with patent false lumen in descending aorta. Transesophageal echocardiography and computed tomography were performed to assess several imaging variables. During follow-up (median, 6.4 years) 49 patients died; 31 died suddenly, and 35 underwent surgical/endovascular treatment. Survival free from complications at 3, 5, and 10 years was 0.90 (95% CI, 0.84–0.94), 0. 81 (95% CI, 0.75–0.87), and 0.46 (95% CI, 0.36–0.55), respectively. Marfan syndrome was the only clinical variable associated with mortality. Concerning imaging variables, patients with complications had a larger baseline maximum diameter in descending aorta and a larger proximal entry tear. Patients with entry tear size ≥10 mm presented a high incidence of aortic-related events (hazard ratio=5.8 (3.3–10; P<0.001). Our findings may help to identify patients at higher risk of complications by imaging techniques performed in subacute phase of aortic dissection. Patients with dilated aorta and large entry tears may benefit from more aggressive surveillance and treatment, including surgical or endovascular therapy, to improve their long-term prognosis.

Conclusions—Aortic dissection with persistent patent false lumen carries a high risk of complications. In addition to Marfan syndrome and aorta diameter, a large entry tear located in the proximal part of the dissection identifies a high-risk subgroup of patients who may benefit from earlier and more aggressive therapy.13

Novel Single-Chain Antibody-Targeted Microbubbles for Molecular Ultrasound Imaging of Thrombosis: Validation of a Unique Noninvasive Method for Rapid and Sensitive Detection of Thrombi and Monitoring of Success or Failure of Thrombolysis in Mice

Summary—Clinical ultrasound is widely used for real-time cardiovascular imaging of anatomic structures and functional evaluation. Contrast-enhancing microbubbles are used in the clinic to support visualization of cardiac structures and myocardial perfusion or to diagnose patent foramen ovale. This study substantially advances the use of microbubbles for a molecular imaging approach by their targeting, and it provides a clinically highly relevant perspective of the detection of activated platelets and thrombi in ultrasound. Successful high-resolution imaging of thrombi induced in the carotid artery of mice and monitoring of the reduction of thrombus size on pharmacological thrombolysis were achieved by coupling microbubbles with a single-chain antibody that binds to a ligand-induced binding site. The latter is exposed only on platelet receptor glycoprotein IIb/IIIa in its activated state, providing a unique target specificity, as shown with our targeted microbubbles in both mice and humans. Several potential clinical applications of this technology can be anticipated such as early detection of unstable carotid artery plaques characterized by microthrombi, visualization of thrombi in cardiac chambers, particularly in the left atrial appendage, and diagnosis of thrombi causing myocardial infarction. Furthermore, the potential to directly monitor and assess pharmacological thrombolysis in real time could provide clinically highly relevant guidance for consequent treatment. Because ultrasound is cost-effective, portable, and widely available, its application for molecular imaging using microbubbles targeted to activated platelets may provide a unique approach for the development of a rapid and noninvasive diagnosis of thrombotic diseases and for monitoring of the success or failure of thrombolysis.

Conclusions—We demonstrate that glycoprotein IIb/IIIa–targeted microbubbles specifically bind to activated platelets in vitro and allow real-time molecular imaging of acute arterial thrombosis and monitoring of the success or failure of pharmacological thrombolysis in vivo.14

Echocardiography Screening for Rheumatic Heart Disease in Ugandan Schoolchildren

Summary—The World Health Organization has made the fight against noncommunicable disease, including acquired cardiovascular disease, a top priority for the next decade. The World Heart Federation has made “eliminating rheumatic fever and minimizing the burden of rheumatic heart disease” 1 of its 6 priorities for the coming 5 years. Rheumatic heart disease affects nearly 20 million people worldwide. It disproportionately affects the developing world, causing death and disability in the prime of life. Widespread screening for rheumatic heart disease based on standardized published echocardiography-based guidelines in the most endemic regions of the developing world will be a critical component of the World Heart Federation effort. Echocardiography allows earlier detection, when penicillin remains an effective and affordable prophylaxis against progressive valvular disease. Our article provides the largest study on prevalence data for echocardiography-based screening for rheumatic heart disease in sub-Saharan Africa and is the first to use published echocardiography-based guidelines in this region. Our results also help to define choices about age, socioeconomic status, and diagnostic protocol that will influence the development and implementation of future screening programs. Furthermore, we emphasize the need for longitudinal follow-up to validate current definitions of subclinical rheumatic heart disease. As echocardiography-based screening protocols increase in prominence and are redefined, these data call for increased awareness and focus on the world’s most prevalent heart disease.

Conclusions—This is one of the largest single-country childhood rheumatic heart disease (RHD) prevalence studies and the first to be conducted in sub-Saharan Africa. Our data support inclusion of echocardiography in screening protocols, even in the most resource-constrained settings, and identify lower socioeconomic groups as most vulnerable. Longitudinal follow-up of children with echocardiographically diagnosed subclinical RHD is needed.15

Noninvasive Assessment of Myocardial Inflammation by Cardiovascular Magnetic Resonance in a Rat Model of Experimental Autoimmune Myocarditis

Summary—Myocarditis is defined as inflammation of myocardial tissue with characteristic inflammatory cellular infiltration into the myocardium. To date, reliable tools to noninvasively diagnose cellular inflammation in myocarditis are lacking. Here we demonstrate that the application of long-circulating magneto-fluorescent nanoparticles combined with cardiac MRI permit noninvasive and robust imaging of myocardial inflammatory cellular infiltrates, enabling spatial mapping, quantification, and assessment of inflammation in experimental autoimmune myocarditis. Compared with clinically conventional cardiac magnetic resonance, magneto-fluorescent nanoparticle cardiac magnetic resonance more accurately detected scattered foci of inflammation and provided better conspicuity of small and less severe myocardial inflammation. Early and prompt diagnosis may lead to a paradigm shift in the therapeutic strategy of myocarditis. In addition, this magneto-fluorescent nanoparticle cardiac magnetic resonance approach could be an effective clinical application in monitoring the evolution of inflammation and response to anti-inflammatory therapy in myocarditis.

Conclusions—Magneto-fluorescent nanoparticle cardiovascular magnetic resonance (CMR) permitted effective visualization of myocardial inflammatory cellular infiltrates and distinction of the extent of inflammation compared with conventional CMR in a preclinical model of experimental autoimmune myocarditis (EAM). Magneto-fluorescent nanoparticle CMR performs best in EAM rats with at least moderate inflammatory response.16

MRI With 3-Dimensional Analysis of Left Ventricular Remodeling in Isolated Mitral Regurgitation: Implications Beyond Dimensions

Summary—Although surgery is indicated in patients with mitral regurgitation when left ventricular (LV) end-systolic dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. A major finding of the present investigation is that LV end-systolic dimension does not accurately reflect the extent of LV remodeling, largely because of spherical LV remodeling from the mid to apical LV by MRI with 3-dimensional analysis. This study demonstrates that even when LV end-systolic dimension remains below the accepted target of 40 mm for surgical intervention of isolated mitral regurgitation, its associated LV end-systolic volume can range as high as twice that of normal control subjects. MRI with 3-dimensional analysis– or 3-dimensional echocardiography–derived LV volumes may be preferred to evaluate disease progression in isolated mitral regurgitation.

Conclusions—Despite apparently preserved left ventricular end-systolic dimesion (LVES) dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR.17

Chronic Inhibition of cGMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy: A Randomized, Controlled Clinical Trial Using MRI With Myocardial Tagging

Summary—Type 2 diabetes mellitus is associated with cardiac remodeling that may occur independently of ischemic heart disease, hypertension, or macrovascular complications. Cardiac magnetic resonance can be used to measure diabetic cardiomyopathy, for which there is currently no specific treatment. In vitro studies have shown that phosphodiesterase 5 overexpression reduces cGMP levels and exacerbates remodeling. Inhibiting cGMP hydrolysis in stimulated cardiomyocytes can prevent hypertrophy. We studied the effects of 3-month daily sildenafil treatment (a phosphodiesterase 5A inhibitor) on cardiac remodeling in a cohort of asymptomatic, middle-aged men with type 2 diabetes mellitus. Cardiac MRI revealed that diabetic cardiomyopathy in these patients produced an uncoupling in left ventricular contraction between longitudinal strain, which is reduced, and cardiac axial rotation, which is increased. We found that long-term sildenafil treatment restored coupling by reducing torsion and improving strain. It also reduced the ratio of left ventricular mass to end-diastolic volume that is increased in the presence of concentric hypertrophy. These data suggest that phosphodiesterase 5 inhibition could work as an antiremodeling drug by acting directly on cardiac tissue, independently of other secondary vascular, endothelial, or metabolic effects. Our findings also have an impact on the clinical monitoring of patients with type 2 diabetes mellitus. We showed that (1) asymptomatic diabetic men may already be undergoing cardiac remodeling; (2) monocyte chemotactic protein-1 [MCP1] could be included as a new potential marker related to diabetic cardiomyopathy evolution; and (3) sildenafil can partially reverse these changes. Large-scale studies are needed to test whether phosphodiesterase 5A inhibition could become a new target for antiremodeling drugs and to discover the molecular pathways affected by this class of drugs.

Conclusions—The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action.18

Mitral Valve Prolapse With Mid-Late Systolic Mitral Regurgitation: Pitfalls of Evaluation and Clinical Outcome Compared With Holosystolic Regurgitation

Summary—Mitral valve prolapse (MVP) is frequent, and its outcome is highly dependent on the severity of mitral regurgitation (MR) it causes. MR of MVP is predominant and often is limited to the mid or later part of systole, but the impact of such MR timing on MR assessment, on the volume overload it causes, and on outcome is unknown. To address this issue, we prospectively quantified MR in patients with MVP and midlate systolic MR and compared them with matched patients with MVP and holosystolic MR. The study shows that midlate systolic MR can be misleading because it presents with similar jet area, velocity, and effective regurgitant orifice but has less regurgitant volume because of its shorter duration. Furthermore, midlate systolic MR causes less volume overload with smaller left ventricles and atria, lower pulmonary pressure, and less frequent flow reversal in the pulmonary veins. In regard to outcome, midlate systolic MR was benign in comparison to holosystolic MR, with much fewer cardiac events during follow-up, independently of any baseline characteristics. This event rate was independently linked to the regurgitant volume (not orifice), which is smaller in midlate systolic MR. Therefore, for clinical management and surgical referral of patients with MVP, clinicians should carefully take into account the timing and consequences of MR.

Conclusions—MR of mitral valve prolapse that is purely midlate systolic causes more benign consequences and outcomes than holosystolic MR. Assessment may be misleading because jet area and effective regurgitant oriface (ERO) by flow convergence appear similar to those of holosystolic MR. However, shorter MR yields lower regurgitant volume, consequences, and benign outcomes. Instantaneous ERO by flow convergence should be interpreted in context, and in midlate systolic MR, regurgitant volume provides information more reflective of MR severity. Therefore, for clinical management and surgical referral, clinicians should carefully take into account the timing and consequences of MR.19

Effects of Catecholamine Stress on Diastolic Function and Myocardial Energetics in Obesity

Summary—Despite the fact that obesity is characterized by diastolic dysfunction, a condition associated with future heart failure, the mechanisms behind it are not known. In this study, we have demonstrated that myocardial energetics are impaired in obesity and that the phosphocreatine/ATP ratio is a predictor of diastolic function. This opens the possibility of a metabolic therapy aimed at improving myocardial energetics in obesity and potentially preventing the progression to heart failure. In addition, we have shown that during moderate inotropic stress, the already lower phosphocreatine/ATP ratio in obesity is further reduced, resulting in additional negative effects on diastolic function. Because the majority of the cardiovascular symptoms in obesity do not occur at rest and occur in subjects with normal left ventricular systolic and respiratory function, these changes in energetics and diastole provide a plausible explanation for exertional breathlessness in obesity. Myocardial energetics appear to be playing a central role in diastolic function in obesity; therefore, metabolic therapies aimed at improving myocardial energetics in obesity may become a means of targeting obesity-related shortness of breath and potentially preventing the development of heart failure.

Conclusions—In obesity, cardiac energetics are further deranged during inotropic stress, in association with continued diastolic dysfunction. Myocardial energetics may play a key role in the impairment of diastolic function in obesity.20

Impact of Progression of Diastolic Dysfunction on Mortality in Patients With Normal Ejection Fraction

Summary—Diastolic dysfunction is an independent predictor of mortality in patients with normal ejection fraction. Diastolic function, whether normal or abnormal (stage 1, 2, or 3), varies dynamically and can pass from 1 stage to the other and in either direction. Although worsening of diastolic function has been associated with the development of congestive heart failure, there have been limited data on mortality with this progression. The present study showed that worsening of diastolic function in outpatients with normal ejection fraction (n=1065; age, 69±13 years) was associated with increased risk of death (hazard ratio, 1.78; 95% confidence interval, 1.21–2.59; P=0.003) independently of baseline or current diastolic function. This hazard ratio was equivalent to that from worsening of systolic function in the same population. Furthermore, progression from normal to abnormal diastolic function and from stage 1 to 2 or 3 diastolic dysfunction was associated with increased mortality (hazard ratio, 3.58; 95% confidence interval, 1.71–7.53; P=0.0001; and hazard ratio, 2.13; 95% confidence interval, 1.19–3.83;P=0.01, respectively). Given the present findings, it is important for clinicians not only to recognize the importance of progression of diastolic function for their patients but also to promote aggressive risk factor modifications, particularly blood pressure control, weight loss, exercise, and salt restriction; these risk factors have traditionally have been associated with worsening of diastolic function.

Conclusions—In patients with normal baseline left ventricular ejection fraction, worsening of diastolic function is an independent predictor of mortality.21

Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis

Summary—Aortic stenosis is the most common form of valvular heart disease in the Western world and represents a major healthcare burden that is projected to increase with an aging population. However, there are currently no effective medical treatments or biomarkers of disease activity. The pathogenesis of aortic stenosis is incompletely understood, and defining the various stages of this process will be highly important to develop the therapies and biomarkers that are required. Positron emission tomography combined with computed tomography is a noninvasive imaging technique that allows the identification and quantification of specific pathological processes within small anatomic structures, such as the aortic valve. In this study, we sought to test the feasibility, repeatability, and validity of this technique in the evaluation of aortic valve stenosis. Positron emission tomography/computed tomography imaging of the aortic valve was performed to assess inflammation (18F-fluorodeoxyglucose) and active calcification (18F-sodium fluoride) of the valve leaflets. The positron emission tomography/computed tomography findings were compared in 121 patients with a full spectrum of disease severity. Our data have clearly established that this technique is both feasible and repeatable, indicating that these tracers may prove to be useful biomarkers of disease activity. Furthermore, we have demonstrated that 18F-fluorodeoxyglucose and 18F-sodium fluoride activity increase with progressive disease severity. However, uptake of 18F-sodium fluoride appears to predominate in both the early and latter stages of the disease. This may explain the disappointing effects of statin therapy in this condition and indicates that calcification might represent a better target for novel therapeutic interventions.

Conclusions—Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF.22

Footnotes

  • The following articles are being highlighted as part of Circulation’s Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the most read manuscripts published on the topic of cardiovascular imaging within the last year.

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    Circulation. 2013;128:e32-e38, originally published July 15, 2013
    https://doi.org/10.1161/CIRCULATIONAHA.113.004366
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