A case report of primary pericardial sarcoma.

Background: Primary pericardial sarcomas are extremely rare malignancies. In this case of primary pericardial synovial sarcoma, we discuss the initial steps to work-up pericardial effusions and review features that warrant more detailed investigation. Case summary: A 29-year-old male with no relevant past medical history presents with a few weeks of fatigue, dyspnoea, orthopnoea, leg swelling, and back pain. Transthoracic echocardiogram revealed pericardial effusion for which pericardiocentesis and drain placement were done. He was discharged with a diagnosis of post-viral pericarditis. He returned 5 months later with worsening symptoms. Advanced imaging with cardiac magnetic resonance imaging (CMR) showed heterogeneous pericardial mass later revealed to be a high-grade synovial sarcoma on biopsy. The patient was started on a doxorubicin-based chemotherapy regimen, but due to kidney dysfunction and multi-organ failure, he was transitioned to palliative care measures. Discussion: Transthoracic echocardiogram and computed tomography are often the initial tests of choice for pericardial effusions with pericardiocentesis recommended for effusions with tamponade physiology, for moderate-to-large effusions, or if there is concern for infection/neoplasm. Due to improved tissue characterization and spatial resolution, CMR and positron emission tomography should also be considered for atypical or recurrent pericardial effusions to assess for less common aetiologies such as malignancy.

Tracking of the beat-to-beat blood pressure changes by the Caretaker physiological monitor against invasive central aortic measurement.

OBJECTIVE: There is an unmet need for noninvasive continuous blood pressure (BP) monitoring technologies in various clinical settings. Continuous and noninvasive central aortic BP monitoring is technically not feasible currently, but if realized, would provide more accurate and real-time global hemodynamic information than any form of peripheral arterial BP monitoring in an acute care setting. As part of our efforts to develop such, herein we examined the tracking correlation between noninvasively-derived peripheral arterial BP by Caretaker device against invasively measured central aortic BP. METHODS: Beat-to-beat BP by Caretaker was recorded simultaneously with central aortic BP measured in patients undergoing cardiac catheterization. Pearson's correlation was also derived for SBP and DBP. A trend comparison analysis of the beat-to-beat BP change was performed using a four-quadrant plot analysis with the exclusion zones of 0.5 mmHg/s to determine concordance, (i.e. the direction of beat-to-beat changes in SBP and DBP). RESULTS: A total of 47 patients were included in the study. A total of 31 369 beats representing an average of 17.3 min of recording were used for analysis. The trend analysis yielded concordances of 84.4 and 83.5% for SBP and DBP, respectively. Respective correlations (Pearson's r) for SBP and DBP trends were 0.87 and 0.86 (P < 0.01). Tracking of beat-to-beat BP by Caretaker showed excellent concordance and correlation in the direction and the degree of BP change with central aortic BP, respectively. CONCLUSION: This study supports the satisfactory performance of the Caretaker device in continuous tracking of central aortic BP beat-to-beat BP and provides a basis to develop an algorithm for absolute central aortic BP estimation in the future.

Early Recanalization of a Traumatic Coronary Artery Dissection With Medical Therapy Alone.

We describe a patient who presents with chest discomfort 30 h after having an accident with an all-terrain vehicle. His follow-up coronary computed tomography angiogram revealed early recanalization of his coronary artery with conservative medical therapy. (Level of Difficulty: Intermediate.).

Initial arterial pH as a predictor of neurologic outcome after out-of-hospital cardiac arrest: A propensity-adjusted analysis.

BACKGROUND: Lower pH after out-of-hospital cardiac arrest (OHCA) has been associated with worsening neurologic outcome, with <7.2 identified as an "unfavorable resuscitation feature" in consensus treatment algorithms despite conflicting data. This study aimed to describe the relationship between decremental post-resuscitation pH and neurologic outcomes after OHCA. METHODS: Consecutive OHCA patients treated with targeted temperature management (TTM) at multiple US centers from 2008 to 2017 were evaluated. Poor neurologic outcome at hospital discharge was defined as cerebral performance category ≥3. The exposure was initial arterial pH after return of spontaneous circulation (ROSC) analyzed in decremental 0.05 thresholds. Potential confounders (demographics, history, resuscitation characteristics, initial studies) were defined a priori and controlled for via ATT-weighting on the inverse propensity score plus direct adjustment for the linear propensity score. RESULTS: Of 723 patients, 589 (80%) experienced poor neurologic outcome at hospital discharge. After propensity-adjustment with excellent covariate balance, the adjusted odds ratios for poor neurologic outcome by pH threshold were: ≤7.3: 2.0 (1.0-4.0); ≤7.25: 1.9 (1.2-3.1); ≤7.2: 2.1 (1.3-3.3); ≤7.15: 1.9 (1.2-3.1); ≤7.1: 2.4 (1.4-4.1); ≤7.05: 3.1 (1.5-6.3); ≤7.0: 4.5 (1.8-12). CONCLUSIONS: No increased hazard of progressively poor neurologic outcomes was observed in resuscitated OHCA patients treated with TTM until the initial post-ROSC arterial pH was at least ≤7.1. This threshold is more acidic than in current guidelines, suggesting the possibility that post-arrest pH may be utilized presently as an inappropriately-pessimistic prognosticator.

C-GRApH: A Validated Scoring System for Early Stratification of Neurologic Outcome After Out-of-Hospital Cardiac Arrest Treated With Targeted Temperature Management.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) results in significant morbidity and mortality, primarily from neurologic injury. Predicting neurologic outcome early post-OHCA remains difficult in patients receiving targeted temperature management. METHODS AND RESULTS: Retrospective analysis was performed on consecutive OHCA patients receiving targeted temperature management (32-34°C) for 24 hours at a tertiary-care center from 2008 to 2012 (development cohort, n=122). The primary outcome was favorable neurologic outcome at hospital discharge, defined as cerebral performance category 1 to 2 (poor 3-5). Patient demographics, pre-OHCA diagnoses, and initial laboratory studies post-resuscitation were compared between favorable and poor neurologic outcomes with multivariable logistic regression used to develop a simple scoring system (C-GRApH). The C-GRApH score ranges 0 to 5 using equally weighted variables: (C): coronary artery disease, known pre-OHCA; (G): glucose ≥200 mg/dL; (R): rhythm of arrest not ventricular tachycardia/fibrillation; (A): age >45; (pH): arterial pH ≤7.0. A validation cohort (n=344) included subsequent patients from the initial site (n=72) and an external quaternary-care health system (n=272) from 2012 to 2014. The c-statistic for predicting neurologic outcome was 0.82 (0.74-0.90, P<0.001) in the development cohort and 0.81 (0.76-0.87, P<0.001) in the validation cohort. When subdivided by C-GRApH score, similar rates of favorable neurologic outcome were seen in both cohorts, 70% each for low (0-1, n=60), 22% versus 19% for medium (2-3, n=307), and 0% versus 2% for high (4-5, n=99) C-GRApH scores in the development and validation cohorts, respectively. CONCLUSIONS: C-GRApH stratifies neurologic outcomes following OHCA in patients receiving targeted temperature management (32-34°C) using objective data available at hospital presentation, identifying patient subsets with disproportionally favorable (C-GRApH ≤1) and poor (C-GRApH ≥4) prognoses.

Endurance Training on Congenital Valvular Regurgitation: An Athlete Case Series.

BACKGROUND: Both intense endurance training and valvular regurgitation place a volume load on the right and left ventricles, potentially leading to dilation, but their effects in combination are not well-known. PURPOSE: The purpose of this case series is to describe the combined volume load of intense endurance athletic training and regurgitant valvular disease as well as the challenging assessment of each component's cardiovascular effect. METHODS: In this article, the clinical course of three elite endurance athletes with congenital valvular disease were reviewed. RESULTS: A swimmer with aortic regurgitation, a cyclist with aortic regurgitation, and a cyclist with pulmonary regurgitation were found to have severe dilation of the associated ventricles despite continuing to train at an elite level without symptoms. CONCLUSIONS: Because of the cumulative effects of endurance training and valvular regurgitation, each athlete manifested ventricular dilation out of proportion to their valvular disease and symptoms. Although the effects of congenital valvular disease and athletic remodeling on ventricular dilation have been thoroughly studied individually, their cumulative effect is not well understood. This complicates the assessment of athletes with valvular regurgitation and underscores the need for athlete-specific recommendations for valve replacement.

Plasma chemokine levels are associated with the presence and extent of angiographic coronary collaterals in chronic ischemic heart disease.

BACKGROUND: In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings. Their role in coronary collateralization has not been investigated. We sought to determine whether plasma levels of angiogenic and angiostatic chemokines are associated with of the presence and extent of coronary collaterals in patients with chronic IHD. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma concentrations of angiogenic and angiostatic chemokine ligands in 156 consecutive subjects undergoing coronary angiography with at least one ≥90% coronary stenosis and determined the presence and extent of spontaneously visible coronary collaterals using the Rentrop scoring system. Eighty-eight subjects (56%) had evidence of coronary collaterals. In a multivariable regression model, the concentration of the angiogenic ligands CXCL5, CXCL8 and CXCL12, hyperlipidemia, and an occluded artery were associated with the presence of collaterals; conversely, the concentration of the angiostatic ligand CXCL11, interferon-γ, hypertension and diabetes were associated with the absence of collaterals (ROC area 0.91). When analyzed according to extent of collateralization, higher Rentrop scores were significantly associated with increased concentration of the angiogenic ligand CXCL1 (p<0.0001), and decreased concentrations of angiostatic ligands CXCL9 (p<0.0001), CXCL10 (p = 0.002), and CXCL11 (p = 0.0002), and interferon-γ (p = 0.0004). CONCLUSIONS/SIGNIFICANCE: Plasma chemokine concentrations are associated with the presence and extent of spontaneously visible coronary artery collaterals and may be mechanistically involved in their recruitment.

Coronary angiography is a better predictor of mortality than noninvasive testing in patients evaluated for renal transplantation.

OBJECTIVES: The goal of this study was to compare whether coronary angiography or noninvasive imaging more accurately identifies coronary artery disease (CAD) and predicts mortality in patients with end-stage renal disease (ESRD) under evaluation for transplantation. BACKGROUND: CAD is a leading cause of mortality in patients with ESRD. The optimal method for identifying CAD in ESRD patients evaluated for transplantation remains controversial with a paucity of prognostic data currently available comparing noninvasive methods to coronary angiography. METHODS: The study cohort consisted of 57 patients undergoing both coronary angiography and stress perfusion imaging. Severe CAD was defined by angiography as ≥ 70% stenosis, and by noninvasive testing as ischemia in ≥ 1 zone. Follow-up for all cause mortality was 3.3 years. RESULTS: On noninvasive imaging, 63% had ischemia. On angiography, 40% had at least one vessel with severe stenoses. Abnormal perfusion was observed in 56% of patients without severe disease angiographically. Noninvasive imaging had poor specificity (24%) and poor positive predictive value (43%) for identifying severe disease. Angiography but not noninvasive imaging predicted survival; 3 year survival was 50% and 73% for patients with and without severe CAD by angiography (p<0.05). CONCLUSIONS: False positive scintigrams limited noninvasive imaging in patients with ESRD. Angiography was a better predictor of mortality compared with noninvasive testing.

Comparison between angiography and fractional flow reserve versus single-photon emission computed tomographic myocardial perfusion imaging for determining lesion significance in patients with multivessel coronary disease.

We hypothesized that myocardial perfusion imaging (MPI) would fail to identify all vascular zones with the potential for myocardial ischemia in patients with multivessel coronary disease (MVD). MPI is based on the concept of relative flow reserve. The ability of these techniques to determine the significance of a particular stenosis in the setting of MVD is questionable. Fractional flow reserve (FFR) can determine the significance of individual stenoses. Thirty-six patients with disease involving 88 arteries underwent angiography, FFR, and MPI. FFR was performed using a pressure wire with hyperemia from intracoronary adenosine. Myocardial perfusion images were analyzed quantitatively and segments assigned to a specific coronary artery. The relation between FFR and perfusion was determined for each vascular zone. Of the 88 vessels, the artery was occluded (n=20) or had an abnormal FFR

High left ventricular mass index does not limit the utility of fractional flow reserve for the physiologic assessment of lesion severity.

OBJECTIVES: To demonstrate that fractional flow reserve (FFR) of vessels in patients with high left ventricular mass index (LVMI) should be similar to that of matched vessels in patients with normal LVMI. BACKGROUND: FFR is a physiologic index of coronary lesion severity. It is not known whether FFR remains useful in the setting of increased LVMI, when microvascular abnormalities may be present. METHODS: LVMI was calculated in 84 patients using contrast left ventriculography after validation with cardiac magnetic resonance imaging. Cardiac risk factors, LV ejection fraction (LVEF), minimal lumen diameter (MLD), percent diameter stenosis (%DS), lesion length and FFR were compared in 22 patients with high LVMI to 62 patients with normal LVMI and angiographically-matched vessels. RESULTS: LVMI was 126 +/- 21 g/m2 in the high LVMI group and 84 +/- 21 g/m2 in the normal LVMI group. There were no differences in age, LVEF, diabetes, hypertension or dyslipidemia between groups. Angiographic lesion characteristics were well matched in patients with high versus normal LVMI (MLD 1.3 +/- 0.6 mm vs. 1.3 +/- 0.6 mm, %DS 61 +/- 13% vs. 62 +/- 13%, and lesion length 14.2 +/- 7.0 mm vs. 14.3 +/- 7.0 mm; p = NS for all). Importantly, no difference in FFR was observed (0.79 +/- 0.12 vs. 0.78 +/- 0.16; p = NS) between the groups, and LVMI did not correlate with FFR in a multivariate analysis. CONCLUSIONS: FFR of coronary lesions in patients with high LVMI is no different than FFR of angiographically-matched lesions in patients with normal LVMI, suggesting that high LV mass should not limit the utility of FFR as an index of coronary lesion severity.

Outcome of patients with acute coronary syndromes and moderate coronary lesions undergoing deferral of revascularization based on fractional flow reserve assessment.

OBJECTIVES: To determine the outcome of consecutive patients with and without acute coronary syndromes (ACS) in whom revascularization was deferred on the basis of fractional flow reserve (FFR). BACKGROUND: FFR < 0.75 correlates with ischemia on noninvasive tests and deferral of treatment on the basis of FFR is associated with low event rates in selected populations. Whether these low event rates apply to patients undergoing assessment of moderate stenoses in association with an ACS is not known and is an important clinical question. METHODS: Retrospective analysis and 12 month follow-up of consecutive, moderate (50-70%) de novo coronary lesions assessed with FFR. RESULTS: Revascularization was deferred in 120 lesions (111 patients) with FFR > or = 0.75. ACS was present in 35 patients (40 lesions). The clinical, angiographic and coronary hemodynamic characteristics of patients with and without ACS were similar. Among the 35 patients with ACS, there were 3 deaths, 1 MI, and 6 target vessel revascularizations (TVRs) (15% of lesions). Among the 76 patients without ACS, there were 5 deaths, 1 MI, and 7 TVR's (9% of lesions). CONCLUSIONS: Deferral of revascularization based on FFR in patients with ACS and moderate coronary stenoses is associated with acceptable and low event rates at 1 year.

Prevalence of unfavorable angiographic characteristics for percutaneous intervention in patients with unprotected left main coronary artery disease.

OBJECTIVES: The goal of this study was to determine the proportion of patients with left main coronary disease (LMCD) with unfavorable characteristics for percutaneous coronary intervention (PCI). BACKGROUND: Published series suggest that LMCD can be treated percutaneously, however, the proportion of patients in whom PCI is an option based on angiographic criteria is unknown. METHODS: In 13,228 consecutive coronary angiograms, 476 (3.6%) patients had < or =60% stenosis of the left main. In 232 patients with unprotected LMCD, the clinical characteristics and angiograms were reviewed with six features chosen as "unfavorable" for PCI: (1) Bifurcation LMCD, (2) occlusion of a major coronary, (3) ejection fraction <30%, (4) occlusion of a dominant RCA, (5) left dominant circulation, and (6) coexisting three-vessel disease. Treatment modality and 1 year mortality were determined. RESULTS: The mean age was 69 years and 68% were male. Unfavorable characteristics were common with at least one unfavorable characteristic seen in 80%. Bifurcation disease was the most common unfavorable characteristic observed (53%) and coexisting three-vessel disease was seen in 38%. Treatment consisted of CABG in 205 (88%), medical therapy in 24 (10%) and PCI in 3 (1%). Among patients referred for CABG, 1 year survival was 88% with similar rates of survival for those with favorable characteristics (86%) compared to those with at least one unfavorable characteristic (88%). CONCLUSIONS: Most patients with LMCD have at least one unfavorable characteristic for PCI suggesting that PCI may be a technically difficult option for most patients with LMCD.

Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction.

OBJECTIVES: We hypothesized that fractional flow reserve (FFR) of an infarct-related artery (IRA) early after myocardial infarction (MI) identifies inducible ischemia on noninvasive imaging. BACKGROUND: Early after MI, IRAs frequently have angiographically indeterminant lesions. Whether FFR can detect reversible perfusion defects early after MI when dynamic microvascular abnormalities are present is not known. METHODS: Rest and dipyridamole (DP)-stress 99mTc sestamibi single-photon emission computed tomography (SPECT) were performed in 48 patients 3.7 +/- 1.3 days after MI, with 23 patients undergoing concurrent myocardial contrast echocardiography (MCE). Angiography, FFR, and percutaneous coronary intervention (PCI) of the IRA (as necessary) were subsequently performed. Follow-up SPECT was performed 11 weeks after PCI to identify true reversibility on baseline SPECT. RESULTS: The sensitivity, specificity, positive and negative predictive value, and concordance of FFR < or =0.75 for detecting reversibility on SPECT were 88%, 50%, 68%, 89%, and 71% (chi-square <0.001), respectively; which improved to 88%, 93%, 88%, 93%, and 91% (chi-square <0.001), respectively, for the detection of true reversibility. The corresponding values of FFR < or =0.75 for detecting reversibility on DP-MCE were 90%, 100%, 100%, 75%, and 93% (chi-square <0.001), respectively, and on either SPECT or MCE were 88%, 93%, 91%, 91%, and 91% (chi-square <0.001), respectively. The optimal FFR value for discriminating inducible ischemia on noninvasive imaging was 0.78. CONCLUSIONS: Fractional flow reserve of the IRA accurately identifies reversibility on noninvasive imaging early after MI. These findings support the utility of FFR early after MI.

Coronary flow reserve abnormalities in patients with diabetes mellitus who have end-stage renal disease and normal epicardial coronary arteries.

BACKGROUND: Diabetic nephropathy is associated with increased cardiovascular events. Coronary atherosclerosis is responsible for many of these events, but other mechanisms such as impaired flow reserve may be involved. The purpose of this study was to define the prevalence and mechanism of abnormal coronary velocity reserve (CVR) in patients with diabetes mellitus who have nephropathy and a normal coronary artery. METHODS: Patients undergoing catheterization for clinical purposes were enrolled. CVR was measured with a Doppler ultrasound scanning wire in a normal coronary in 32 patients without diabetes mellitus, 11 patients with diabetes mellitus who did not have renal failure, and 21 patients with diabetes mellitus who had nephropathy. A CVR <2.0 was considered to be abnormal. RESULTS: Patients with diabetes mellitus who had renal failure had a higher incidence of hypertension and left ventricular hypertrophy. The average peak velocity (APV) at baseline was higher in patients with diabetes mellitus who had renal failure. At peak hyperemia, APV increased in all 3 groups, with no difference between groups. The mean CVR for patients without diabetes was 2.8 +/- 0.8 and was not different from that in patients with diabetes mellitus who did not have renal failure (2.7 +/- 0.7), but was lower than that in patients with diabetes mellitus who had renal failure (1.6 +/- 0.5; P < 0.001). Abnormal CVR was observed in 9% of patients without diabetes mellitus, 18% of patients with diabetes mellitus who did not have renal failure, and 57% of patients with diabetes mellitus who had renal failure, and abnormal CVR was caused by an elevation of baseline APV in 66% of these cases. The baseline heart rate and the presence of diabetes mellitus with renal failure were independent predictors of abnormal CVR by multivariable analysis. CONCLUSIONS: Patients with diabetic nephropathy have abnormalities in CVR in the absence of angiographically evident coronary disease.

Effect of acute myocardial infarction on the utility of fractional flow reserve for the physiologic assessment of the severity of coronary artery narrowing.

Fractional flow reserve (FFR) has been shown to be a useful physiologic index of coronary lesion severity in myocardial beds of patients without prior infarction and in those with remote infarction. Acute myocardial infarction (AMI) causes myocardial necrosis and microvascular stunning, embolization, and damage. Whether FFR remains a useful index of epicardial flow in the setting of recent myocardial infarction is not established. Cardiac risk factors, serum troponin I, angiographic minimal lumen diameter (MLD), percent diameter stenosis (DS), lesion length, vessel reference diameter, hyperemic central aortic pressure, hyperemic pressure distal to stenosis, and FFR were compared in 43 vessels subtending recent AMI beds to 25 control vessels, matched by lesion length and MLD, in patients without AMI. There were no differences in DS, MLD, lesion length, or reference diameter between AMI and non-AMI groups. Patients with AMI had mean troponin I levels of 91.8 +/- 162 ng/ml. Left ventricular ejection fraction was significantly lower in patients with than without AMI (55 +/- 9% vs 62 +/- 8%, p <0.05). There were no significant differences in hyperemic central aortic pressure (92 +/- 13 vs 99 +/- 15 mm Hg, p = NS), hyperemic pressure distal to the stenosis (62 +/- 17 vs 66 +/- 19 mm Hg, p = NS), or FFR (0.67 +/- 17 vs 0.68 +/- 17, p = NS) between recent AMI and non-AMI control patients. There was a significant correlation between DS and FFR for both patients with (p <0.001) and without (p = 0.003) infarctions. Thus, FFR and the relation between FFR and DS of lesions subtending AMI was not significantly different from FFR of angiographically matched lesions in patients without AMI.

Percutaneous treatment of focal vs. diffuse in-stent restenosis: a prospective randomized comparison of conventional therapies.

Few randomized studies compare outcomes for focal vs. diffuse in-stent restenosis (ISR) using conventional treatments. The purpose of this study was to compare the rates of major adverse cardiac events (MACEs) for focal vs. diffuse ISR using conventional techniques. One hundred thirteen patients with ISR were prospectively classified as focal (< 10 mm) or diffuse (> 10 mm). Focal ISR was randomized to balloon angioplasty (n = 29) or restenting (n = 29) and diffuse ISR randomized to rotational atherectomy (n = 30) or restenting (n = 25). At 9 months, patients with focal ISR had higher survival free of MACEs than patients with diffuse ISR (86% vs. 63%; P < 0.005), with no difference between techniques. Only the presence of diffuse ISR was an independent predictor of MACE at 9 months. Thus, focal ISR has a low rate of MACE compared to diffuse ISR, which carries a high event rate regardless of treatment employed.

Comparison between visual assessment and quantitative angiography versus fractional flow reserve for native coronary narrowings of moderate severity.

We tested the hypothesis that experienced interventional cardiologists can identify patients with fractional flow reserve (FFR) <0.75 either by visual assessment of the angiogram or by quantitative coronary angiography (QCA). Estimation of the significance of moderate lesions is difficult. FFR can determine the physiologic significance of a stenosis. Data comparing visual assessment and QCA of moderate lesions with FFR are limited. FFR was measured in 83 moderate lesions defined as having a 40% to 70% stenosis by visual inspection. An FFR <0.75 was considered "significant." Lesions were visually assessed by 3 experienced interventional cardiologists and their significance estimated. QCA was performed. Both analyses were compared with FFR. FFR averaged 0.82 +/- 0.11 and was <0.75 in 15 of 83 lesions (18%). The reviewers' classification was concordant with the FFR in about half the lesions. Concordance between reviewers was poor (Spearman's rho = 0.36). Visual assessment resulted in good sensitivity (80%) and negative predictive value (91%), but poor specificity (47%) and positive predictive value (25%) compared with FFR. By QCA, no patient with stenosis <60% or minimal luminal diameter >1.4 mm had FFR <0.75. QCA did not discriminate the significance of lesions outside of these parameters. Thus, neither visual assessment of an angiogram by experienced interventional cardiologists nor QCA can accurately predict the significance of most moderate narrowings.