The Prognostic Value of Right Ventricular Function in Patients with Chronic Heart Failure-A Prospective Study.

Background: In patients with stable chronic heart failure with a reduced ejection fraction (HFrEF), left ventricular ejection fraction (LVEF) provides limited prognostic value, especially in patients with moderately to severely reduced LVEF. Echocardiographic parameters of right ventricular function may be associated with adverse clinical events in these patients. Therefore, we analyzed 164 patients with HFrEF in a prospective single-center cohort study to evaluate whether the parameters of right ventricular function are associated with worsening heart failure (WHF) hospitalizations, cardiovascular and all-cause deaths and combined endpoints. Methods: Echocardiographic cine loops were analyzed using vendor-independent post-processing software. Multivariate Cox regression analyses were performed, which were then adjusted for clinical characteristics and left ventricular functional parameters. Results: In these models, higher tricuspid annular plane systolic excursion (TAPSE) was significantly associated with lower rates of WHF hospitalizations (HR 0.880, 95%CI 0.800-0.968, p = 0.008), a composite endpoint of WHF hospitalizations and cardiovascular death (HR 0.878, 95%CI 0.800-0.964, p = 0.006), and a composite endpoint of WHF hospitalization and all-cause death (HR 0.918, 95%CI 0.853-0.988, p = 0.023). These associations were more pronounced in patients with LVEF ≤ 35%. Conclusions: In conclusion, in patients with HFrEF, TAPSE is an independent prognosticator for adverse clinical outcomes, warranting further studies to elucidate whether incorporating TAPSE into established risk scores improves their diagnostic accuracy.

Prevalence and prognostic impact of bone disease in chronic heart failure with reduced ejection fraction.

AIMS: Chronic heart failure is associated with a bone-catabolic state and increases the risk of osteoporosis and fractures. Prospective studies investigating the clinical relevance of bone disease in heart failure are lacking. We aimed to assess the prevalence and prognostic impact of osteoporosis and vertebral fractures (VFs) in chronic heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Symptomatic outpatients with chronic heart failure and a previous diagnosis of overtly reduced left ventricular ejection fraction < 40% on stable, optimal HFrEF therapy and left ventricular ejection fraction < 50% at enrolment were included into a prospective single-centre study. Osteoporosis was determined with dual-energy X-ray absorptiometry and defined as a T-score ≤ 2.5 at any site. VFs were assessed using X-ray of both thoracic and lumbar spine applying the semiquantitative Genant score. We enrolled 205 patients (22% women), with a median age of 66 (IQR 58-74) years. Median left ventricular ejection fraction was 37 (IQR 30-43) % and median N-terminal pro B-type natriuretic peptide was 964 (IQR 363-2173) pg/mL. Osteoporosis, as defined by bone mineral density, and at least one VF were prevalent in 31 (15%) and 29 patients (14%). Osteoporosis or VF were present in 55 patients (27%) and 5 patients (2%) had both osteoporosis and a VF. During a median follow-up of 4.7 (IQR 4.0-5.3) years, 18 patients (9%) died due to cardiovascular (CV) cause, and 46 patients (22%) had a worsening heart failure (WHF) hospitalization. In multivariate Cox regression analyses, presence of VF independently predicted CV death (HR 2.82, 95% CI 1.04-7.65, P = 0.042), WHF hospitalizations (HR 2.39, 95% CI 1.18-4.82, P = 0.015), and a composite endpoint of CV death and WHF hospitalizations (HR 2.44, 95% CI 1.23-4.82, P = 0.011). Osteoporosis was not significantly associated with CV events. CONCLUSIONS: In a prospective study, bone disease affected every fourth patient with HFrEF, and patients with VF at baseline had a two-fold risk of subsequent CV death or WHF hospitalization. Prevalent bone disease, particularly VF, should be considered as a clinically relevant comorbidity in HFrEF.

Low-grade systemic inflammation and left ventricular dysfunction in hypertensive compared to non-hypertensive hypertrophic cardiomyopathy.

BACKGROUND: Arterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive. The objective of this study was to investigate the association between HTN and markers of left ventricular (LV) dysfunction and low-grade systemic inflammation in a HCM cohort. METHODS: This was a single-center cross-sectional case-control study comparing echocardiographic and plasma-derived indices of LV dysfunction and low-grade systemic inflammation between 30 adult patients with HCM and HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by blinded investigators. RESULTS: Mean age of the study population was 55.1 ± 10.4 years, 30% were women. Echocardiographic measures of systolic and diastolic dysfunction, including speckle-tracking derived parameters, did not differ between HTN+ and HTN-. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between cases and controls. Compared with HTN-, HTN+ patients exhibited a higher white blood cell count [8.1 ± 1.8 109/l vs. 6.4 ± 1.6 109/l; p < 0.001] as well as higher plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004]. CONCLUSION: This study demonstrates that HTN is associated with indices of low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that the adverse impact of HTN in HCM patients is a consequence of systemic effects rather than alterations of cardiac function, as measures of LV systolic and diastolic dysfunction did not differ between HTN+ and HTN-.

Non-eligibility for pivotal HFpEF/HFmrEF outcome trials and mortality in a contemporary heart failure cohort.

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m2, COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need.

Spatial relationship between mitral valve and ventricular septum assessed by resting echocardiography to diagnose left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

AIMS: Echocardiographic diagnosis of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) often requires extensive provocative manoeuvers. We investigated, whether echocardiography-derived parameters obtained at rest can aid to determine the presence of LVOTO in persons with HCM. METHODS AND RESULTS: Consecutive patients with HCM admitted to a referral centre underwent standardized transthoracic echocardiographic examination including provocative manoeuvers. Under resting conditions, the length of mitral leaflets and distances between mitral valve coordinates and ventricular walls were blindly measured in parasternal long axis (PLAX) and apical three-chamber (3ch) views, both at early and late systole. Among 142 patients (mean age 59 ± 13 years, 42% women), 68 (42%) had resting or provocable LVOTO with maximal LVOT gradients ≥30 mmHg. Late-systolic distance between mitral leaflet tip and ventricular septum (TIS) was measurable in 137 participants (96%) in 3ch view and independently associated with LVOTO in multivariable logistic regression analysis. The area under the ROC curve of TIS for the identification of LVOTO was 0.91 [95% confidence interval (CI) 0.87-0.96]. TIS ≤ 14 mm yielded 97% sensitivity and 57% specificity regarding LVOTO. TIS >14 mm ruled out LVOTO with a negative predictive value of 95%. TIS ≤9 mm ruled in LVOTO with a positive predictive value of 92% (sensitivity 73%, specificity 95%). Among 43 patients with TIS between 10 and 14 mm, 35% had LVOTO. CONCLUSION: In our study, the novel echocardiographic parameter TIS showed high negative and positive predictive values for LVOTO in HCM. These exploratory results await confirmation in larger collectives and prospective investigations.

Diagnostic Accuracy of Bone Scintigraphy for the Histopathological Diagnosis of Cardiac Transthyretin Amyloidosis-A Retrospective Austrian Multicenter Study.

We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients (22% women) with suspected CA from seven Austrian amyloidosis referral centers. The inclusion criteria comprised the available results of bone scintigraphy, FLC assessment, and EMB with histopathological analysis. ATTR and AL were diagnosed in 60 and 21 patients (59%, 21%), respectively, and concomitant AL and ATTR was identified in one patient. The specificity and positive predictive value (PPV) of Perugini score ≥ 2 for ATTR CA were 95% and 96%. AL was diagnosed in three out of 31 patients (10%) who had evidence of monoclonal proteins and a Perugini score ≥ 2. When excluding all patients with detectable monoclonal proteins (n = 62) from analyses, the PPV of Perugini score ≥ 2 for ATTR CA was 100% and the NPV of Perugini score < 2 for ATTR CA was 79%. Conclusively, ATTR CA can be diagnosed non-invasively in the case of a Perugini score ≥ 2 and an unremarkable FLC assessment. However, tissue biopsy is mandatory in suspected CA in any other constellation of non-invasive diagnostic work-up.

Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy-The Graz Hypertrophic Cardiomyopathy Registry.

Accumulating evidence suggests that individuals with sarcomeric hypertrophic cardiomyopathy (HCM) carrying MYH7 mutations may have a worse prognosis than MYBPC3 mutation carriers. Myocardial deformation analysis is superior to standard echocardiography in detecting subtle myocardial dysfunction and scar formation, but studies evaluating the association with HCM genotype are scarce. We therefore aimed to compare myocardial strain parameters between MYBPC3 and MYH7 mutation carriers with proven HCM. Participants of the prospective Graz HCM Registry carrying at least one causative mutation in MYBPC3 (n = 39) or MYH7 (n = 18) were enrolled. MYBPC3 mutation carriers were older, predominantly male and more often treated with an implantable cardioverter-defibrillator (39% vs. 0%; p = 0.002). Using analyses of covariance, there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to left ventricular global longitudinal strain (estimated marginal means ± standard deviation: -16.9 ± 0.6% vs. -17.3 ± 0.9%; p = 0.807) and right ventricular 6-segments endocardial strain (-24.3 ± 1.0% vs. 26.3 ± 1.5%; p = 0.285). Our study suggests, that myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.

Advanced isolated light chain amyloid cardiomyopathy with negative immunofixation and normal free light chain ratio.

Amyloid light chain (AL) cardiomyopathy is the most malignant specific cardiomyopathy. According to international recommendations, it should be ruled out non-invasively using the serum free light chain (FLC) ratio and immunofixation electrophoresis in both serum and urine. Here, we report on a 69-year-old female patient with new-onset heart failure with mid-range ejection fraction. Cardiac imaging was highly suggestive of cardiac amyloidosis. Amyloid scintigraphy showed faint myocardial tracer uptake according to Perugini Score 1, but immunofixation was negative and the FLC ratio was normal, despite a slight increase in lambda FLCs. Endomyocardial biopsy revealed advanced myocardial lambda immunoglobulin light chain deposition. Clinically relevant extracardiac amyloid organ infiltration could not be detected. Conclusively, non-invasive testing can in rare cases fail to exclude isolated AL amyloid cardiomyopathy. We suggest that even slight increases in serum lambda or kappa FLCs should be considered abnormal in suspected cardiac amyloidosis if non-invasive testing delivers discrepant results.

Fluorescence image-guided brain tumour resection with adjuvant metronomic photodynamic therapy: pre-clinical model and technology development.

Fluorescence-guided resection (FGR) and photodynamic therapy (PDT) have previously been investigated separately with the objectives, respectively, of increasing the extent of brain tumour resection and of selectively destroying residual tumour post-resection. Both techniques have demonstrated trends towards improved survival, pre-clinically and clinically. We hypothesize that combining these techniques will further delay tumour re-growth. In order to demonstrate technical feasibility, we here evaluate fluorescence imaging and PDT treatment techniques in a specific intracranial tumour model. The model was the VX2 carcinoma grown by injection of tumour cells into the normal rabbit brain. An operating microscope was used for white light imaging and a custom-built fluorescence imaging system with co-axial excitation and detection was used for FGR. PDT treatment light was applied by intracranially-implanted light emitting diodes (LED). The fluorescent photosensitizer used for both FGR and PDT was ALA-induced PpIX. For PDT, ALA (100 mg kg(-1)) and low light doses (15 and 30 J) were administered over extended periods, which we refer to as metronomic PDT (mPDT). Eighteen tumour bearing rabbits were divided equally into three groups: controls (no resection); FGR; and FGR followed by mPDT. Histological whole brain sections (H&E stain) showed primary and recurrent tumours. No bacteriological infections were found by Gram staining. Selective tumour cell death through mPDT-induced apoptosis was demonstrated by TUNEL stain. These results demonstrate that the combined treatment is technically feasible and this model is a candidate to evaluate it. Further optimization of mPDT treatment parameters (drug/light dose rates) is required to improve survival.