Quantitative assessment of effective regurgitant orifice: impact on risk stratification, and cut-off for severe and torrential tricuspid regurgitation grade.

AIMS: Asses the added value of quantitative evaluation of tricuspid regurgitation (TR), the proper cut-off value for severe TR and 'torrential TR' based on outcome data. The added value of quantitative evaluation of TR, and the cut-off values associated with increased mortality are unknown. METHODS AND RESULTS: In patients with all-cause TR assessed both qualitatively and quantitatively by proximal iso-velocity surface area method, long-term and 1-year outcome analysis was conducted. Thresholds for excess mortality were assessed using spline curves, receiver-operating characteristic curves, and minimum P-value analysis. The study involved 676 patients with all-cause TR (age 73.9 ± 14 years, male 45%, ejection fraction 52.9 ± 14%). Effective regurgitant orifice (ERO) was strongly associated with decreased survival in unadjusted [hazard ratio (HR) 2.38 (1.79-3.01), P < 0.0001 per 0.1 cm2 increment] and adjusted [2.6 (1.25-5.0), P = 0.01] analyses. Quantitative grading was superior to qualitative grading in prediction of outcome (P < 0.01). The optimal cut-off value for the best separation in survival between groups of patients with severe vs. lesser degree of TR was 0.35 cm2 [P < 0.0001, HR =2.0 (1.5-2.7)]. ERO negatively impacted survival, even when including only the subgroup of patients with severe TR [HR 1.5 (1.01-2.3); P = 0.04]. The optimal threshold corresponding for the best separation for survival between groups of patients with severe vs. 'torrential' TR was 0.7 cm2 [P = 0.005, HR =2.6 (1.2-5.1)]. CONCLUSION: TR can be severe and even 'torrential' and is associated with excess mortality. Quantitative assessment of TR by ERO measurement is a powerful independent predictor of outcome, superior to standard qualitative assessment. The optimal cut-off above which mortality is increased is 0.35 cm2, similar albeit slightly lower than suggested in recent guidelines. Torrential TR >0.7 cm2 is associated with poorer survival compared to patients with severe TR (ERO > 0.4 cm2 and <0.7 cm2).

Impact of right ventricular dysfunction and end-diastolic pulmonary artery pressure estimated from analysis of tricuspid regurgitant velocity spectrum in patients with preserved ejection fraction.

AIMS: We aimed to analyse the association between right haemodynamic parameters, right ventricular (RV) dysfunction parameters, and outcomes in patients with preserved ejection fraction (EF). METHODS AND RESULTS: Retrospective analysis of right haemodynamic (systolic pulmonary pressure and end-diastolic pulmonary pressure based on tricuspid regurgitation (TR) velocity at pulmonary valve opening time), and RV parameters including size (end-diastolic and end-systolic area), function (RV fractional area change, Tei index, Tricuspid Annular Plane Systolic Excursion, and speckle tracking derived free wall strain), from 557 consecutive patients with preserved EF [EF ≥ 50%; age 64.9 + 20; 52% female; co-morbidity Charlson index 4.7 (2.9, 6.4)]. All cause and cardiac mortality were retrospectively analysed and correlated to echo haemodynamic and co-morbid parameters. TR velocity at pulmonary valve opening time and calculated end-diastolic pulmonary artery pressure were obtainable in 71% of patients. The best haemodynamic univariate predictor of mortality was calculated end-diastolic pulmonary artery pressure [hazard ratio 1.06 (1.04-1.07); P < 0.0001], superior to TR peak velocity and systolic pulmonary artery pressure. Elevated end-diastolic pulmonary artery pressure was associated with all cause and cardiac mortality even when adjusted for all significant clinical (age, gender, and Charlson index), and echo (stroke volume index, left atrial volume index, systolic pulmonary pressure, E/e', and Tei index) parameters. Tei index was superior to all other RV functional parameters (P < 0.05 for all parameters). CONCLUSION: TR velocity at pulmonary valve opening time and calculated end-diastolic pulmonary artery pressure are obtainable in most patients, and add prognostic information on top of clinical and routine haemodynamic and diastolic parameters.

Clinical Outcome of Isolated Tricuspid Regurgitation in Patients with Preserved Left Ventricular Ejection Fraction and Pulmonary Hypertension.

BACKGROUND: The outcome of tricuspid regurgitation (TR) remains unclear because of heterogeneity of etiology and the contradictory results of outcome studies. The aim of this study was to evaluate the clinical outcomes of TR in patients with pulmonary hypertension (PH) and normal left systolic function, stratified to patients with post- or precapillary PH. METHODS: In patients with no left valvar disease (isolated) functional TR, preserved left systolic function (ejection fraction ≥ 50%), and PH (systolic pulmonary pressure > 50 mm Hg), TR was assessed both qualitatively (grade) and semiquantitatively using the vena contracta method, and retrospective analysis of long-term outcomes was conducted. Patients with severe comorbid diseases were excluded. RESULTS: The study included 245 patients (age 80.5 years, 37% men, ejection fraction 57%, all with pulmonary systolic pressure > 50 mm Hg). At least moderate to severe TR was diagnosed in 178 patients, and their outcomes were compared with those of 67 patients with the same characteristics and less than mild TR. At least moderate to severe TR was associated with lower survival, independent of all characteristics, right ventricular size or function, comorbidity, or pulmonary pressure (P = .03 for grade and P = .02 for vena contracta). Cox proportional-hazard analysis with interaction terms for TR severity and etiology of PH (post- vs precapillary) showed that the etiology of PH did not affect the association of TR with outcome (P = .90 for the interaction term). CONCLUSIONS: At least moderate to severe isolated TR is independently associated with excess mortality in patients with preserved systolic function and PH, warranting heightened attention to diagnosis and grading. This is irrespective of etiology (pre- or postcapillary) of PH. Semiquantitative assessment of TR by vena contracta is an independent associate of outcome, superior to standard qualitative assessment.

Impact of Right Ventricular Dysfunction and Tricuspid Regurgitation on Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: Right ventricular (RV) dysfunction and tricuspid regurgitation (TR) may coexist with aortic stenosis. The aim of this study was to assess the association between RV dysfunction, TR, associated comorbidities, and outcomes following transcatheter aortic valve replacement (TAVR). METHODS: A retrospective analysis was conducted of baseline and 6-month clinical and echocardiographic parameters, including TR grade, RV size (grade, end-diastolic and end-systolic areas, annular diameter), and function (grade, tricuspid annular plane systolic excursion [TAPSE], fractional area change, Tei index), in 519 consecutive TAVR patients. RESULTS: The prevalence of moderate or greater TR was 11% (n = 59). Although TR was associated with increased mortality (P = .02) in unadjusted analysis, it did not demonstrate an independent association with outcome when adjusted for RV dysfunction (TAPSE; P = .30) or multiple clinical parameters (P ≥ .20). RV parameters associated with poor outcomes included TAPSE (P = .006) and Tei index (P = .005). TAPSE was associated with lower survival even when adjusted for TR (P = .009) and all clinical parameters (P = .01). Persistence of moderate or greater TR 6 months after TAVR seemed to be associated with lower survival (P = .02), even when adjusted for clinical and RV parameters (P = .07). CONCLUSIONS: TR in association with aortic stenosis is frequently progressive despite TAVR but is not independently associated with outcomes. RV function is a stronger driver of adverse outcomes compared with TR itself, and RV quantitative rather than qualitative evaluation is the key to stratify these patients.

Mechanisms of Effort Intolerance in Patients With Rheumatic Mitral Stenosis: Combined Echocardiography and Cardiopulmonary Stress Protocol.

OBJECTIVES: This study sought to evaluate mechanisms of effort intolerance in patients with rheumatic mitral stenosis (MS). BACKGROUND: Combined stress echocardiography and cardiopulmonary testing allows assessment of cardiac function, hemodynamics, and oxygen extraction (A-Vo2 difference). METHODS: Using semirecumbent bicycle exercise, 20 patients with rheumatic MS (valve area 1.36 ± 0.4 cm2) were compared to 20 control subjects at 4 pre-defined activity stages (rest, unloaded, anaerobic threshold, and peak). Various echocardiographic parameters (left ventricular volumes, ejection fraction, stroke volume, mitral valve gradient, mitral valve area, tissue s' and e') and ventilatory parameters (peak oxygen consumption [Vo2] and A-Vo2 difference) were measured during 8 to 12 min of graded exercise. RESULTS: Comparing patients with MS to control subjects, significant differences (both between groups and for group by time interaction) were seen in multiple parameters (heart rate, stroke volume, end-diastolic volume, ejection fraction, s', e', Vo2, and tidal volume). Exercise responses were all attenuated compared to control subjects. Comparing patients with MS and poor exercise tolerance (<80% of expected) to other subjects with MS, we found attenuated increases in tidal volume (p = 0.0003), heart rate (p = 0.0009), and mitral area (p = 0.04) in the poor exercise tolerance group. These patients also displayed different end-diastolic volume behavior over time (group by time interaction p = 0.05). In multivariable analysis, peak heart rate response (p = 0.01), tidal volume response (p = 0.0001), and peak A-Vo2 difference (p = 0.03) were the only independent predictors of exercise capacity in patients with MS; systolic pulmonary pressure, mitral valve gradient, and mitral valve area were not. CONCLUSIONS: In patients with rheumatic MS, exercise intolerance is predominantly the result of restrictive lung function, chronotropic incompetence, limited stroke volume reserve, and peripheral factors, and not simply impaired valvular function. Combined stress echocardiography and cardiopulmonary testing can be helpful in determining mechanisms of exercise intolerance in patients with MS.

Impact of left ventricular filling parameters on outcome of patients undergoing trans-catheter aortic valve replacement.

AIM: To assess the impact of left ventricular (LV) filling parameters on outcomes following trans-catheter aortic valve replacement (TAVR). METHODS AND RESULTS: A total of 526 TAVR patients were compared with 300 patients with severe aortic stenosis (AS) treated conservatively. Clinical variables were collected along with echocardiographic data at baseline, 1 month, and 6 months after study entry. End points included all-cause mortality and the combination of death and heart failure admission. LV filling parameters associated with mortality included reduced A wave velocity (P = 0.005) and shorter deceleration time (DT) (P = 0.0005). DT was superior to all other parameters (P = 0.05) apart from patients with atrial fibrillation in whom E/e' was better. Short DT (<160 ms) was associated with lower survival than long DT (≥220 ms; P = 0.002) or intermediate DT (P = 0.05), even after adjustment for age, gender, stroke volume index (SVI), and co-morbidities. However, patients with short baseline DT exhibited greater improvement in DT, E/A, and systolic pulmonary pressure at follow-up than patients with baseline DT ≥160 ms (P < 0.05 for all time x group interactions). Most importantly, among patients with short DT, TAVR was associated with better survival than conservative treatment (46 ± 7 vs. 28 ± 12% at 3 years, P = 0.05), even after adjustment for age, gender, and SVI (P = 0.05). CONCLUSION: Short DT is an independent predictor of adverse outcome following TAVR. Nevertheless, LV filling parameters improve in most patients post TAVR, and TAVR is associated with improved survival compared with conservative therapy, even in patients with evidence of elevated LV filling. Thus, evidence of elevated LV filling should not be viewed as a contraindication for TAVR.

Determinants of Effort Intolerance in Patients With Heart Failure: Combined Echocardiography and Cardiopulmonary Stress Protocol.

OBJECTIVES: The purpose of this study was to assess individual mechanisms of effort intolerance in patients with heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or normal cardiac function using combined echocardiography and cardiopulmonary stress testing. BACKGROUND: Combined stress echocardiography and cardiopulmonary tests visualize cardiac chambers in 4 well-defined activity levels (rest, unloaded, anaerobic threshold, and peak), allowing noninvasive assessment of cardiac function, hemodynamics, and arterial venous oxygen content difference (AVo(2)Diff) during all stages. METHODS: Left ventricular volumes, stroke volume (SV), S', E/e', oxygen consumption (Vo(2)), and AVo(2)Diff were measured in all effort stages using ramp semirecumbent cycle prolonged (≥8 min) exercise in 45 consecutive subjects evaluated for effort intolerance (14 normal cardiac function, 16 HFpEF, and 15 HFrEF patients; age 56.5 ± 16 years; 73% male). RESULTS: In HFpEF and HFrEF, the changes in Vo2 were attenuated (between group p = 0.003; group by time interaction p < 0.0001), as well as peak heart rate (p = 0.0001; p = 0.0001) and SV (p = 0.006; p = 0.0001). End-diastolic volume to E/e' ratio (measure of compliance) was superior in HFrEF and normal patients at baseline but worsened in HFpEF and HFrEF at peak exercise (8.3 ± 4 vs. 11.6 ± 5 vs. 19.1 ± 8; p = 0.004; p = 0.01). Functional mitral regurgitation worsened even during the unloaded stage, mostly in patients with HFrEF, but also in several patients with HFpEF. In multivariable analysis, heart rate response (p = 0.007), and AVo(2)Diff (p < 0.0001) were the most significant independent predictors of effort capacity; SV was not. CONCLUSIONS: Combined tests are feasible and allow noninvasive evaluation of effort intolerance. In HFpEF and HFrEF patients, exercise intolerance is predominantly due to chronotropic incompetence and peripheral factors. Combined stress echocardiography and cardiopulmonary tests may have potential for clinical management and selection of patients for trials.

Added value of pulmonary venous flow Doppler assessment in patients with preserved ejection fraction and its contribution to the diastolic grading paradigm.

AIMS: To evaluate the prognostic role of pulmonary venous flow parameters and their role in patients with preserved ejection fraction (EF). METHODS AND RESULTS: Pulmonary venous flow parameters were measured in 365 patients in sinus rhythm, without significant mitral disease, and EF >50% (age 64.9 ± 19; 52% female) by a single sonographer. Survival, time to re-admission for heart failure, and to a combined cardiac end point (cardiac death, heart failure, and atrial fibrillation) were retrospectively analysed and correlated to echo parameters. Systolic (S) and diastolic (D) pulmonary vein flow were obtainable in 73% of patients and Ar in 65%. The lower peak S/D ratio and higher ΔAr-A time were associated with higher rate of heart failure readmission (P = 0.03 for both). The S/D integral ratio was the best pulmonary vein flow predictor of heart failure readmissions (P = 0.0009), better than the peak S/D ratio, or ΔA-Ar time (P < 0.01 for both), and independently predicted worse outcome even when adjusted for diastolic grading (using recent guidelines), left ventricle mass index, E/e', and left atrial volume index (P < 0.05 for all). The addition S/D ratio to diastolic grading recognized patients with pseudo-normal filling pattern and S/D ratio >1 with similar clinical outcomes to grade I (P > 0.5), but worse clinical outcomes than in the pseudo-normal patients with lower S/D ratio (P < 0.01). CONCLUSIONS: PVFP are obtainable in most patients, add prognostic information on top of routine diastolic parameters, and define an early stage of diastolic dysfunction resembling the pseudo-normal pattern in which S/D ratio is >1, and outcome is excellent.

Arginine uptake is attenuated, through post-translational regulation of cationic amino acid transporter-1, in hyperlipidemic rats.

Endothelial cell dysfunction (ECD) is a common feature of hypercholesterolemia. Defective nitric oxide (NO) generation due to decreased endothelial nitric oxide synthase (eNOS) activity is a crucial parameter characterizing ECD. L-arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as a specific arginine transporter for eNOS. Our hypothesis implies that CAT-1 is a major determinant of eNOS activity in hypercholesterolemia. We studied aortic arginine uptake, CAT-1 and CAT-2 mRNA expression, and CAT-1, and PKC alpha protein in: (a) control, untreated animals (CTL), (b) rats fed with 4% cholesterol+1% cholate and 2% corn oil for 6 weeks (CHOL) and (c) rats with hypercholesterolemia treated orally with either atorvastatin (CHOL+ATORVA, 20mg/kg BW/day) or arginine 1% (CHOL+ARG) in the drinking water (modalities which have been shown to enhance CAT-1 activity and improve endothelial function). Serum cholesterol levels significantly increased in cholesterol fed animals, an increase which was blocked by atorvastatin (CTL: 66.8+/-15, CHOL: 133.9+/-22, CHOL+ARG: 128.2+/-20, CHOL+ATORVA: 77+/-15 mg/dl). Arginine transport was significantly decreased in CHOL. Treatment with neither arginine nor atorvastatin had an effect. Using RT-PCR, we found no change in aortic CAT-1 and CAT-2 mRNA expression in CHOL as well as following arginine or atorvastatin administration. The abundance of CAT-1 protein was significantly augmented in cholesterol fed rats and was not affected by arginine or atorvastatin. PKC alpha protein content, which was previously shown to regulate CAT-1 activity, increased significantly in CHOL and was neither affected by atorvastatin nor arginine. In conclusion, aortic arginine uptake is attenuated in hypercholesterolemia, through post-translational modulation of CAT-1 protein, possibly via upregulation of PKC alpha.

Differential regulation of L-arginine transporters (cationic amino acid transporter-1 and -2) by peroxynitrite in rat mesangial cells.

BACKGROUND: It has become evident that increased nitric oxide (NO) generation may be associated with production of reactive oxygen species, such as peroxynitrite (ONOO-). Peroxynitrite has been postulated to be responsible for several of the cytotoxic effects previously ascribed to NO. Since cellular arginine uptake has been shown to modulate nitric oxide synthase activity, we were intrigued to study the effect of ONOO- on arginine traffic in renal mesangial cells. METHODS: Arginine uptake, CAT-1 and CAT-2 mRNA expression by northern blotting analysis, and CAT-1 protein content using western blotting were determined in mesangial cells pre-treated with peroxynitrite (0.1 and 0.5 mM) for 2 h. RESULTS: Peroxynitrite induced a significant increase in arginine uptake and CAT-2 mRNA expression compared with untreated cells. In contrast, CAT-1 mRNA expression and protein abundance were diminished. CONCLUSIONS: In rat mesangial cells, peroxynitrite augments arginine uptake via augmentation of CAT-2 while decreasing CAT-1 expression.