Identification of a Multiplex Biomarker Panel for Hypertrophic Cardiomyopathy Using Quantitative Proteomics and Machine Learning.

Hypertrophic cardiomyopathy (HCM) is defined by pathological left ventricular hypertrophy (LVH). It is the commonest inherited cardiac condition and a significant number of high risk cases still go undetected until a sudden cardiac death (SCD) event. Plasma biomarkers do not currently feature in the assessment of HCM disease progression, which is tracked by serial imaging, or in SCD risk stratification, which is based on imaging parameters and patient/family history. There is a need for new HCM plasma biomarkers to refine disease monitoring and improve patient risk stratification. To identify new plasma biomarkers for patients with HCM, we performed exploratory myocardial and plasma proteomics screens and subsequently developed a multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay to validate the 26 peptide biomarkers that were identified. The association of discovered biomarkers with clinical phenotypes was prospectively tested in plasma from 110 HCM patients with LVH (LVH+ HCM), 97 controls, and 16 HCM sarcomere gene mutation carriers before the development of LVH (subclinical HCM). Six peptides (aldolase fructose-bisphosphate A, complement C3, glutathione S-transferase omega 1, Ras suppressor protein 1, talin 1, and thrombospondin 1) were increased significantly in the plasma of LVH+ HCM compared with controls and correlated with imaging markers of phenotype severity: LV wall thickness, mass, and percentage myocardial scar on cardiovascular magnetic resonance imaging. Using supervised machine learning (ML), this six-biomarker panel differentiated between LVH+ HCM and controls, with an area under the curve of ≥ 0.87. Five of these peptides were also significantly increased in subclinical HCM compared with controls. In LVH+ HCM, the six-marker panel correlated with the presence of nonsustained ventricular tachycardia and the estimated five-year risk of sudden cardiac death. Using quantitative proteomic approaches, we have discovered six potentially useful circulating plasma biomarkers related to myocardial substrate changes in HCM, which correlate with the estimated sudden cardiac death risk.

Individualized surgical strategies for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

OBJECTIVES: Surgical strategies to treat drug refractory left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy include septal myectomy (SM) and, less frequently, mitral valve (MV) repair or replacement. The primary aim of this study was to report the surgical technique and management outcomes in a consecutive group of patients with variable phenotypes of hypertrophic cardiomyopathy in a broad national specialist practice. METHODS: A total of 203 consecutive patients, 132 men (mean age 48.6 ± 14.6 years) underwent surgery for the management of LVOTO. Surgical approaches included SM (n = 159), SM with MV repair (n = 25), SM with MV replacement (n = 9) and MV replacement alone (n = 10). Specific surgical approaches were performed based on the underlying mechanism of obstruction. Eleven (5.4%) patients had previous alcohol septal ablation for the management of LVOTO. Concomitant non-mitral cardiac procedures were carried out in 22 (10.8%) patients. RESULTS: Operative survival rate was 99.0% with 2 deaths within 30 days. The mean bypass time was 92.9 ± 47.8 min, with a mean length of hospital stay of 10.5 ± 7.8 days. Surgical complications included 3 ventricular septal defects requiring repair (1.5%), 1 Gerbode defect surgically repaired, 2 aortic valve repairs (1.0%), 2 transient ischaemic attacks (1.0%) and 4 strokes (2.0%). Thirty-nine (19.2%) patients had perioperative new-onset atrial fibrillation and 8 (3.9%) patients had unexpected atrioventricular block requiring a permanent pacemaker. Mean resting left ventricular outflow tract gradient improved from 70.6 ± 40.3 mmHg preoperatively to 11.0 ± 10.5 mmHg at 1 year postoperatively (P < 0.001). Mean New York Heart Association class improved from 2.6 ± 0.5 preoperatively to 1.6 ± 0.6 at 1 year after the procedure. CONCLUSIONS: In variable phenotypes of LVOTO in hypertrophic cardiomyopathy, an individualized surgical approach provided effective reductions in left ventricular outflow tract gradients and good symptomatic relief with acceptable mortality and morbidity.

Long-term outcomes for different surgical strategies to treat left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

AIMS: Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity. METHODS AND RESULTS: In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P < 0.05). Overall, 72.4% of patients improved by >1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (>30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P < 0.05). Long-term (>30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years. CONCLUSION: Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

Early and medium-term outcomes of Alfieri mitral valve repair in the management of systolic anterior motion during septal myectomy.

BACKGROUND: This report studies the early and medium-term clinical and echocardiographic outcomes of the Alfieri edge-to-edge mitral valve repair, as adjunctive therapy, to prevent and treat systolic anterior motion (SAM) at the time of septal myectomy (SM) for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. METHODS: From 2009-2015, 11 consecutive patients had a trans-atrial Alfieri repair, to prevent (n = 7) or treat (n = 4) SAM at the time of SM. RESULTS: No patients were lost to follow-up. There were no perioperative or late deaths. Pre-bypass, the mean left ventricular outflow tract gradient, measured directly by simultaneous needle insertion, was 40.7 ± 19.9 mmHg at rest and 115.8 ± 30.4 mmHg on provocation with Isoproterenol, which reduced after SM and Alfieri repair and discontinuation of bypass, to a mean gradient of 8.3 ± 9.8 mmHg at rest and 25.8 ± 9.2 mmHg on provocation. One patient who required mitral valve replacement on day 4, was hospitalized at 2.7 years with heart failure requiring diuresis and remains well at 6 years. One patient developed postoperative atrial fibrillation. There were no other early or late complications. At a median follow-up of 6.6 years (international quartile range 1.2-7.4), clinical and echocardiographic data demonstrated maintained improvement in mean New York Heart Association class from 2.6 ± 0.9 preoperatively to 1.7 ± 0.4 and reduction in mean grade of mitral regurgitation from 2.7 ± 0.8 preoperatively to 0.7 ± 0.6. CONCLUSIONS: The Alfieri repair, as adjunctive therapy, for the prevention or treatment of SAM at the time of SM demonstrates satisfactory early and medium-term clinical and echocardiographic outcomes supporting the ongoing utility of this approach.

An acquired Gerbode defect from the left ventricle to the coronary sinus following mitral valve replacement.

We report the management of an acquired Gerbode defect, from the left ventricle to the coronary sinus, following mechanical mitral valve replacement. Following a failed percutaneous closure, surgical patch closure of the defect was performed.