Mitral Regurgitation: Advanced Imaging Parameters and Changing Treatment Landscape.

Mitral regurgitation is a common valvular heart disease with increasing prevalence due to the aging population. In degenerative (primary) mitral regurgitation, medical therapies are limited and the mainstay of treatment is mitral valve surgery. Patients are referred for mitral valve surgery based on the American College of Cardiology/American Heart Association guidelines, which recommend surgery in patients with severe mitral regurgitation. Echocardiography uses multiple parameters that lack reproducibility and accuracy. Studies comparing cardiovascular magnetic resonance (CMR) and echocardiography have shown that CMR is a better predictor of clinical outcome and postsurgical left ventricular remodeling than echocardiography.

American Society of Echocardiography Algorithm for Degenerative Mitral Regurgitation: Comparison With CMR.

OBJECTIVES: The purpose of this study was to compare the American Society of Echocardiography (ASE) algorithm for assessing mitral regurgitation (MR) to cardiac magnetic resonance (CMR) and left ventricular (LV) remodeling following mitral intervention. BACKGROUND: The ASE recommends integrating multiple echocardiographic parameters for assessing MR. The ASE guidelines include an algorithm that weighs the parameters and highlights those considered indicative of definitely mild or definitely severe MR. METHODS: We prospectively enrolled 152 (age 62 ± 13 years; 59% male) patients with degenerative MR who underwent ASE algorithm-guided echocardiographic and CMR grading of MR severity. Using the ASE algorithm, patients were graded as definitely mild, grade I, grade II, grade III, grade IV, or definitely severe MR. CMR MR volume was graded as mild (<30 mL), grade II moderate (30-44 mL), grade III moderate (45-59 mL), or severe (≥60 mL). A subgroup of 63 patients underwent successful mitral intervention, of whom 48 had postintervention CMR. RESULTS: Only 52% of patients with definitely severe MR by the ASE algorithm had severe MR by CMR, and 10% had mild MR by CMR. There was an increase in post mitral intervention LV reverse remodeling with worsening MR severity using CMR (P < 0.0001) but not the ASE algorithm (P = 0.07). Severe MR by CMR was an independent predictor of post mitral intervention LV reverse remodeling and definitely severe MR by the ASE algorithm was not. CONCLUSIONS: In patients with degenerative MR, agreement between CMR and the ASE algorithm was suboptimal. Severe MR by CMR was an independent predictor of post mitral intervention LV reverse remodeling, whereas definitely severe MR by the ASE algorithm was not. These findings suggest an important role for CMR in surgical decision making in degenerative MR. (Comparison Study of Echocardiography and Cardiovascular Magnetic Resonance Imaging in the Assessment of Mitral and Aortic Regurgitation; NCT04038879).

Characterization of Primary Mitral Regurgitation With Flail Leaflet and/or Wall-Impinging Flow.

BACKGROUND: Echocardiography guidelines note that a flail leaflet is a specific criterion for severe mitral regurgitation (MR) and that regurgitant severity is underestimated in wall-impinging jets (Coanda effect). Both findings are often considered to be pathognomonic of severe MR. OBJECTIVES: In this study, the authors sought to determine the association of flail leaflet and Coanda effect with MR severity quantified by means of cardiac magnetic resonance (CMR). METHODS: The authors enrolled 158 consecutive patients with primary MR according to echocardiography and CMR. The presence of a flail leaflet or Coanda was determined for each patient. CMR regurgitant volume (RV) and regurgitant fraction (RF) were quantified for all patients. RESULTS: There were 55 patients (35%) with a flail leaflet, 52 (33%) with Coanda, and 22 (14%) with a flail leaflet and Coanda. The mean CMR mitral RV and RF progressively increased in patients without a Coanda or flail, a Coanda, a flail, or a Coanda and a flail (RV: 28 ± 21 mL vs 43 ± 23 mL vs 58 ± 29 mL vs 64 ± 25 mL [P < 0.001]; RF: 25% ± 16% vs 34% ± 14% vs 41% ± 12% vs 45% ± 12% [P < 0.001]). With the use of CMR RV, 35%, 46%, and 59% of patients had severe MR with the presence of a Coanda, flail leaflet, or both, respectively. With the use of CMR RF, 25%, 31%, and 40% of patients had severe MR with the presence of a Coanda, flail leaflet, or both, respectively. CONCLUSIONS: While the presence of a flail leaflet and Coanda effect on echocardiography are associated with higher regurgitant volumes and fractions, they are frequently not associated with severe MR as assessed by means of CMR. (Comparison Study of Echocardiography and Cardiovascular Magnetic Resonance Imaging in the Assessment of Mitral and Aortic Regurgitation; NCT04038879).

Imaging strategies for safety surveillance after renal artery denervation.

Renal denervation has emerged as a safe and effective therapy to lower blood pressure in hypertensive patients. In addition to the main renal arteries, branch vessels are also denervated in more contemporary studies. Accurate and reliable imaging in renal denervation patients is critical for long-term safety surveillance due to the small risk of renal artery stenosis that may occur after the procedure. This review summarizes three common non-invasive imaging modalities: Doppler ultrasound (DUS), computed tomography angiography (CTA), and magnetic resonance angiography (MRA). DUS is the most widely used owing to cost considerations, ease of use, and the fact that it is less invasive, avoids ionizing radiation exposure, and requires no contrast media use. Renal angiography is used to determine if renal artery stenosis is present when non-invasive imaging suggests renal artery stenosis. We compiled data from prior renal denervation studies as well as the more recent SPYRAL-HTN OFF MED Study and show that DUS demonstrates both high sensitivity and specificity for detecting renal stenosis de novo and in longitudinal assessment of renal artery patency after interventions. In the context of clinical trials DUS has been shown, together with the use of the baseline angiogram, to be effective in identifying stenosis in branch and accessory arteries and merits consideration as the main screening imaging modality to detect clinically significant renal artery stenosis after renal denervation and this is consistent with guidelines from the recent European Consensus Statement on Renal Denervation.

Defining the left ventricular base in mitral valve prolapse: impact on systolic function and regurgitation.

In bileaflet mitral valve prolapse (BMVP) systolic leaflet displacement creates a pocket of blood on the left ventricular (LV) side of the leaflets, but on the atrial side of the annulus. This blood is excluded from the LV end-systolic volume if the mitral valve annulus is used to determine the most basal extent of the LV. The purpose of this study is to describe the quantitative implications of defining the LV base on mitral regurgitant severity and LV systolic function in BMVP. In 30 consecutive patients (53% male, 58 ± 14 years) with BMVP, LV endocardial and epicardial borders were determined from SSFP images. The LV base at end-systole was defined by the "Functional" method (at the mitral valve annulus) or the "Anatomic" method (at the mitral valve leaflets). Regurgitant volume was the difference between the LV stroke volume and mean forward flow. LV myocardial strain measurements were determined from the short axis endocardial and epicardial borders. The "Functional" method resulted in higher regurgitant volumes (mean difference: 22 ml, range 0-40 ml) and higher ejection fractions (mean difference: 9%, range 0-21%). The correlation between LV end-diastolic volume and regurgitant volume was better with the "Functional" method (r = 0.79, p < 0.0001) than the "Anatomic" method (r = 0.67, p < 0.0001). The correlation between global myocardial radial strain and LV EF was better with the "Functional" method (r = 0.86, p < 0.0001) than the "Anatomic" method (r = 0.68, p < 0.0001). In BMVP, the base of the LV should be defined at the level of the mitral valve annulus so that regurgitant volume most accurately reflects the functional significance of the mitral valve disease and LVEF most accurately reflects global systolic LV function. Defining the basal extent of the LV at the mitral valve leaflets leads to substantially lower regurgitant volumes and lower ejection fractions that could have important clinical consequences.

Usefulness of Mitral Regurgitant Volume Quantified Using Magnetic Resonance Imaging to Predict Left Ventricular Remodeling After Mitral Valve "Correction".

MRI studies have shown a tight correlation between mitral regurgitant volume and left ventricular end-diastolic volume (LV EDV) in patients with primary chronic mitral regurgitation (MR). They have also shown a tight correlation between regurgitant volume and the decrease in LVEDV following mitral valve surgery. The purpose of this study is to validate an empiric calculation that can be used preoperatively to predict the amount of left ventricular remodeling following mitral valve correction. This is a prospective multicenter study of 63 (61 ± 13 years, male 65%) patients who underwent an MRI before and after mitral valve correction. Pre and postmitral valve correction ventricular volumes and ejection fractions were quantified. The predicted change in LV EDV was empirically calculated as mitral regurgitant volume/left ventricular ejection fraction. The observed change in LV EDV was compared to the predicted change in LV EDV. The LVEDV decreased in 61 (97%) patients following mitral valve correction (237 ± 66 ml vs 164 ± 46 ml, p <0.0001). Correlation between the observed and predicted change in LVEDV was good for the entire cohort (r = 0.77, p <0.0001) and excellent in patients with <10 ml of residual MR (r = 0.87, p <0.0001). This tight correlation was seen in both patients with primary (0.86, p <0.0001) and secondary MR (0.97, p <0.0001) and <10 ml of residual MR. Multivariate predictors of LV remodeling were MR volume, primary MR, and LVESV. In conclusion cardiac MRI volumetric measurements accurately predict LV remodeling following mitral valve correction. This finding supports the notion that MRI accurately quantifies the severity of chronic mitral regurgitation and a cardiac MRI should be strongly considered before mitral valve correction.

Discordance between echocardiography and MRI in the assessment of mitral regurgitation severity: a prospective multicenter trial.

BACKGROUND: The decision to undergo mitral valve surgery is often made on the basis of echocardiographic criteria and clinical assessment. Recent changes in treatment guidelines recommending surgery in asymptomatic patients make the accurate assessment of mitral regurgitation (MR) severity even more important. OBJECTIVES: The purpose of this study was to compare echocardiography and magnetic resonance imaging (MRI) in the assessment of MR severity using the degree of left ventricular (LV) remodeling after surgery as the reference standard. METHODS: In this prospective multicenter trial, MR severity was assessed in 103 patients using both echocardiography and MRI. Thirty-eight patients subsequently had isolated mitral valve surgery, and 26 of these had an additional MRI performed 5 to 7 months after surgery. The pre-surgical estimate of regurgitant severity was correlated with the postoperative decrease in LV end-diastolic volume. RESULTS: Agreement between MRI and echocardiographic estimates of MR severity was modest in the overall cohort (r = 0.6; p < 0.0001), and there was a poorer correlation in the subset of patients sent for surgery (r = 0.4; p = 0.01). There was a strong correlation between post-surgical LV remodeling and MR severity as assessed by MRI (r = 0.85; p < 0.0001), and no correlation between post-surgical LV remodeling and MR severity as assessed by echocardiography (r = 0.32; p = 0.1). CONCLUSIONS: The data suggest that MRI is more accurate than echocardiography in assessing the severity of MR. MRI should be considered in those patients when MR severity as assessed by echocardiography is influencing important clinical decisions, such as the decision to undergo MR surgery.

Significance of a positive family history for coronary heart disease in patients with a zero coronary artery calcium score (from the Multi-Ethnic Study of Atherosclerosis).

Although a coronary artery calcium (CAC) score of 0 is associated with a very low 10-year risk for cardiac events, this risk is nonzero. Subjects with a family history of coronary heart disease (CHD) has been associated with more subclinical atherosclerosis than subjects without a family history of CHD. The purpose of this study was to assess the significance of a family history for CHD in subjects with a CAC score of 0. The Multi-Ethnic Study of Atherosclerosis cohort includes 6,814 participants free of clinical cardiovascular disease (CVD) at baseline. Positive family history was defined as reporting a parent, sibling, or child who had a heart attack. Time to incident CHD or CVD event was modeled using the multivariable Cox regression; 3,185 subjects were identified from the original Multi-Ethnic Study of Atherosclerosis cohort as having a baseline CAC score of 0 (mean age 58 years, 37% men). Over a median follow-up of 10 years, 101 participants (3.2%) had CVD events and 56 (1.8%) had CHD events. In age- and gender-adjusted analyses, a family history of CHD was associated with an ∼70% increase in CVD (hazard ratio 1.73, 95% confidence interval 1.17 to 2.56) and CHD (hazard ratio 1.72, 95% confidence interval 1.01 to 2.91) events. CVD events remained significant after further adjustment for ethnicity, risk factors, and baseline medication use. In conclusion, asymptomatic subjects with a 0 CAC score and a positive family history of CHD are at increased risk for CVD and CHD events compared with those without a family history of CHD, although absolute event rates remain low.

Synergistic effect of coronary artery disease risk factors on long-term survival in patients with normal exercise SPECT studies.

BACKGROUND: Normal exercise single-photon emission computed tomography (SPECT) studies are associated with a low event rate (<1.0%/year) during short-term follow-up. The influence of cardiac risk factors on long-term outcomes in such patients has not been well studied. MATERIAL AND METHODS: 2,597 patients (55 ± 12 years, male 41%) without a history of heart disease and a normal exercise SPECT between the years 1995 and 2006 were followed for a mean 6.8 ± 3.1 years for all-cause mortality assessed for using the Social Security Death Index. Baseline clinical risk factors and other clinical information were recorded for each patient and compared to outcomes. RESULTS: The mortality rate was 0.9%/year for our overall study population but varied according to individual baseline risk factors. Three coronary artery disease (CAD) risk factors were significant predictors of all-cause mortality: hypertension, diabetes, and smoking. When all three were absent, long-term all-cause mortality rate averaged 0.2%/year and when all three were present, all-cause mortality averaged 1.8%/year, constituting a 5.7-fold adjusted increase in risk (95% CI 2.7-12.8, P < .0001). CONCLUSIONS: During follow-up, annualized mortality rate varies markedly according to the number of CAD risk factors in patients without known heart disease and a normal exercise SPECT stress. Despite overall excellent long-term prognosis of a normal exercise SPECT, the burden of traditional CAD risk factors exert a strong synergistic influence on long-term survival and warrant aggressive treatment in this patient population.

The presence, characterization and prognosis of coronary plaques among patients with zero coronary calcium scores.

Patients with coronary artery calcium (CAC) scores of zero are generally considered not to have atherosclerosis. Recent studies involving computed tomography coronary angiography (CTCA) challenge this assumption. This goal of the present study is to assess the frequency, morphology, location, and the prognosis of patients with plaque detected on CTCA and zero CAC. 1,119 patients (51 ± 12 years, 52% male) with a zero CAC score during CTCA study were retrospectively identified. The CTCA studies were assessed for the presence, morphology, location and severity of all coronary plaques. All-cause mortality was assessed. The prevalence of coronary plaque was 13% (147 patients). Among the 212 plaques identified 154 (73%) were non-calcified, 28 (13%) were calcified, and 30 (14%) were of mixed morphology. Notably, ≥70% stenosis was noted among only 0.4% of all patients. ROC analysis revealed that coronary artery disease risk factors did not add to the prediction of plaque among our patients. Over a mean follow-up of 2.5 ± 0.6 years there were 4 deaths (0.4%), all in patients without coronary plaque on CTCA. The presence of coronary plaque is not uncommon among patients with zero CAC scores. These plaques were rarely associated with hemodynamically significant stenoses and were associated with an excellent prognosis. Clinical factors do not appear to be useful in predicting which patients with zero CAC scores have undetected coronary plaque.

Comparison of image quality and radiation dose of coronary computed tomographic angiography between conventional helical scanning and a strategy incorporating sequential scanning.

Radiation dose from coronary computed tomographic angiography may be decreased using a sequential scanning protocol rather than a conventional helical scanning protocol. We compared radiation dose and image quality from coronary computed tomographic angiography in a single center between an initial period during which helical scanning with electrocardiographically controlled tube current modulation was used for all patients (n = 138) and after adoption of a strategy incorporating sequential scanning whenever appropriate (n = 261). Using the sequential-if-appropriate strategy, sequential scanning was employed in 86.2% of patients. Compared to the helical-only strategy, this strategy was associated with a 65.1% dose decrease (mean dose-length product [DLP] 305.2 vs 875.1 and mean effective dose 14.9 vs 5.2 mSv, respectively), with no significant change in overall image quality, step artifacts, motion artifacts, or perceived image noise. For the 225 patients undergoing sequential scanning, the DLP was 201.9 +/- 90.0 mGy x cm; for patients undergoing helical scanning under either strategy, the DLP was 890.9 +/- 293.3 mGy x cm (p <0.0001), corresponding to mean effective doses of 3.4 and 15.1 mSv, respectively, a 77.5% decrease. Image quality was significantly greater for the sequential studies, reflecting the poorer image quality in patients undergoing helical scanning in the sequential-if-appropriate strategy. In conclusion, a sequential-if-appropriate diagnostic strategy decreases dose markedly compared to a helical-only strategy, with no significant difference in image quality.

Transforming growth factor-beta, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium.

Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-beta (TGF-beta) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-beta-mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) to arrest cells in G(1) phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-beta induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-beta, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P < or = 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase-driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-beta induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-beta cannot induce p27 levels due to dysregulated TGF-beta signaling, thereby causing 17beta-estradiol-driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA.