mPAP/CO Slope and Oxygen Uptake Add Prognostic Value in Aortic Stenosis.

BACKGROUND: Recent guidelines redefined exercise pulmonary hypertension as a mean pulmonary artery pressure/cardiac output (mPAP/CO) slope >3 mm Hg·L-1·min-1. A peak systolic pulmonary artery pressure >60 mm Hg during exercise has been associated with an increased risk of cardiovascular death, heart failure rehospitalization, and aortic valve replacement in aortic valve stenosis. The prognostic value of the mPAP/CO slope in aortic valve stenosis remains unknown. METHODS: In this prospective cohort study, consecutive patients (n=143; age, 73±11 years) with an aortic valve area ≤1.5 cm2 underwent cardiopulmonary exercise testing with echocardiography. They were subsequently evaluated for the occurrence of cardiovascular events (ie, cardiovascular death, heart failure hospitalization, new-onset atrial fibrillation, and aortic valve replacement) during a follow-up period of 1 year. Findings were externally validated (validation cohort, n=141). RESULTS: One cardiovascular death, 32 aortic valve replacements, 9 new-onset atrial fibrillation episodes, and 4 heart failure hospitalizations occurred in the derivation cohort, whereas 5 cardiovascular deaths, 32 aortic valve replacements, 1 new-onset atrial fibrillation episode, and 10 heart failure hospitalizations were observed in the validation cohort. Peak aortic velocity (odds ratio [OR] per SD, 1.48; P=0.036), indexed left atrial volume (OR per SD, 2.15; P=0.001), E/e' at rest (OR per SD, 1.61; P=0.012), mPAP/CO slope (OR per SD, 2.01; P=0.002), and age-, sex-, and height-based predicted peak exercise oxygen uptake (OR per SD, 0.59; P=0.007) were independently associated with cardiovascular events at 1 year, whereas peak systolic pulmonary artery pressure was not (OR per SD, 1.28; P=0.219). Peak Vo2 (percent) and mPAP/CO slope provided incremental prognostic value in addition to indexed left atrial volume and aortic valve area (P<0.001). These results were confirmed in the validation cohort. CONCLUSIONS: In moderate and severe aortic valve stenosis, mPAP/CO slope and percent-predicted peak Vo2 were independent predictors of cardiovascular events, whereas peak systolic pulmonary artery pressure was not. In addition to aortic valve area and indexed left atrial volume, percent-predicted peak Vo2 and mPAP/CO slope cumulatively improved risk stratification.

Tricuspid regurgitation after cardiac resynchronization therapy: evolution and prognostic significance.

AIMS: Tricuspid regurgitation (TR) is common in patients with heart failure (HF) and is associated with worse outcome. This study investigated the effect of cardiac resynchronization therapy (CRT) on TR severity and long-term outcome. METHODS AND RESULTS: Tricuspid regurgitation severity was assessed at baseline and 6 months after CRT implantation, using a multiparametric approach. Patients were divided into four groups: (i) no or mild TR without progression; (ii) no or mild TR with progression to significant (moderate-severe) TR; (iii) significant TR with improvement to no or mild TR; and (iv) significant TR without improvement. The primary endpoint was all-cause mortality. A total of 852 patients (mean age 65 ± 11 years, 77% male) were included. At baseline, 184 (22%) patients had significant TR, with 75 (41%) showing significant improvement at 6-month follow-up. After a median follow-up of 92 (50-137) months, 494 (58%) patients died. Patients with significant TR showing improvement at follow-up had better outcomes than those showing no improvement (P = 0.016). On multivariable analysis, no or mild TR progressing to significant TR [hazard ratio (HR) 1.745; 95% confidence interval (CI): 1.287-2.366; P < 0.001] and significant TR without improvement (HR 1.572; 95% CI: 1.198-2.063; P = 0.001) were independently associated with all-cause mortality, whereas significant TR with improvement at follow-up was not (HR: 1.153; 95% CI: 0.814-1.633; P = 0.424). CONCLUSION: Improvement of significant TR after CRT is observed in a substantial proportion of patients, highlighting the potential benefit of CRT for patients with HF having significant TR. Significant TR at 6 months after CRT is independently associated with increased long-term mortality.

Focus on Diagnosis and Prognosis to Guide Timing of Intervention in Valvular Heart Disease.

PURPOSE OF REVIEW: The present article reviews the role of multimodality imaging to improve risk stratification and timing of intervention in patients with valvular heart disease (VHD), and summarizes the latest developments in transcatheter valve interventions. RECENT FINDINGS: Growing evidence suggests that intervention at an earlier stage may improve outcomes of patients with significant VHD. Multimodality imaging, including strain imaging and tissue characterization with cardiac magnetic resonance imaging, has the ability to identify early markers of myocardial damage and can help to optimize the timing of intervention. Transcatheter interventions play an increasing role in the treatment of patients who remain at high surgical risk or present at a late stage of their disease. Multimodality imaging identifies markers of cardiac damage at an early stage in the development of VHD. Together with technological innovations in the field of percutaneous valvular devices, these developments have the potential to improve current management and outcomes of patients with significant VHD.

Association Between Left Ventricular Apical-to-Basal Strain Ratio and Conduction Disorders after Aortic Valve Replacement.

BACKGROUND: The aim of the study was to evaluate whether left ventricular apical-to-basal longitudinal strain differences, representing advanced basal interstitial fibrosis, are associated with conduction disorders after aortic valve replacement (AVR) in patients with severe aortic stenosis. METHODS: Patients with aortic stenosis undergoing AVR were included. The apical-to-basal strain ratio was calculated by dividing the average strain of the apical segments by the average strain of the basal segments. Values >1.9 were considered abnormal, as previously described. All patients were followed up for the occurrence of complete left or right bundle branch block or permanent pacemaker implantation within 2 years after AVR. Subgroup analysis was performed in patients undergoing transcatheter AVR. RESULTS: Two hundred seventy-four patients were included (median age of 74 years [interquartile range, 65, 80], 46.4% male). During a median follow-up of 12.2 months (interquartile range, 0.2, 24.3), 74 patients (27%) developed complete bundle branch block or were implanted with a permanent pacemaker. These patients more often had an abnormal apical-to-basal strain ratio. Cumulative event-free survival analysis showed worse outcome in patients with an abnormal apical-to-basal strain ratio (log rank χ2 = 7.258, P = .007). In multivariable Cox regression analysis, an abnormal apical-to-basal strain ratio was the only independent factor associated with the occurrence of complete bundle branch block or permanent pacemaker implantation after adjusting for other factors previously shown to be associated with conduction disorders after AVR. Subgroup analysis confirmed the independent association of an abnormal apical-to-basal strain ratio with conduction disorders after transcatheter AVR. CONCLUSION: The apical-to-basal strain ratio is independently associated with conduction disorders after AVR and could guide risk stratification in patients potentially at risk for pacemaker implantation.

Significant Mitral Regurgitation After Permanent Right Ventricular Pacemaker Implantation: Prognostic Implications.

The underlying mechanisms leading to the development of mitral regurgitation (MR) after right ventricular (RV) pacemaker (PM) implantation and its prognostic value have yet to be fully understood. The purpose of this study was to evaluate the prevalence and clinical variables associated with the development of MR after RV pacing and its association with outcomes. A total of 451 patients (mean age 69 ± 15 years, 61% male) who underwent de novo RV PM implantation were included. The development of significant MR, defined as ≥moderate from mild or none/trace at baseline, occurred in 131 (29%) patients at a median of 2.4 years (interquartile range: 1.0 to 3.8 years) after PM implantation. Multivariate logistic regression analysis demonstrated that implantation of a single-chamber PM, left ventricular end-systolic volume index, and the presence of mild MR (vs no MR) at baseline were independently associated with the development of significant MR post-implant. Cardiac events, defined as the composite of all-cause mortality or heart failure hospitalization, occurred in 143 patients (31.7%) during a median follow-up of 5.4 years (interquartile range: 3.0 to 8.1 years). Multivariate Cox regression analysis demonstrated that the development of significant MR was independently related to the occurrence of cardiac events. In conclusion, the development of significant MR after PM implantation is seen in about one-third of recipients and is independently associated with adverse cardiac events.

The prognostic value of changes in pulmonary vein flow patterns after surgical repair for primary mitral regurgitation.

BACKGROUND: The pulmonary vein (PV) flow pattern is influenced by the presence of mitral regurgitation (MR). After a successful reduction in MR severity, the pattern is expected to be changed. We aimed to evaluate the prognostic value of a change in the PV flow pattern in patients with primary MR undergoing mitral valve repair (MVR). METHODS: The PV flow pattern was assessed with transthoracic echocardiography in 216 patients (age 65 [IQR 56-72] years, 70% male) with primary MR before and after surgical MVR. The population was divided according to a change in the PV flow pattern following MVR into 'improvers' and 'non-improvers'. RESULTS: Non-improvers (15%) had a higher prevalence of paroxysmal AF at baseline (46% vs. 22%, p = 0.004), left ventricular dysfunction (LVEF ≤60%) (39% vs. 21%, p = 0.020), and had lower systolic pulmonary artery pressure (28[IQR 25-38] vs. 35[IQR 26-48] mmHg, p = 0.018) compared to improvers (85%). After a median follow-up of 83[IQR 43-140] months, 26(12%) patients died. Non-improvers had higher mortality rates than improvers (p = 0.009). On multivariable Cox regression analysis, a lack of improvement in the PV flow pattern remained independently associated with all-cause mortality (HR 2.322, 95% CI 1.140 to 4.729, P = 0.020). CONCLUSION: A lack of improvement in the PV flow pattern is independently associated with worse long-term survival in patients with primary MR undergoing MVR.

Short-term effects of sacubitril/valsartan therapy on myocardial oxygen consumption and energetic efficiency of cardiac work in heart failure with reduced ejection fraction: A randomized controlled study.

AIMS: We sought to evaluate the mechanism of angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with New York Heart Association class II-III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11 C-acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan-only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (-4.5 mmHg; p = 0.026) and systolic blood pressure (-9.8 mmHg; p = 0.0007), myocardial perfusion (-0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (-296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (-5.4%) compared with the run-in period and remained unchanged in the control group (+0.5%), the between-treatment group difference was not significant (p = 0.088). CONCLUSIONS: We found no differences in the energetic efficiency of cardiac work between ARNI and valsartan-only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients.

Exercise pulmonary hypertension by the mPAP/CO slope in primary mitral regurgitation.

AIMS: Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms. METHODS AND RESULTS: A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2. CONCLUSION: Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2.

Impact of chronic obstructive pulmonary disease on right ventricular function and remodeling after aortic valve replacement.

BACKGROUND: Both chronic obstructive pulmonary disease (COPD) and right ventricular (RV) dysfunction are common factors that have been associated with poor prognosis after aortic valve replacement (AVR). Since there is still uncertainty about the impact of COPD on RV function and dilatation in patients undergoing AVR, we sought to explore RV function and remodeling in the presence and absence of COPD as well as their prognostic implications. METHODS: Patients who received surgical or transcatheter AVR due to severe AS were screened for COPD. Demographic and clinical data were collected at baseline while echocardiographic measurements were performed at baseline and 1 year after AVR. The study end-point was all-cause mortality. RESULTS: In total 275 patients were included, with 90 (33%) patients having COPD. At 1-year follow-up, mild worsening of tricuspid annular planar systolic excursion and RV dilatation were observed in patients without COPD, while there were significant improvements in RV longitudinal strain, RV wall thickness but dilatation of RV outflow tract distal dimension in the COPD group compared to the baseline. On multivariable analysis, the presence of COPD provided significant incremental prognostic value over RV dysfunction and remodeling. CONCLUSIONS: At 1-year after AVR, RV function and dimensions mildly deteriorated in non-COPD group whereas COPD group received significant benefit of AVR in terms of RV function and hypertrophy. COPD was independently associated with >2-fold all-cause mortality and had incremental prognostic value over RV dysfunction and remodeling.

Mitral Annular Disjunction in the Context of Mitral Valve Prolapse: Identifying the At-Risk Patient.

Mitral annular disjunction (MAD), a separation between the left atrium/mitral valve annulus and the left ventricular myocardium, is frequently seen in patients with arrhythmic mitral valve prolapse. Although an association exists between MAD and ventricular arrhythmias, little is known regarding the identification of individuals at high risk. Multimodality imaging including echocardiography, computed tomography, cardiac magnetic resonance, and positron emission tomography can play an important role in both the diagnosis and risk stratification of MAD. Due to a paucity of data, clinical decision making in a patient with MAD is challenging and remains largely empirical. Although MAD itself can be corrected surgically, the prevention and treatment of associated arrhythmias may require medical therapy, catheter ablation, and an implantable cardioverter-defibrillator. Prospective data are required to define the role of implantable cardioverter-defibrillators, targeted catheter ablation, and surgical correction in selected, at-risk patients.

Prognostic Implications and Alterations in Left Atrial Deformation Following Transcatheter Aortic Valve Implantation.

AIMS: To evaluate the prognostic implications of left atrial reservoir strain-defined diastolic dysfunction (LARS-DD) grade in patients undergoing TAVI for severe aortic stenosis (AS) and to determine if post-TAVI LARS was more closely associated with new-onset atrial fibrillation than pre-TAVI LARS. METHODS AND RESULTS: Pre-TAVI LARS-DD was evaluated by speckle-tracking echocardiography and was assigned as grade 0 to 1 (LARS≥24%), grade 2 (LARS≥19 to <24%) and grade 3 (LARS<19%). Patients were followed-up for the primary endpoint of all-cause mortality from the date of TAVI. For the secondary endpoint, patients with pre- and post-TAVI LARS measurements and no history of atrial fibrillation were evaluated for the occurrence of new-onset atrial fibrillation. A total of 601 patients (median age 81 [76-85] years, 53% male) were included. Overall, 169 patients (28%) were LARS-DD grade 0/1, 96 patients (16%) were LARS-DD grade 2 and 336 (56%) were LARS-DD grade 3. Over a median follow-up of 40 (IQR 26-58) months, a total of 258 (43%) patients died. In a comprehensive multivariable Cox regression model, LARS-DD grade was independently associated with all-cause mortality (adjusted HR 1.28 per one-grade increase, 95%CI 1.07-1.53, P=0.007). For the secondary endpoint of new-onset atrial fibrillation, a total of 285 patients were evaluated. Post-TAVI LARS (SDHR 1.14 per 1%<20%, 95%CI 1.05-1.23, P=0.0009), but not pre-TAVI LARS (P=0.93) was independently associated with new-onset atrial fibrillation. CONCLUSIONS: Increasing LARS-DD grade was independently associated with long-term post-TAVI survival in patients with severe AS. Post-TAVI LARS was closely related to the occurrence of new-onset atrial fibrillation.

The Oxygen Cascade According to HFpEF Likelihood: A Focus on Sex Differences.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student's t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression. Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference -4.4 mL/kg/min [95% CI: -3.7 to -5.1 mL/kg/min]) secondary to a reduced O2 delivery (-0.5 L/min [95% CI: -0.4 to -0.6 L/min]) and less oxygen extraction (-2.9 mL/dL [95% CI: -2.5 to -3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (-1.2 g/dL [95% CI: -0.9 to -1.5 g/dL]) and smaller stroke volume (-15 mL [95% CI: -14 to -17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (-9 mL/m2 [95% CI: -8 to -11 mL/m2]) and mass (-12 g/m2 [95% CI: -9 to -14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001). Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Left Atrial Improvement in Patients With Secondary Mitral Regurgitation and Heart Failure: The COAPT Trial.

BACKGROUND: Functional mitral regurgitation induces adverse effects on the left ventricle and the left atrium. Left atrial (LA) dilatation and reduced LA strain are associated with poor outcomes in heart failure (HF). Transcatheter edge-to-edge repair (TEER) of the mitral valve reduces heart failure hospitalization (HFH) and all-cause death in selected HF patients. OBJECTIVES: The aim of this study was to evaluate the impact of LA strain improvement 6 months after TEER on the outcomes of patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. METHODS: The difference in LA strain between baseline and the 6-month follow-up was calculated. Patients with at least a 15% improvement in LA strain were labeled as "LA strain improvers." All-cause death and HFH were assessed between the 6 and 24-month follow-up. RESULTS: Among 347 patients (mean age 71 ± 12 years, 63% male), 106 (30.5%) showed improvement of LA strain at the 6-month follow-up (64 [60.4%] from the TEER + guideline-directed medical therapy [GDMT] group and 42 [39.6%] from the GDMT alone group). An improvement in LA strain was significantly associated with a reduction in the composite of death or HFH between the 6-month and 24-month follow-up, with a similar risk reduction in both treatment arms (Pinteraction = 0.27). In multivariable analyses, LA strain improvement remained independently associated with a lower risk of the primary composite endpoint both as a continuous variable (adjusted HR: 0.94 [95% CI: 0.89-1.00]; P = 0.03) and as a dichotomous variable (adjusted HR: 0.49 [95% CI: 0.27-0.89]; P = 0.02). The best outcomes were observed in patients treated with TEER in whom LA strain improved. CONCLUSIONS: In symptomatic HF patients with severe mitral regurgitation, improved LA strain at the 6-month follow-up is associated with subsequently lower rates of the composite endpoint of all-cause mortality or HFH, both after TEER and GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).

Clinical Significance of Exercise Pulmonary Hypertension With a Negative Diastolic Stress Test for Suspected Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF. METHODS AND RESULTS: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e' (exE/e') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/e'<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/e'≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/e'<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/e'<15 but a high slope had NT-proBNP levels and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope. CONCLUSIONS: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.