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Background: Atrial functional mitral regurgitation (AFMR) is associated with increased morbidity and mortality. Left atrial (LA) size and function in AFMR are poorly characterized. We aimed to assess LA function by reservoir strain (LASr) and estimated reservoir work (LAWr) and their impact on outcome in AFMR. Methods: Consecutive patients at our institution between 2001 and 2019 and with significant (moderate or greater) AFMR were examined. LAWr was estimated as LASr×LA reservoir volume, and patients were grouped by median LASr and LAWr. Outcomes were all-cause death or heart failure hospitalizations. Results: Five hundred fifteen AFMR patients were followed up for 5 (1–17) years. Patients had previously documented atrial fibrillation (AF; 37%), heart failure with preserved ejection fraction (HFpEF) without AF (24%), or both (HFpEF+AF, 39%). LA volume was largest in AF, while LA function parameters were most impaired in the combined HFpEF+AF group. During follow-up, patients with low LASr or LAWr had higher risk of death ( P P P Conclusions: LA reservoir function but not LA size is a robust predictor of outcome in significant AFMR. This provides mechanistic insights into the interplay of functional versus geometric LA changes in AFMR.

Background: The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. Methods: We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). Results: Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis ( P P 6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. Conclusions: Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.

Background: Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown. Methods: Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and Streptococcus pyogenes proteomes were used to identify mimic epitopes. Results: A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8 + T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8 + T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8 + T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8 + T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and S pyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8 + T-cell activation in vitro. Conclusions: ProTα-dependent CD8 + T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8 + T cells, suggesting mechanisms provoking autoimmunity.

Background: Recent studies have linked mitral valve prolapse to localized myocardial fibrosis, ventricular arrhythmia, and even sudden cardiac death independent of mitral regurgitation or hemodynamic dysfunction. The primary mechanistic theory is rooted in increased papillary muscle traction and forces due to prolapse, yet no biomechanical evidence exists showing increased forces. Our objective was to evaluate the biomechanical relationship between prolapse and papillary muscle forces, leveraging advances in ex vivo modeling and technologies. We hypothesized that mitral valve prolapse with limited hemodynamic dysfunction leads to significantly higher papillary muscle forces, which could be a possible trigger for cellular and electrophysiological changes in the papillary muscles and adjacent myocardium. Methods: We developed an ex vivo papillary muscle force transduction and novel neochord length adjustment system capable of modeling targeted prolapse. Using 3 unique ovine models of mitral valve prolapse (bileaflet or posterior leaflet prolapse), we directly measured hemodynamics and forces, comparing physiologic and prolapsing valves. Results: We found that bileaflet prolapse significantly increases papillary muscle forces by 5% to 15% compared with an optimally coapting valve, which are correlated with statistically significant decreases in coaptation length. Moreover, we observed significant changes in the force profiles for prolapsing valves when compared with normal controls. Conclusions: We discovered that bileaflet prolapse with the absence of hemodynamic dysfunction results in significantly elevated forces and altered dynamics on the papillary muscles. Our work suggests that the sole reduction of mitral regurgitation without addressing reduced coaptation lengths and thus increased leaflet surface area exposed to ventricular pressure gradients (ie, billowing leaflets) is insufficient for an optimal repair.

Introduction: Functional mitral regurgitation (FMR) alters left ventricular (LV) remodeling, providing a nidus for non-ischemic fibrosis (NIF). Cardiac magnetic resonance (CMR) can measure FMR and LV tissue properties. Prevalence, remodeling manifestations, and prognostic implications of NIF in patients with FMR are unknown. Hypothesis: Among post-myocardial infarction (MI) patients with FMR, NIF associates with advanced LV remodeling and predicts adverse prognosis. Methods: The population comprised post-MI patients with FMR undergoing CMR. CMR exams were retrieved from a single-center registry, reviewed for MR etiology (degenerative excluded) and analyzed for FMR severity, LV structure/function, and late gadolinium enhancement (LGE) including ischemic pattern MI and NIF, which was defined via established criteria (mid-myocardial or epicardial LGE). Follow-up was performed for all-cause mortality. Results: 467 consecutive FMR patients (74% male, 63±16 years old) were studied, of whom 14% had NIF. Prevalence of NIF increased stepwise with FMR severity (12% mild, 16% moderate, 21% severe; p=0.33). Patients with NIF had higher LV end-diastolic (241±72ml vs 194±64ml) and end-systolic volumes (174±70ml vs 120±63ml), paralleled by lower EF (31±13% vs 41±15%) and stroke volumes (67±20ml vs 74±24ml); all p Conclusions: Among post-MI patients with FMR, NIF identifies an aggressive phenotype as evidenced by associations with adverse LV remodeling on CMR and increased mortality.

Introduction: Imaging studies patients with mitral valve prolapse (MVP) have previously shown cross sectional evidence of left ventricular (LV) fibrosis as well as increased risk for sudden cardiac death. This, along with evidence for post-repair ventricular dysfunction in Mitral valve surgery patients support a link between fibrosis and MVP. The development of fibrosis as a result of MVP, however, remains poorly understood. Hypothesis: Regionalized LV Fibrosis in MVP patients is driven by increased mechanical tension through the chordae tendineae by billowing leaflets. Methods: We performed histopathologic analysis on cardiac biopsies of 6 patients who underwent surgical repair for MV prolapse. We additionally performed longitudinal histopathologic analysis on hearts harvested from a mouse modal of human non-syndromic MVP (Dzip1 S14R/+). To assess the cellular response to increased mechanical tension, pathological stretch assays on human cardiac fibroblasts were performed in tandem with RNA seq, as well ATP luminescence assays to assess ATP release from stretched cells. Results: Biopsies from peripapillary regions, inferobasal wall, LV septum, and LV apex demonstrated regionalized myocardial fibrosis that correlated with increased macrophages and myofibroblasts. Our mouse model demonstrated similar regionalized deposition of collagen that increased over time, as well as an increase in macrophages and myofibroblasts. Stretching of human cardiac fibroblasts caused significant changes in 232 transcripts (Bonferroni corrected P value Conclusions: A mouse model of human MVP phenocopied regionalized myocardial fibrosis seen in humans and will provide a useful tool to investigate mechanisms of myocardial fibrosis in MVP patients. Stretch initiates changes in pro-fibrotic gene transcription, and causes ATP release from human cardiac fibroblasts.

Objectives To determine the cause of sudden brief unilateral tapering tinnitus (SBUTTs). Patients Five adults evaluated at a tertiary tinnitus referral center. Intervention Dry needling of lateral pterygoid muscle of one patient; jaw maneuvers in two patients. Main outcome measures Halting of SBUTTs. Results Trauma to the region of the lateral pterygoid muscle is associated with ipsilateral SBUTTs. Dry needling of the lateral pterygoid muscles abolishes SBUTTs. Some SBUTTs can be heard by others. Conclusions Some, if not all, SBUTTs appear to be closely related to trigger points within the lateral pterygoid muscle. SBUTTs may be generated by a local twitch response from trigger points within the lateral pterygoid muscle.

Introduction: Acute rheumatic fever (ARF) results from autoimmune responses to group A streptococcus. ARF can cause chronic rheumatic heart valve disease (RHVD), a major public health burden in low- and middle-income countries. Although ARF affects both sexes equally, females have a higher prevalence of RHVD. We identified a target protein, ProTα, that may contribute to pathophysiology of and gender predisposition in RHVD. Estradiol regulates ProTα, which influences transcriptional activity of the estrogen receptor (ER). Methods: Human heart valves (n=120) obtained from heart transplantation and valve replacement surgeries, including non-diseased mitral and aortic valves (NDMV and NDAV, n=17/group), rheumatic mitral and aortic valves (RMVD, n=45; RAVD, n=8) and calcifying valves from patients with calcific aortic valve disease (CAVD, n=33) underwent proteomic and network analyses, and immunohistochemical assessment of CD68, CD4, CD8 and ProTα. ProTα levels were measured in plasma and peripheral mononuclear cells (PBMCs) from RHVD patients and healthy donors (n=14/group) by ELISA and flow cytometry. Results: A comparison of proteomes from NDMV and NDAV established the baseline differences between valve types. 12 proteins were enriched (q Conclusion: We propose that ProTα is a novel contributor to the immunopathogenesis of RHVD and may regulate sex predisposition in this disease.

Secondary mitral valve regurgitation (MR) remains a challenging problem in the diagnostic workup and treatment of patients with heart failure. Although secondary MR is characteristically dynamic in nature and sensitive to changes in ventricular geometry and loading, current therapy is mainly focused on resting conditions. An exercise-induced increase in secondary MR, however, is associated with impaired exercise capacity and increased mortality. In an era where a multitude of percutaneous solutions are emerging for the treatment of patients with heart failure, it becomes important to address the dynamic component of secondary MR during exercise as well. A critical reappraisal of the underlying disease mechanisms, in particular the dynamic component during exercise, is of timely importance. This review summarizes the pathophysiological mechanisms involved in the dynamic deterioration of secondary MR during exercise, its functional and prognostic impact, and the way current treatment options affect the dynamic lesion and exercise hemodynamics in general.

Background: In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty. Methods: Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size). Results: At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd ( P =0.02) and LVESd/ring size ( P =0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05–4.62; P =0.038) remained significantly associated with 1-year MR recurrence. Conclusions: LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifiers: NCT00806988 and NCT00807040.

Background— Net atrioventricular compliance (C n ) has been reported to be an important determinant of pulmonary hypertension in mitral stenosis (MS). We hypothesized that it may be useful in assessing prognosis because C n reflects hemodynamic consequences of MS. To date, limited data with an assumed C n cutoff have indicated the need for larger prospective studies. This prospective study was designed to determine the impact of C n on clinical outcome and its contribution to pulmonary pressure in MS. In addition, we aimed to identify a cutoff value of C n for outcome prediction in this setting. Methods and Results— A total of 128 patients with rheumatic MS without other significant valve disease were prospectively enrolled. Comprehensive echocardiography was performed and Doppler-derived C n estimated using a previously validated equation. The end point was either mitral valve intervention or death. C n was an important predictor of pulmonary pressure, regardless of classic measures of MS severity. During a median follow-up of 22 months, the end point was reached in 45 patients (35%). Baseline C n predicted outcome, adding prognostic information beyond that provided by mitral valve area and functional status. C n ≤4 mL/mm Hg best predicted unfavorable outcome in derivation and validation sets. A subgroup analysis including only initially asymptomatic patients with moderate to severe MS without initial indication for intervention (40.6% of total) demonstrated that baseline C n predicted subsequent adverse outcome even after adjustment for classic measures of hemodynamic MS severity (hazard ratio, 0.33; 95% confidence interval, 0.14–0.79; P =0.013). Conclusions— C n contributes to pulmonary hypertension beyond stenosis severity itself. In a wide spectrum of MS severity, C n is a powerful predictor of adverse outcome, adding prognostic value to clinical data and mitral valve area. Importantly, baseline C n predicts a progressive course with subsequent need for intervention in initially asymptomatic patients. C n assessment therefore has potential value for clinical risk stratification and monitoring in MS patients.

Background— Mitral valve (MV) enlargement is a compensatory mechanism capable of preventing functional mitral regurgitation (FMR) in dilated ventricles. Total leaflet area and its relation with closure area measured by 3-dimensional (3D) echocardiography have been related to FMR. Whether these parameters can be assessed with other imaging modalities is not known. Our objectives are to compare cardiac computed tomography (CT)–based measurements of MV leaflets with 3D echocardiography and determine the relationship of these metrics to the presence of FMR. Methods and Results— We used 2 cohorts of patients who had cardiac CT to measure MV total leaflet, closure, and annulus areas. In cohort 1 (26 patients), we validated these CT metrics to 3D echocardiography. In cohort 2 (66 patients), we assessed the relation of MV size with the presence of FMR in 3 populations: heart failure with FMR, heart failure without FMR, and normal controls. Cardiac CT and 3D echocardiography produced similar results for total leaflet ( R 2 =0.97), closure ( R 2 =0.89), and annulus areas ( R 2 =0.84). MV size was the largest in heart failure without FMR compared with controls and patients with FMR (9.1±1.7 versus 7.5±1.0 versus 8.1±0.9 cm 2 /m 2 ; P P Conclusions— MV size measured by CT is comparable with 3D echocardiography. MV enlargement in cardiomyopathy suggests leaflet adaptation. Patients with FMR have inadequate adaptation as reflected by decreased ratios of leaflet area and areas determined by ventricle size (annulus and closure areas). These measurements provide additional insight into the mechanism of FMR.

Objective: To characterize work-related knee injuries treated in US emergency departments (EDs). Methods: We characterized work-related knee injuries treated in EDs in 2007 and examined trends from 1998 to 2007 by using the National Electronic Injury Surveillance System-occupational supplement. Results: In 2007, 184,300 (+/- 54,000; 95% confidence interval) occupational knee injuries were treated in US EDs, accounting for 5% of the 3.4 (+/- 0.9) million ED-treated occupational injuries. The ED-treated knee injury rate was 13 (+/- 4) injuries per 10,000 full-time equivalent workers. Younger workers and older female workers had high rates. Strains/sprains and contusions/abrasions were common-frequently resulting from falls and bodily reaction/overexertion events. Knee injury rates declined from 1998 through 2007. Conclusions: Knee injury prevention should emphasize reducing falls and bodily reaction/overexertion events, particularly among all youth and older women.

Background— Right ventricular (RV) and left ventricular (LV) function are closely linked due to a variety of factors, including common coronary blood supply. Altered LV perfusion holds the potential to affect the RV, but links between LV ischemia and RV performance, and independent impact of RV dysfunction on effort tolerance, are unknown. Methods and Results— The population comprised 2051 patients who underwent exercise stress myocardial perfusion imaging and echo (5.5±7.9 days), among whom 6% had echo-evidenced RV dysfunction. Global summed stress scores were ≈3-fold higher among patients with RV dysfunction, attributable to increments in inducible and fixed LV perfusion defects (all P ≤0.001). Regional inferior and lateral wall ischemia was greater among patients with RV dysfunction (both P P =0.13). In multivariable analysis, inducible inferior and lateral wall perfusion defects increased the likelihood of RV dysfunction (both P P P P P P Conclusions— Among patients with known or suspected coronary artery disease, regional LV ischemia involving the inferior and lateral walls confers increased likelihood of RV dysfunction. RV dysfunction impairs exercise tolerance independent of LV dysfunction.

Ischemic mitral regurgitation (MR) is common and increases heart failure and mortality after myocardial infarction.1,2 It is caused by left ventricle (LV) remodeling and subsequent papillary muscle (PM) displacement, with secondary mitral leaflet tethering. It can be seen classically in global LV dilatation and dysfunction or with more local remodeling involving the posterior PM and inferoposterior basal to mid LV wall.3 We report a case in which mitral leaflet tethering and severe MR occurred without either of these typical scenarios. An 82-year-old woman presented to the emergency department for recent-onset progressive exertional dyspnea, orthopnea, and lower extremity edema. She had known hypertension with LV hypertrophy, normal systolic function, mitral annular calcification, and mild mitral regurgitation by echocardiogram 6 months previously. Medical history was notable for hyperlipidemia, transient ischemic attack, and family history of coronary artery disease. Initial evaluation revealed overt heart failure with elevated NT-proBNP (> 9000 pg/mL). Chest X-ray showed bilateral pleural effusions and pulmonary vascular redistribution (Figure 1). Cardiac troponins were negative, but ECG showed new T-wave inversions suggestive of anteroseptal ischemia (Figure 2). Echocardiogram revealed …

To systematically characterize unilateral tinnitus typically lasting less than a minute.Observational study.Outpatient clinic in a tertiary referral hospital.Study I: 62 unselected adults. Study II: 74 adults with sudden brief unilateral tapering tinnitus (SBUTT).Study I: Structured interview regarding SBUTTs and other types of tinnitus. Study II: Maintaining an SBUTT log for 4 consecutive months.Study I: Retrospective prevalence of SBUTTs. Study II: Prospective frequency and characteristics of SBUTTs.Study I: 76% of the participants recalled having at least one SBUTT in the past. There was no significant difference in the incidence of SBUTTs with respect to handedness, age, sex, the presence or absence of chronic tinnitus, whether tinnitus could be brought on by exposure to loud sounds, or whether auditory perception could be modulated with strong muscle contractions of the neck or jaw. Study II: SBUTTs mean rate was 1.2 per month (range, 0-11.5). The rate in people with chronic tinnitus was twice that of those without chronic tinnitus. Right ear SBUTTs predominated nearly 2 to 1. Pitch estimates ranged between 0.1 and 4.4 kHz; 75% of SBUTTs lasted 25 seconds or less. A quarter occurred with simultaneous ear fullness.In the 76% of adults with SBUTTs, the average rate of occurrence was about once a month. SBUTTs are twice as common for the right ear as the left. One of 4 SBUTTs occurs with ear fullness. A quarter of adults never recalled ever having an SBUTT.

Background— Mitral regurgitation (MR) generally accompanies inferobasal myocardial infarction (MI), with leaflet tethering by displaced papillary muscles. Mitral regurgitation is also reported with anteroapical MI without global dilatation or inferior wall motion abnormalities. We hypothesized that anteroapical MI extending to the inferior apex displaces the papillary muscles, tethering the mitral leaflets to cause MR. Methods and Results— In the retrospective part of the study, consecutive anteroapical MI patients were studied. Moderate-severe MR occurred in 9% of 234 patients with only anteroapical MI versus 17% of 242 with inferoapical extension ( P P P r =0.70) and its diminished systolic shortening ( r =−0.65). In the animal study, 9 sheep with left anterior descending coronary artery ligation were analyzed. Four sheep that developed MR had inferoapical MI extension with tethering length increasing over 1.5 months (2.1±0.4 to 2.9±0.4 cm, P P not statistically significant). In MR sheep, the normal decrease in tethering length from diastole to systole was eliminated ( P Conclusions— Anteroapical MI with inferoapical extension can mechanically displace papillary muscles, causing MR despite the absence of basal and midinferior wall motion abnormalities. This suggests the possibility of repositioning treatments for this condition.

Objective— Cardiac valvular endothelium is unique in its ability to undergo endothelial-to-mesenchymal transformation, a differentiation process that is essential for valve development and has been proposed as mechanism for replenishing the interstitial cells of mature valves. We hypothesized that the valvular endothelium contains endothelial cells that are direct precursors to osteoblastic valvular interstitial cells (VICs). Methods and Results— Clonal cell populations from ovine mitral valve leaflets were isolated by single cell plating. Mitral valvular endothelial and mesenchymal clones were tested for osteogenic, adipogenic, and chondrogenic differentiation, determined by the expression of lineage-specific markers. Mitral valvular endothelial clones showed a propensity for osteogenic, as well as chondrogenic differentiation that was comparable to a mitral valvular VIC clone and to bone marrow–derived mesenchymal stem cells. Osteogenic differentiation was not detected in nonvalvular endothelial cells. Regions of osteocalcin expression, a marker of osteoblastic differentiation, were detected along the endothelium of mitral valves that had been subjected in vivo to mechanical stretch. Conclusion— Mitral valve leaflets contain endothelial cells with multilineage mesenchymal differentiation potential, including osteogenic differentiation. This unique feature suggests that postnatal mitral valvular endothelium harbors a reserve of progenitor cells that can contribute to osteogenic and chondrogenic VICs.

OBJECTIVE:: Identify factors associated with obstructive sleep apnea (OSA) risk during commercial driver medical examinations. METHODS:: A case-control study was conducted at an occupational health clinic by reviewing the commercial driver medical examinations medical records performed from January 2007 to December 2008. The magnitude of association with OSA was estimated with logistic regression. RESULTS:: Among 1890 commercial motor vehicle drivers, 51 were confirmed positive for OSA by polysomnography after initial screening by Joint Task Force guidelines, yielding estimated positive predictive values of 78.5% for the screening criteria. Multivariable logistic regression showed that body mass index ≥ 30 (odds ratio: 26.86), hypertension (odds ratio: 2.57), and diabetes (odds ratio: 2.03) were independently associated with OSA. CONCLUSION:: Medical examiners' use of objectively measurable risk factors, such as obesity, history of hypertension, and/or diabetes, rather than symptoms, may be more effective in identifying undiagnosed OSA in commercial drivers during the commercial driver medical examinations. Language: en

Background— One of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting. Methods and Results— A posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting ( P P P P Conclusions— Reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes.

Background— Cardiac resynchronization therapy (CRT) has been shown to reduce functional mitral regurgitation (MR). It has been proposed that the mechanism of MR reduction relates to geometric change or, alternatively, changes in left ventricular (LV) contractile function. Normal mitral valve (MV) function relies on a balance between tethering and closing forces on the MV leaflets. Functional MR results from a derangement of this force–balance relationship, and CRT may be an important modulator of MV function by its ability to enhance the force–balance relationship on the MV. We hypothesized that CRT improves the comprehensive force balance acting on the valve, including favorable changes in both geometry and LV contractile function. Methods and Results— We examined the effect of CRT on 34 patients with functional MR before and after CRT (209�81 days). MR regurgitant volume, closing forces on MV (derived from Doppler transmitral pressure gradients), including dP/dt and a factor (closing pressure ratio) expressing how long the peak closing gradient is maintained over systole (closing pressure ratio=velocity time integral/MR peak velocity�mitral regurgitation time), and dyssynchrony by tissue Doppler were measured. End-diastolic volume, end-systolic volume, mitral valve annular area (MAA) and contraction (percent change in MAA from end-diastole to midsystole), leaflet closing area (leaflet area during valve closure), and tenting volume (volume under leaflets to annular plane) were measured by 3D echocardiography. After CRT, end-diastolic volume (253�111 versus 221�110 mL, P P P P 2 ( P 2 ( P P P =0.01); dP/dt also improved after CRT. There was no change in dyssynchrony or MAA contraction. Conclusions— Reduction in MR after CRT is associated with favorable changes in MV geometry and closing forces on the MV. It does so by favorably affecting the force balance acting on the MV in 2 ways: reducing tethering through reversal of LV remodeling and increasing the systolic duration of peak transmitral closing pressures.

It is often asserted in international health policy discussions that a woman's school attainment protects her children's health and survival chances, particularly in the less-developed countries (LDCs) of Asia, Africa, Latin America, and the Pacific, however questions concerning the processe

Noninvasive serum markers of liver fibrosis are being used as an alternative to liver biopsy. Currently available tests distinguish, with accuracy, only absent/minimal fibrosis (Ishak stages 0-1) and advanced fibrosis/cirrhosis (Ishak stages 4-6), but not intermediate fibrosis (Ishak stages 2-3). Our aim was to evaluate the diagnostic accuracy of hyaluronic acid (HA), FIBROSpect II (FS-II), and YKL-40 (chondrex, human cartilage glycoprotein-39) in various clinically important categories of fibrosis, and further correlate these serum markers with digital quantification of fibrosis (DQF) and Ishak stages.Serum HA, YKL-40, and FS-II were retrospectively assessed and correlated with Ishak stages and DQF scores in 75 patients with chronic hepatitis C (HCV). Spearman's rho statistics assessed relationships among all parameters, and receiver operator characteristic curves evaluated accuracy of each parameter when compared to the Ishak stages.All three serum markers and DQF correlated highly with one another (Por = 0.01) and with Ishak stages of fibrosis. Among the serum markers, HA was effective in discriminating between Ishak stages 0-1 and Ishak stages 2-3 compared with FS-II, with an area under the curve of 0.76 versus 0.66 and a false-positive rate of 0.33 versus 0.67, respectively. All three serum markers predicted advanced fibrosis and cirrhosis. YKL-40 had the highest false-positive rates in all categories of fibrosis.HA can be utilized as a reliable surrogate marker in distinguishing three clinically relevant stages of fibrosis: absent/minimal, intermediate, and advanced/cirrhosis. HA should be considered as a cost-effective alternative to other serum markers for staging fibrosis and for determining the timing and selection of HCV treatment.

This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 μg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [

We thank Dr Barison and colleagues for their interest in our article.1 In our manuscript, we demonstrate that both parental mitral valve prolapse (MVP) and parental mild, nondiagnostic MVP are associated with increased prevalence of MVP in the offspring in the Framingham Heart Study community. In their letter, Barison et al underline the importance of age when assessing MVP prevalence, stating that MVP is more common among older participants in the offspring or generation 2 (Gen 2) than in the younger generation 3 (Gen 3). Based on published Framingham Heart Study literature,2 the prevalence of MVP in Gen 2 is 2.4% at their fifth examination cycle. This percentage is slightly higher in the same cohort at their sixth examination cycle (98/3380 or 2.9%) and at their eighth examination cycle (94/2725 or 3.4%; ie, 11 to 17 years …

Background— Tricuspid regurgitation (TR) is a risk factor for mortality in pulmonary hypertension (PH). TR severity varies among patients with comparable degrees of PH and right ventricular remodeling. The contribution of leaflet adaptation to the pathophysiology of TR has yet to be examined. We hypothesized that tricuspid leaflet area (TLA) is increased in PH, and that the adequacy of this increase relative to right ventricular remodeling determines TR severity. Methods and Results— A prospective cohort of 255 patients with PH from pre and postcapillary pathogeneses was assembled from 2 centers. Patients underwent a 3-dimensional echocardiogram focused on the tricuspid apparatus. TLA was measured with the Omni 4D software package. Compared with normal controls, patients with PH had a 2-fold increase in right ventricular volumes, 62% increase in annular area, and 49% increase in TLA. Those with severe TR demonstrated inadequate increase in TLA relative to the closure area, such that the ratio of TLA:closure area Conclusions— TLA plays a significant role in determining which patients with PH develop severe functional TR. The ratio of TLA:closure area, reflecting the balance between leaflet adaptation versus annular dilation and tethering forces, is an indicator of TR severity that may identify which patients stand to benefit from leaflet augmentation during tricuspid valve repair.

Oxidative stress is implicated in the premature death of dopamine neurons in substantia nigra in Parkinson's disease. The incidence of Parkinson's disease is higher in men than in women, and estrogen may provide neuroprotection against oxidative damage. We examined the protective effects of estrogen on rat nigral death after chronic ozone inhalation. Ozone inhalation produced impaired nigral cell morphology and loss of dopamine neurons in ovariectomized rats. This was counteracted after 60 days of 17beta-estradiol treatment, when blood levels were highest. These results indicate that ozone exposure may be a useful Parkinson's disease model and neuroprotection afforded by 17beta-estradiol is dependent on the high levels achieved after its prolonged administration.

Background— Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation, endocarditis, heart failure, and sudden death. To date, 2 MVP loci have been described, but the defective genes have yet to be discovered. In the present study, we analyzed a large family segregating MVP, and identified a new locus, MMVP3 . This study and others have enabled us to explore mitral valve morphological variations of currently uncertain clinical significance. Methods and Results— Echocardiograms and blood samples were obtained from 43 individuals who were classified by the extent and pattern of displacement. Genotypic analyses were performed with polymorphic microsatellite markers. Evidence of linkage was obtained on chromosome 13q31.3-q32.1, with a peak nonparametric linkage score of 18.41 ( P D13S132 . Of the 6 related individuals with mitral valve morphologies not meeting diagnostic criteria but resembling fully developed forms, 5 carried all or part of the haplotype linked to MVP. Conclusions— The mapping of a new MVP locus to chromosome 13 confirms the observed genetic heterogeneity and represents an important step toward gene identification. Furthermore, the genetic analysis provides clinical lessons with regard to previously nondiagnostic morphologies. In the familial context, these may represent early expression in gene carriers. Early recognition of gene carriers could potentially enhance the clinical evaluation of patients at risk of full expression, with the ultimate aim of developing interventions to reduce progression.

Background—Current data demonstrate that progressive atherosclerosis is associated with activation of the inflammatory process, as evidenced by systemic elevations of molecules such as tumor necrosis factor, interleukin (IL)-6, and IL-1. It has been postulated that inflammatory events within an atherogenic lesion are induced by oxidized LDL. Recent evidence suggests that infectious agents, including those that cause periodontal disease, may also play an important role. Studies presented here tested the hypothesis that IL-1 receptor (IL-1R1) signaling plays a crucial role in bacteria- and/or high-fat diet (HFD)–enhanced atherogenesis.Methods and Results—Ten-week-old ApoE+/−mice lacking either 1 IL-1R1 allele (ApoE+/−/IL-1R1+/−) or 2 IL-1R1 alleles (ApoE+/−/IL-1R1−/−) fed either an HFD or regular chow were inoculated intravenously with livePorphyromonas gingivalis(P gingivalis) (107CFU), an important periodontal pathogen, or vehicle once per week for 14 or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, and ELISA for systemic proinflammatory mediators were performed. Atherosclerotic lesions of proximal aortas and aortic tree were substantially reduced in ApoE+/−/IL-1R1−/−mice than in ApoE+/−/IL-1R1+/−mice challenged withP gingivalis.At 24 weeks afterP gingivalisinoculation, proximal aortic lesion size quantified by histomorphometry was 5-fold–reduced in chow-fed ApoE+/−/IL-1R1−/−mice than in ApoE+/−/IL-1R1+/−mice (P+/−/IL-1R1−/−mice exhibited marked attenuation of the progression of atherosclerotic lesions (78% to 97%), with and withoutP gingivalisinoculation (PConclusion—Ablation of IL-1R1 underP gingivalischallenge and/or an HFD reduced the progression of atherosclerotic plaques. These results indicate that IL-1 plays a crucial role in bacteria- and/or HFD-enhanced atherogenesis.

Background— Manipulating gene expression in the failing heart has therapeutic promise, but until now efficient and homogeneous cardiac gene delivery has required an open-chest approach. This study examines the hypothesis that vector delivery promoted by echo contrast microbubbles will be maximized by injection of the vectors into the aortic root with brief balloon occlusion above the sinuses, while at the same time prolonging diastole and vasodilating with acetylcholine (ACh) to maximize coronary exposure. Methods and Results— After incubation with albumin-coated perfluorocarbon microbubbles, an adenovirus encoding a reporter gene was infused into the aortic root of rats. To maximize delivery, the aortic root was transiently occluded with a balloon catheter during a brief ACh-induced asystole. Ultrasound was used to image the delivery and disrupt the microbubbles. Aortic occlusion with concomitant ACh increased myocardial gene expression for virus + microbubbles by >2.5-fold, from 925±165 to 2358±376 relative units (RU; P Conclusions— An adenoviral delivery system combining echo contrast with a catheter-based technique to maximize coronary perfusion increases gene delivery compared with echo contrast alone. This novel method permits efficient percutaneous gene delivery in closed-chest animals.

Introduction: Restrictive mitral valve annuloplasty (RMA) for secondary mitral regurgitation (MR) might cause functional (mitral) stenosis, yet underlying pathophysiological mechanisms remain debated. Hypothesis: Diastolic restriction of the anterior leaflet (AL) opening, due to papillary muscle tethering, plays a key role in the inflow obstruction after RMA. Increasing AL opening during exercise is associated with greater mitral valve area (MVA). Methods: Consecutive RMA patients (n=39, 63±11 years, 77% male) performed a symptom-limited (supine) bicycle exercise test with stepwise Doppler echocardiography and respiratory gas analysis. Diastolic AL opening angle (3-chamber view, Figure A), transmitral flow rate, mean transmitral gradient, and effective MVA were assessed at rest and during peak exercise. Results: At rest, effective MVA (1.5±0.4cm2) correlated moderately to the AL opening angle (68±10°) (r=0.4, p=0.014; Figure B). During exercise, effective MVA increased significantly to 2.0±0.5cm2 (p4° AL angle increase, respectively), a higher increase was significantly associated with greater effective MVA during exercise (p=0.013, Figure C). Patients with AL opening angle 4° (n=13) had a significantly lower maximal oxygen uptake compared to patients with AL opening angle at rest above the median or a greater dynamic AL angle increase with exercise (n=22) (VO2max 12.5±2.8 versus 16.4±4.7 mL/kg/min, p=0.005). Conclusions: Diastolic restriction of AL opening plays a key role in functional mitral stenosis after RMA for secondary MR. Increasing AL opening at rest, or better AL opening reserve during exercise, are associated with higher MVA and improved exercise capacity.

Introduction: Mitral annulus (MA) is generally enlarged in patients with mitral valve prolapse (MVP), which may raise MV closing force acting to shift the MV and its adjacent basal left ventricular (LV) wall toward left atrium. Hypothesis: MA dilatation with augmented MV closing force may disturb basal LV wall systolic contraction in patients with MVP. Methods: In 11 healthy controls and 34 patients with MVP, 3 apical views were obtained to assess longitudinal strain of basal- and mid-LV segments by speckle tracking analysis. The ratio of basal- to mid-LV strain value was then calculated. MA area was calculated by annulus diameters in apical 4- and 2- chamber views. MV closing force was calculated as MA area х (systolic blood pressure - 10). Results: Patients with MVP showed significantly larger MA area (5.3±1.0 vs 3.8±0.7 cm2/m2) and MV closing force (638±192 vs 431±66 mmHg•cm2/m2), and reduced basal-LV strain (-18±3 vs -21±2%) than controls (all p Conclusions: In patients with MVP, an increase in MV closing force corresponding to MA dilatation, as opposed to the severity of mitral regurgitation, was related to attenuated basal LV wall contraction, which can be restored by MV plasty with annular size reduction.

The prognosis of patients with mitral stenosis (MS) depends on the severity of obstruction and hemodynamic burden affecting the pulmonary vasculature. Net atrioventricular compliance (C n ) reflects the overall adverse hemodynamic consequence of MS and may be useful in predicting mortality. Methods: A total of 402 MS patients (mean age 51 ± 16 years, valve area of 1.04 ± 0.24 cm 2 , 84% female) undergoing percutaneous mitral valvuloplasty (PMV) between 2000 and 2013 at 2 centers were enrolled. Invasive hemodynamic and echocardiographic measures (pre and 24 hours post PMV) were examined and patients were followed for a median of 28 months post PMV. Endpoints were cardiovascular death (primary), and a composite of death from any cause, mitral valve replacement (MVR) or repeat PMV (secondary). Results: At baseline, 138 (34%) were in atrial fibrillation and 48% were NYHA functional class III or IV. PMV resulted in significant increase in valve area, decrease in transmitral pressure gradients, pulmonary pressures and an improvement in right ventricular (RV) function. A total of 47 (12%) died (39 cardiovascular deaths). In addition, 48 patients underwent MVR, and 12 required repeat PMV with an overall incidence of adverse events of 11.4 events per 100 patient-years. Baseline C n was a strong predictor of both cardiac death (adjusted hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.49 - 0.86, p = 0.008), and composite endpoint (adjusted HR 0.81, 95% CI 0.67 - 0.91, p = 0.016). Cardiac mortality was significantly higher in patients with C n ≤ 4 ml/mmHg than in patients with C n > 4 ml/mmHg (adjusted HR 0.35, 95% CI 0.16 - 0.75, p=0.007), after adjusting for clinical factors, pulmonary artery pressure, tricuspid regurgitation (TR) severity, RV function and immediate procedural results. Survival rate at 1-, 3- and 5-years follow-up was 96%, 94% and 87% in patients with C n > 4 ml/mmHg compared to 89%, 79% and 75% in patients with C n ≤ 4 ml/mmHg. Conclusions: Baseline C n is a strong predictor of cardiovascular-related mortality in patients with significant MS, after adjustment for other prognostic factors including postprocedural pulmonary artery pressure. C n assessment therefore has potential value in evaluation of mortality risk in the setting of MS.

Background: Mitral valve repair with ring annuloplasty for ischemic mitral regurgitation (IMR) is associated with significant recurrent IMR due to continued left ventricular (LV) remodeling as it does not directly address LV and mitral valve tethering. We aimed to assess chronic implantation of novel polymer based mesh device to reduce IMR reduction and reverse LV remodeling. Methods: Five Dorset sheep underwent ligation of second and third circumflex obtuse marginal branches to produce chronic IMR after 8 weeks. Poly-mesh was attached to the infarcted myocardium underlying the papillary muscle with a further 8 weeks follow-up. In addition, chronic IMR was produced in 5 untreated control sheep. IMR severity was assessed by 2D vena contracta width (VCW) and 3D vena contracta area (VCA). LV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF) by 2D echo and hemodynamic data were also obtained at each baseline, chronic MR, and chronic poly-mesh stages. Results: In all sheep, after poly-mesh attachment, IMR decreased and this reduction persisted over 8 weeks (VCW 0.42±0.09 to 0.08±0.12cm; VCA 0.13±0.08 to 0.05±0.08cmsq, p Conclusions: Chronic follow up after polymer-mesh device attachment shows the stabilization of mitral-LV complex in a chronic IMR model, causing persistent reduction of IMR and preventing continued LV remodeling.

Mitral valve prolapse (MVP) is a common disease affecting nearly 1 in 40 individuals. It is the leading surgical indication for mitral valve regurgitation. Despite a clear heritable component, the genetic etiology of non-syndromic MVP has remained elusive. Individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of a previously linked interval on chromosome 11. We found a novel missense mutation in DCHS1, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. The familial mutation reduced protein stability in zebrafish and cultured cells. Morpholino knockdown of zebrafish dachsous1b yielded a regurgitant atrioventricular canal defect that could be rescued by wild-type human DCHS1 but not by mRNA with the familial mutation. Adult haploinsufficient Dchs1 mice had anatomic and functional prolapse of thickened, elongated leaflets recapitulating the human MVP phenotype. Dchs1 haploinsufficiency was associated with developmental defects in valve shape, cell migration and patterning during fetal morphogenesis, suggesting cell polarity as a previously unrecognized facet of valve morphogenesis. Studies of downstream changes identified increased MAP kinase activities and α-SMA+ cells (myofibroblasts) in the valves preceding myxomatous degeneration; these suggest potential future directions for blunting disease progression. Additional genetic studies identified a second family with a DCHS1 mutation and a significantly increased burden of novel DCHS1 mutations in sporadic MVP cases Interdisciplinary studies strongly support DCHS1 as the first identified disease-causing gene for non-syndromic MVP and suggest potential mechanisms for modifying disease natural history.

Background Ischemic mitral regurgitation (MR) was first ascribed to papillary muscle (PM) contractile dysfunction. Current theories include apical leaflet tethering caused by left ventricular (LV) distortion, but PM dysfunction is still postulated and commonly diagnosed. PM contraction, however, parallels apical tethering, suggesting the hypothesis that PM contractile dysfunction can actually diminish MR due to ischemic distortion of the inferior base alone. Methods and Results We therefore occluded the proximal circumflex circulation in 7 sheep while maintaining PM perfusion, confirmed by contrast echocardiography. By 3D echocardiography, we measured the tethering distance between the ischemic medial PM tip and anterior annulus and LV ejection volume to give MR (by subtracting flowmeter LV outflow). In 6 sheep without initial MR, inferior ischemia alone produced PM tip retraction with restricted leaflet closure and mild-to-moderate MR (regurgitant fraction, 25.2±2.8%). Adding PM ischemia consistently decreased MR and tethering distance (5.2±0.3 to 1.4±0.3 mL; +3.8±0.5 mm to −2.2±0.7 mm axially relative to baseline; P P Conclusions PM contractile dysfunction can paradoxically decrease MR from inferobasal ischemia by reducing leaflet tethering to improve coaptation. This emphasizes the role of geometric factors in ischemic MR mechanism and potential therapy.

UNLABELLED: The conventional continuity equation uses nonsimultaneous measurements of blood flow velocities through the left ventricular outflow tract and across the aortic valve to calculate aortic valve area (AVA). We have noted that both velocities can be simultaneously obtained from continuous wave (CW) Doppler analysis (double-envelope [DE]). We hypothesize that prosthetic AVA can be calculated by using the DE technique, during transesophageal echocardiography (TEE). Prosthetic AVA was calculated in 41 of 45 patients immediately after aortic valve replacement by using the DE/AVA technique. Left ventricular outflow tract diameter was obtained from an esophageal view, while subvalvular (V(1)) and valvular (V(2)) peak velocities were simultaneously obtained from transgastric views by using CW Doppler. Prosthetic AVA and V(1)/V(2) ratio (Doppler velocity index) were calculated. V(1) was also measured by using pulse wave Doppler, as is conventionally done. Twenty-three Carbomedic (CM) and 18 Carpentier-Edwards (CE) AVA were evaluated. DE/AVAs for CM and CE valves correlated and agreed with that reported by the manufacturer (CM r(2) = 0.91, mean bias -0.25 cm(2) [SD 0.18]; CE r(2) = 0.73, mean bias -0.02 cm(2) [SD 0.27]). Calculated Doppler velocity index values agree with available data (mean bias 0.03 [SD 0.05]). The V(1) obtained by using the DE method was nearly identical to the V(1) obtained by using pulse wave (r(2) = 0.95, mean bias 0.02 m/s [SD 0.04 m/s]). TEE assessment of prosthetic AVA using the DE technique agrees with data reported by the manufacturer. Obtaining subvalvular and valvular velocities from the same CW Doppler trace may simplify the continuity equation and help avoid errors caused by beat-to-beat changes in blood flow. Quantitative prosthetic aortic valve assessment can be performed, on-line, with TEE by using the DE technique. IMPLICATIONS: Quantitative assessment of prosthetic aortic valve area can be performed on-line by using transesophageal echocardiography using the double envelope technique.

Patients with chronic hepatitis C and low serum and hepatic iron stores may have an improved response to interferon (IFN). We tested whether iron reduction before and during IFN therapy would lead to an improved sustained biochemical and virological response compared with IFN alone. Eighty-two previously untreated patients with chronic hepatitis C were randomized to either: group A IFN-alpha2b 3 MU 3 times per week for 6 months, or group B iron reduction before and during IFN-alpha2b 3 MU 3 times per week for 6 months. Group B patients had lower mean serum alanine transaminase (ALT) levels than group A patients during treatment and follow-up. Group B patients had significantly lower mean hepatitis C virus (HCV)-RNA levels at treatment weeks 4 and 12 (P

Background —In hypertrophic cardiomyopathy, a spectrum of mitral leaflet abnormalities has been related to the mechanism of mitral systolic anterior motion (SAM), which causes both subaortic obstruction and mitral regurgitation. In the individual patient, SAM and regurgitation vary in parallel; clinically, however, great interindividual differences in mitral regurgitation can occur for comparable degrees of SAM. We hypothesized that these differences relate to variations in posterior leaflet length and mobility, restricting its ability to follow the anterior leaflet (participate in SAM) and coapt effectively. Methods and Results —Different mitral geometries produced surgically in porcine valves were studied in vitro. Comparable degrees of SAM resulted in more severe mitral regurgitation for geometries characterized by limited posterior leaflet excursion. Mitral geometry was also analyzed in 23 patients with hypertrophic cardiomyopathy by intraoperative transesophageal echocardiography. All had typical anterior leaflet SAM with significant outflow tract gradients but considerably more variable mitral regurgitation; therefore, regurgitation did not correlate with obstruction. In contrast, mitral regurgitation correlated inversely with the length over which the leaflets coapted ( r =−0.89), the most severe regurgitation occurring with a visible gap. Regurgitation increased with increasing mismatch of anterior to posterior leaflet length ( r =0.77) and decreasing posterior leaflet mobility ( r =−0.79). Conclusions —SAM produces greater mitral regurgitation if the posterior leaflet is limited in its ability to move anteriorly, participate in SAM, and coapt effectively. This can explain interindividual differences in regurgitation for comparable degrees of SAM. Thus, the spectrum of leaflet length and mobility that affects subaortic obstruction also influences mitral regurgitation in patients with SAM.

Background Recent advances in three-dimensional (3D) echocardiography allow us to address uniquely 3D scientific questions, such as the mechanism of functional mitral regurgitation (MR) in patients with left ventricular (LV) dysfunction and its relation to the 3D geometry of mitral leaflet attachments. Competing hypotheses include global LV dysfunction with inadequate leaflet closing force versus geometric distortion of the mitral apparatus by LV dilatation, which increases leaflet tethering and restricts closure. Because geometric changes generally accompany dysfunction, these possibilities have been difficult to separate. Methods and Results We created a model of global LV dysfunction by esmolol and phenylephrine infusion in six dogs, initially with LV expansion limited by increasing pericardial restraint and then with the pericardium opened. The mid-systolic 3D relations of the papillary muscle (PM) tips and mitral valve were reconstructed. Despite severe LV dysfunction (ejection fraction, 18±6%), only trace MR developed when pericardial restraint limited LV dilatation; with the pericardium opened, moderate MR accompanied LV dilatation (end-systolic volume, 44±5 mL versus 12±5 mL control, P P R 2 =.82 to .85, P =2×10 −7 to 6×10 −8 ). Conclusions LV dysfunction without dilatation fails to produce important MR. Functional MR relates strongly to changes in the 3D geometry of the mitral valve attachments at the PM and annular levels, with practical implications for approaches that would restore a more favorable configuration.

Background Three-dimensional echocardiography can allow us to address uniquely three-dimensional scientific questions, for example, the hypothesis that the impact of a stenotic valve depends not only on its limiting orifice area but also on its three-dimensional geometry proximal to the orifice. This can affect the coefficient of orifice contraction (Cc=effective/anatomic area), which is important because for a given flow rate and anatomic area, a lower Cc gives a higher velocity and pressure gradient, and Cc, routinely assumed constant in the Gorlin equation, may vary with valve shape (60% for a flat plate, 100% for a tube). To date, it has not been possible to study this with actual valve shapes in patients. Methods and Results Three-dimensional echocardiography reconstructed valve geometries typical of the spectrum in patients with mitral stenosis: mobile doming, intermediate conical, and relatively flat immobile valves. Each geometry was constructed with orifice areas of 0.5, 1.0, and 1.5 cm 2 by stereolithography (computerized laser polymerization) (total, nine valves) and studied at physiological flow rates. Cc varied prominently with shape and was larger for the longer, tapered dome (more gradual flow convergence proximal and distal to the limiting orifice): for an anatomic orifice of 1.5 cm 2 , Cc increased from 0.73 (flat) to 0.87 (dome), and for an area of 0.5 cm 2 , from 0.62 to 0.75. For each shape, Cc increased with increasing orifice size relative to the proximal funnel (more tubelike). These variations translated into important differences of up to 40% in pressure gradient for the same anatomic area and flow rate (greatest for the flattest valves), with a corresponding variation in calculated Gorlin area (an effective area) relative to anatomic values. Conclusions The coefficient of contraction and the related net pressure loss are importantly affected by the variations in leaflet geometry seen in patients with mitral stenosis. Three-dimensional echocardiography and stereolithography, with the use of actual information from patients, can address such uniquely three-dimensional questions to provide insight into the relations between cardiac structure, pressure, and flows.

OBJECTIVE: Details on airbag injuries to the upper extremity are relatively unknown to clinicians. The injuries presented here should provide a clear understanding of the mechanisms of forearm, hand, and wrist injuries that may be seen by emergency room physicians. MATERIALS AND METHODS: From our crash investigations of 325 airbag-equipped passenger cars, a subset of upper extremity injuries are presented that are related to airbag deployments. MAIN RESULTS: Minor hand, wrist, or forearm injuries--contusions, abrasions, and sprains--are not uncommonly reported. Infrequently, hand fractures have been sustained and, in isolated cases, fractures of the forearm bones or of the thumb, wrist, and fingers. The close proximity of the forearm to the airbag module door is related to most of the fractures identified. Steering wheel airbag deployments can fling the hand-forearm into the instrument panel, rearview mirror, or windshield, as indicated by contact scuffs, tissue debris, or the star burst (spider web) pattern of windshield breakage in fron of the steering wheel. CONCLUSION: Minor injuries of the upper extremity can occur when contacted by the deploying airbag either directly or by flinging the hand-forearm into interior car structures. Fractures of the forearm are rare and usually are due to direct impact by the forceful opening of the airbag module door.

Background Current two-dimensional (2D) echocardiographic measures of left ventricular (LV) volume are most limited by aneurysmal distortion, which restricts application of simple geometric models that assume symmetrical shape. 2D methods also fail to provide separate volumes of the aneurysm and nonaneurysmal residual LV cavity, which could help assess the stroke volume wasted by dyskinesis and the potential residual LV body to guide surgical approaches and predict their outcome. Three-dimensional (3D) echocardiographic reconstruction has potential advantages for assessing aneurysmal left ventricles because it is not dependent on geometric assumptions, does not require standardized views that may exclude portions of the aneurysm, and can potentially measure separate aneurysm and nonaneurysm cavity volumes of any shape. The purpose of this study was first, to validate the accuracy of 3D echocardiographic reconstruction for quantifying total LV and separate LV body and aneurysm volumes in vitro so as to provide direct standards for the separate volumes; and second, to determine the feasibility and accuracy of 3D echocardiographic reconstruction for quantifying the total volume and function of aneurysmal left ventricles in an animal model, providing a reference standard for instantaneous LV volume. Methods and Results A recently developed 3D system that automatically combines 2D images and their locations was applied (1) to reconstruct 10 aneurysmal ventricular phantoms and 12 gel-filled autopsied human hearts with aneurysms, comparing cavity volumes (total and aneurysm) to those measured by fluid displacement; and (2) to reconstruct the left ventricle during 19 hemodynamic stages in four dogs with surgically created LV aneurysms, comparing total volumes with actual instantaneous values measured by an intracavitary balloon attached to an external column for validation and also calculating the stroke volume wasted by aneurysmal dyskinesis. 3D reconstruction reproduced the distorted aneurysmal LV shapes. In vitro, calculated volumes (aneurysm, nonaneurysm, and total) agreed well with actual values, with correlation coefficients of .99 and SEEs of 3.2 to 6.1 cm 3 for phantoms and 3.4 to 4.2 cm 3 for autopsied hearts (mean error, r =.99, .99, .95, and .99, respectively) and agreed closely with them (SEE=4.3 cm 3 , 3.5 cm 3 , 1.7 cm 3 , and 2%, respectively). The stroke volumes wasted by the aneurysm were −20.1±19.3% of LV body (nonaneurysm) stroke volume. Conclusions Despite distorted ventricular shapes, a recently developed 3D echocardiographic system and surfacing algorithm can accurately reconstruct aneurysmal left ventricles and quantify total LV volume (validated in vivo and in vitro) as well as the separate volumes of the aneurysm and residual LV body (validated in vitro). This should improve our ability to evaluate such ventricles and guide surgical approaches.

BACKGROUND It has been proposed recently that measuring the flow convergence region proximal to an orifice by Doppler flow mapping can provide a means of calculating regurgitant flow rate. Although verified in experimental models, this approach is difficult to validate clinically because there is no ideal gold standard for regurgitant flows in patients. However, this method also can be used to derive cardiac output or flow rate proximal to stenotic orifices and therefore to calculate their areas by the continuity equation (area = flow rate/velocity). Applying this method in mitral stenosis would provide a unique way of validating the underlying concept because the predicted areas could be compared with those measured directly by planimetry. METHODS AND RESULTS We studied 40 patients with mitral stenosis using imaging and Doppler echocardiography. Doppler color flow recordings of mitral inflow were obtained from the apex, and the radius of the proximal flow convergence region was measured at its peak diastolic value from the orifice to the first color alias along the axis of flow. Flow rate was calculated assuming uniform radial flow convergence toward the orifice, modified by a factor that accounted for the inflow funnel angle formed by the mitral leaflets. Mitral valve area was then calculated as peak flow rate divided by peak velocity by continuous-wave Doppler. The calculated areas agreed well with those from three comparative techniques over a range of 0.5 to 2.2 cm2: 1) cross-sectional area by planimetry (y = 1.08x-0.13, r = .91, SEE = 0.21 cm2); 2) area derived from the Doppler pressure half-time (y = 1.02x-0.14, r = .89, SEE = 0.24 cm2); and 3) area calculated by the Gorlin equation in the 26 patients who underwent catheterization (y = 0.89x + 0.08, r = .86, SEE = 0.24 cm2). Agreement with planimetry was similar for 22 patients with mitral regurgitation and 18 without it (P > .6), as well as for 6 in atrial fibrillation (P > .2). CONCLUSIONS These results validate the proximal flow convergence concept in the clinical setting and also demonstrate that it can be extended to orifice area calculation using the continuity equation.

Analysis of velocity acceleration proximal to a regurgitant valve has been proposed as a method to quantify the regurgitant flow rate (Qo). Previous work has assumed inviscid flow through an infinitesimal orifice, predicting hemispheric isovelocity shells, with calculated flow rate given by Qc = 2 pi rN2vN, where vN is user-selected velocity of interest and rN is the distance from that velocity to the orifice. To validate this approach more rigorously and investigate the impact of finite orifice size on the assumption of hemispheric symmetry, numerical and in vitro modeling was used. Finite-difference modeling demonstrated hemispheric shape for contours more than two orifice diameters from the orifice. More proximal than this (where the measured velocity vN exceeded 3% of the orifice velocity vo), flow was progressively underestimated, with a proportional error delta Q/Qo nearly identical to the ratio of contour velocity to orifice velocity, vN/vo. For the in vitro investigations, flow rates from 4.3 to 150 cm3/sec through 0.3 and 1.0 cm2 circular orifices were imaged with color Doppler with aliasing velocities from 19 to 36 cm/sec. Overall, the calculated flow (assuming hemispheric symmetry) correlated well with the true flow, Qc = 0.88Qo-7.82 (r = 0.945, SD = 12.2 cm3/sec, p less than 0.0001, n = 48), but progressively underestimated flow when the vN approached the orifice velocity vo. Applying a correction factor predicted by the numerical modeling, delta Q was improved from -13.81 +/- 13.01 cm3/sec (mean +/- SD) to +1.54 +/- 5.67 cm3/sec.(ABSTRACT TRUNCATED AT 250 WORDS)

Background— Ischemic mitral regurgitation is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about how chronic tethering affects leaflet area, in part because it cannot be measured repeatedly in situ. Recently, a new method for 3D echocardiographic measurement of mitral leaflet area was developed and validated in vivo against sheep valves, later excised. Clinical studies (n=80) showed that mitral leaflet area increased by >30% in patients with inferior myocardial infarction and dilated cardiomyopathy versus normal; greater adaptation independently predicted less mitral regurgitation. This study explored whether mitral valve area changes over time within the same heart with ischemic mitral regurgitation. Methods and Results— Twelve sheep were studied at baseline and 3 months after inferior myocardial infarction by 3D echocardiography; 6 were untreated and 6 were treated initially with an epicardial patch to limit left ventricular dilation and mitral regurgitation. Untreated sheep developed left ventricular dilation at 3 months, with global dysfunction (mean±SD ejection fraction, 24±10% versus 44±10% with patching, P =0.02) and moderate mitral regurgitation (vena contracta, 5.0±1.0 versus 0.8±1.0 mm, P 2 ( P =0.0001). In patched sheep, leaflet area at 3 months was not significantly different from baseline sheep values (13.0±1.1 versus baseline, 12.1±1.8 cm 2 , P =0.31). Conclusions— Mitral valve area, independent of systolic stretch, increases over time as the left ventricular remodels after inferior myocardial infarction. This increase, however, fails to compensate adequately for tethering to prevent mitral regurgitation. Understanding the mechanism of valve adaptation can potentially suggest new biological and surgical therapeutic targets.

Using data from a case-control study conducted in Group Health Cooperative (GHC) of Puget Sound, we examined the relation between the use of electric blankets or heated water beds and the risk of prostate cancer. Cases were 175 prostate cancer patients ages 40-69 years. Controls were 258 male GHC members frequency matched to cases. The odds ratio (OR) for prostate cancer associated with the use of an electric blanket or heated water bed was 1.4 (95% confidence interval (CI) 0.9-2.2). The risk, however, did not tend to be higher with increasing months per year or years of use. This study did not provide clear evidence on the hypothesized association.

Ischemic mitral regurgitation (IMR) relates to displacement of the papillary muscles from ischemic ventricular distortion. Recurrent IMR is frequent after annuloplasty, particularly when left ventricular remodeling continues to progress. Our hypothesis is that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) polymer into the myocardium, in chronic MR with great left ventricle remodeling. Methods : we studied 8 sheep underwent ligation of circumflex branches to produce chronic ischemic MR over eight weeks. Once MR developed, PVA was injected into the myocardium underlying the infarcted PM. 2D and 3D echocardiograms were used pre infarct (baseline), pre PVA (Chronic MR) and post PVA. Hemodynamic data were obtained Results: One animal died, in the remaining 7 moderate MR developed. With PVA, the MR decreased significantly from moderate to trace-mild (vena contracta: 5.3 ± 0.9 mm vs 2.3 ± 0.9 mm, post MR vs post PVA; p Conclusions : PVA polymer injections improve coaptation and reduce remodeling chronic MR without impairing LV systolic function. This new approach offers a potential alternative for relieving ischemic mitral regurgitation by correcting papillary muscle position, thus relieving tethering that causes ischemic mitral regurgitation.