Circulating Plasma Proteins in Aortic Stenosis: Associations With Severity, Myocardial Response, and Clinical Outcomes.

BACKGROUND: Echocardiographic indexes of aortic stenosis may not comprehensively reflect disease morbidity. Plasma proteomic profiling may add prognostic value in these patients. METHODS AND RESULTS: Proximity extension assays (Olink) of 183 circulating cardiovascular and inflammatory proteins were performed in a prospective follow-up study of 122 asymptomatic/minimally symptomatic patients (mean±SD age, 69.1±10.9 years; 61% men) with moderate to severe aortic stenosis and preserved left ventricular ejection fraction. Protein signatures of higher-risk echocardiographic subgroups were determined. Associations of proteins with the primary composite outcome (heart failure hospitalization, progression to New York Heart Association class III-IV, or all-cause mortality) were evaluated using competing risk analyses, with aortic valve replacement being the competing risk. Network analysis unveiled mutually exclusive communities of proteins and echocardiographic parameters, connected only through NT-proBNP (N-terminal pro-B-type natriuretic peptide). Members of the tumor necrosis factor receptor superfamily (TNFRSF1A, TNFRSF1B, and TNFRSF14), and trefoil factor-3 were major hub proteins among the circulating biomarkers. Left ventricular global longitudinal strain >-15% was associated with higher levels of proteins, primarily of inflammation and immune regulation, whereas aortic valve area <1 cm2, E/e' >15, and left atrial reservoir strain <20% were associated with higher levels of NT-proBNP. Of 14 proteins associated with the primary end point, phospholipase-C, C-X-C motif chemokine-9, and interleukin-10 receptor subunit ß demonstrated the highest hazard ratios after adjusting for clinical factors (q<0.05). CONCLUSIONS: Plasma proteins involved in inflammation and immune regulation were differentially expressed in patients with aortic stenosis with reduced left ventricular global longitudinal strain, and associated with adverse clinical outcomes. Their incorporation into aortic stenosis risk stratification warrants further assessment.

Prognostic Value of Left Atrial Strain in Aortic Stenosis: A Competing Risk Analysis.

BACKGROUND: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%. METHODS: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk. RESULTS: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value. CONCLUSIONS: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes.

Treatment of Primary Aldosteronism and Reversal of Renin Suppression Improves Left Ventricular Systolic Function.

Introduction: Primary aldosteronism (PA) is associated with increased risk of cardiovascular events. However, treatment of PA has not been shown to improve left ventricular (LV) systolic function using the conventional assessment with LV ejection fraction (LVEF). We aim to use speckle-tracking echocardiography to assess for improvement in subclinical systolic function after treatment of PA. Methods: We prospectively recruited 57 patients with PA, who underwent 24-h ambulatory blood pressure (BP) measurements and echocardiography, including global longitudinal strain (GLS) assessment of left ventricle, at baseline and 12 months post-treatment. Results: At baseline, GLS was low in 14 of 50 (28.0%) patients. On multivariable analysis, GLS was associated with diastolic BP (P = 0.038) and glomerular filtration rate (P = 0.026). GLS improved post-surgery by -2.3, 95% CI: -3.9 to -0.6, P = 0.010, and post-medications by -1.3, 95% CI: -2.6 to 0.03, P = 0.089, whereas there were no changes in LVEF in either group. Improvement in GLS was independently correlated with baseline GLS (P < 0.001) and increase in plasma renin activity (P = 0.007). Patients with post-treatment plasma renin activity ≥1 ng/ml/h had improvements in GLS (P = 0.0019), whereas patients with persistently suppressed renin had no improvement. Post-adrenalectomy, there were also improvements in LV mass index (P = 0.012), left atrial volume index (P = 0.002), and mitral E/e' (P = 0.006), whereas it was not statistically significant in patients treated with medications. Conclusion: Treatment of hyperaldosteronism is effective in improving subclinical LV systolic dysfunction. Elevation of renin levels after treatment, which reflects adequate reversal of sodium overload state, is associated with better systolic function after treatment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03174847.

Primary Aldosteronism More Prevalent in Patients With Cardioembolic Stroke and Atrial Fibrillation.

Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension, and patients are at an increased risk of atrial fibrillation (AF) and stroke. We assessed the prevalence of PA in patients with recent stroke. Methods: We recruited 300 patients admitted to an acute stroke unit with diagnosis of cerebrovascular accident (haemorrhagic/ischaemic) or transient ischaemic attack. Three months post-stroke, plasma renin and aldosterone were measured. Patients with an elevated aldosterone-renin ratio proceeded to the confirmatory saline loading test. Results: Twenty-six of 192 (14%) patients had an elevated aldosterone-renin ratio. Three of 14 patients who proceeded to saline loading were confirmed with PA (post-saline aldosterone >138 pmol/l). Another three patients were classified as confirmed/likely PA based on the markedly elevated aldosterone-renin ratio and clinical characteristics. The overall prevalence of PA amongst stroke patients with hypertension was 4.0% (95% confidence interval (CI): 0.9%-7.1%). Prevalence of PA was higher amongst patients with cardioembolic stroke, 11% (95% CI: 1.3%-33%), resistant hypertension, 11% (95% CI: 0.3%-48%), and hypertension and AF, 30% (95%CI: 6.7%-65%). If only young patients or those with hypokalaemia were screened for PA, half of our patients with PA would not have been diagnosed. Our decision tree identified that stroke patients with AF and diastolic blood pressure ≥83mmHg were most likely to have PA. Conclusion: We found that amongst hypertensive patients with stroke, PA was more prevalent in those with AF, or cardioembolic stroke. Screening for PA should be considered for all patients with stroke.

Novel predictive role for mid-regional proadrenomedullin in moderate to severe aortic stenosis.

OBJECTIVE: We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS). METHODS: N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses. RESULTS: Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker. CONCLUSION: MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS.

Echocardiographic Global Longitudinal Strain Is Associated With Myocardial Fibrosis and Predicts Outcomes in Aortic Stenosis.

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF.

Improvement in quality of life and psychological symptoms after treatment for primary aldosteronism: Asian Cohort Study.

BACKGROUND: In addition to increased cardiovascular risk, patients with primary aldosteronism (PA) also suffer from impaired health-related quality of life (HRQoL) and psychological symptoms. We assessed for changes in HRQoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy. METHODS: Thirty-four patients with PA were prospectively recruited and completed questionnaires from 2017 to 2020. HRQoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms were assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment. RESULTS: At 1 year post-treatment, significant improvement was observed in both physical and mental summative scores of RAND-36, +3.65, P = 0.023, and +3.41, P = 0.033, respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional, and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (n = 21) had significant improvement in EQ-5D index score post-treatment and better EQ-5D outcomes compared to the medical group (n = 13) at 1 year post-treatment. 37.9, 41.6 and 58.6% of patients had symptoms in the cognitive, affective and somatic domains of BDI-II, respectively. There was a significant improvement in the affective domain of BDI-II at 1 year post-treatment. CONCLUSION: Both surgical and medical therapy improve HRQoL and psychological symptoms in patients with PA, with surgery providing better outcomes. This highlights the importance of early diagnosis, accurate subtyping and appropriate treatment of PA.

Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.

BACKGROUND: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. METHODS: We used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF. RESULTS: In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-ß binding protein-4, and follistatin-related protein-3, as well. CONCLUSIONS: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.

Prognostic impact of stress echocardiography with discordant stress electrocardiography in patients with suspected coronary artery disease.

INTRODUCTION: During stress echocardiography, the echocardiologist routinely collects both echocardiographic images and stress electrocardiogram (ECG) concurrently. The managing physician faces a dilemma when the stress ECG and stress echocardiography results are discordant; for example, when a patient has negative stress echocardiography but positive stress ECG. We therefore sought to evaluate the prognostic value of stress echocardiography in relation to concordant or discordant stress ECG findings in our local Singapore setting, which has a well-defined Southeast Asian population. METHODS: This was a retrospective observational study of all patients who underwent stress echocardiography in 2012 at Changi General Hospital, Singapore. All study patients were followed up for 18 months via electronic medical records. RESULTS: There was no difference in the major adverse cardiovascular events (MACE) outcome of patients with normal stress echocardiography and normal stress ECG (reference group) as compared with patients with normal stress echocardiography but positive (discordant) stress ECG (odds ratio 2.02, 95% confidence interval 0.82‒4.98; p = 0.125). CONCLUSION: This study will help to reassure cardiologists that discordant results (negative stress echocardiography but positive stress ECG) do not portend a higher risk of MACE when compared to concordant results (i.e. both stress echocardiography and stress ECG are negative).

A review of the safety and clinical utility of contrast echocardiography.

There are limitations to the sensitivity and specificity of conventional two-dimensional echocardiograms in making an accurate diagnosis in certain patient populations. This led to the development of specific contrast-enhancing agents with the following characteristics: small enough to cross the pulmonary capillary bed, remain stable throughout the length of the procedure, do not dissolve in blood, and rapidly cleared from the body with low toxicity. Unfortunately, the use of contrast echocardiography has not taken off as expected. The low take-up rate among clinicians can largely be attributed to the black box warning by the United States Food and Drug Administration in 2007, after the coincidental occurrence of four patient deaths and about 190 severe cardiopulmonary reactions shortly after contrast agent administration. In this article, we address the clinical safety of contrast agents, share our institution's experience in using it and elaborate on the clinical indications of contrast echocardiography.

"Catch Me If You Can": Recurrent ST-Segment Elevation Myocardial Infarction Due to Aortic Thrombus.

A 42-year-old male patient presented with recurrent inferior ST-segment elevation myocardial infarction with minimal atherosclerotic disease on intracoronary imaging. Transesophageal echocardiogram and computed tomography aortogram revealed the underlying cause to be a mobile aortic thrombus in the right coronary cusp, prolapsing into and out of the right coronary ostium. (Level of Difficulty: Beginner.).

Sex Differences in 1-Year Rehospitalization for Heart Failure and Myocardial Infarction After Primary Percutaneous Coronary Intervention.

It is unclear whether universal access to primary percutaneous coronary intervention (pPCI) may reduce sex differences in 1-year rehospitalization for heart failure (HF) and myocardial infarction (MI) after ST-elevation myocardial infarction (STEMI). We studied 7,597 consecutive STEMI patients (13.8% women, n = 1,045) who underwent pPCI from January 2007 to December 2013. Cox regression models adjusted for competing risk from death were used to assess sex differences in rehospitalization for HF and MI within 1 year from discharge. Compared with men, women were older (median age 67.6 vs 56.0 years, p < 0.001) with higher prevalence of co-morbidities and multivessel disease. Women had longer median door-to-balloon time (76 vs 66 minutes, p < 0.001) and were less likely to receive drug-eluting stents (19.5% vs 24.1%, p = 0.001). Of the medications prescribed at discharge, fewer women received aspirin (95.8% vs 97.6%, p = 0.002) and P2Y12 antagonists (97.6% vs 98.5%, p = 0.039), but there were no significant sex differences in other discharge medications. After adjusting for differences in baseline characteristics and treatment, sex differences in risk of rehospitalization for HF attenuated (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.79 to 1.40), but persisted for MI (HR 1.68, 95% CI 1.22 to 2.33), with greater disparity in patients aged ≥60 years (HR 1.83, 95% CI 1.18 to 2.85) than those aged <60 years (HR 1.45, 95% CI 0.84 to 2.50). In conclusion, in a setting of universal access to pPCI, the adjusted risk of 1-year rehospitalization for HF was similar in both sexes, but women had significantly higher adjusted risk of 1-year rehospitalization for MI, especially older women.

Prognostic Factors After Index Hospitalization for Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) has a high clinical burden and constitutes approximately 20% to 30% of patients with heart failure in Asia. Impaired global longitudinal strain (GLS), defined as an absolute value of <15.8%, has been shown to be a predictor of heart failure hospitalization, cardiovascular death, and aborted cardiac arrest in HFpEF. We sought to validate this finding in our Asian cohort and identify other prognostic factors in HFpEF. In this cohort study, we included all patients with an index hospitalization for heart failure and left ventricular ejection fraction of >45%, from January 1, 2012, to December 31, 2012. All patients had follow-up for at least 3 years. In our study, the absolute value of mean GLS was impaired at 13.50 ± 4.00%, whereas mean left ventricular ejection fraction was 52.00 ± 7.67%. In multivariate Cox regression, impaired GLS of absolute value <15.8% (hazard ratio 4.72, 95% CI 1.25 to 17.81, p = 0.022), every unit increase in age-adjusted Charlson Comorbidity Index (hazard ratio 1.46, 95% CI 1.03 to 2.05, p = 0.031) and low body mass index <18.5 kg/m2 (hazard ratio 4.30, 95% CI 1.25 to 14.78, p = 0.020) were associated with a shorter time to mortality over the 3-year period. Our study validates absolute GLS value of <15.8% to be a prognostic marker for patients with HFpEF.