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SummaryThe prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatment, and structured patient care. This requires intensive collaboration across several disciplines, and between resident physicians and specialized centers. The aim of this consensus statement is to provide guidance for the rapid and efficient diagnosis and treatment of light-chain amyloidosis and transthyretin amyloidosis, which are the most common forms of cardiac amyloidosis.

Background In heart failure with preserved ejection fraction (HFpEF), echocardiographic studies suggest that global longitudinal strain (GLS) has an impact on survival. Feature-tracking cardiovascular MRI also allows for strain analysis; however, to the knowledge of the authors, little is known about its prognostic value and whether it reflects severity of diffuse fibrosis, as assessed by cardiovascular MRI T1 mapping. Purpose To investigate the association between myocardial strain at cardiovascular MRI with extracellular volume by T1 mapping and outcome in participants with HFpEF. Materials and Methods In this secondary analysis of a prospective study (NCT03405987), consecutive participants with HFpEF underwent cardiovascular MRI between July 2012 and March 2018, including T1 mapping and three-dimensional strain analysis. Extracellular volume and strain results were assessed to determine if there was a correlation between these two factors. Cox regression was performed to determine the prognostic relevance of MRI-derived myocardial strain for a combined end point (events) of heart failure hospitalizations and cardiovascular death. Results In total, 206 consecutive participants with HFpEF (mean age, 71 years ± 8 [standard deviation]; 69% women) were included. Median myocardial global longitudinal strain (GLS) at MRI was -8.5% and showed low correlation with extracellular volume (r = 0.28; P = .003). A total of 109 events (53%) were recorded during a follow-up of 38 months ± 29. Participants with a GLS above the median had higher event rates (log-rank test, P < .001). By multivariable Cox regression analysis, GLS remained independently associated with outcome (hazard ratio, 1.06 per 1% strain increase; 95% confidence interval: 1.01, 1.11; P = .03) when corrected for risk factors including age, diabetes, renal function, N-terminal pro-b-type natriuretic peptide serum concentration, and right ventricular size and function. Conclusion In participants with heart failure with preserved ejection fraction, global longitudinal strain at cardiovascular MRI was correlated with extracellular volume by T1 mapping and was associated with cardiovascular events. © RSNA, 2020 Online supplemental material is available for this article.

The percutaneous coronary intervention (PCI) for chronic total occlusions (CTO) remains debated. Therefore the aim of this large-scale observational multi-center registry was to compare the long-term outcome of CTO patients undergoing different therapeutic approaches comparing successful CTO revascularization either by PCI or coronary artery bypass graft (CABG), failed CTO-PCI and optimal medical therapy (OMT) alone.A total of 6630 CTO patients were enrolled from two high-volume centers to compare different treatment strategies. All procedures were performed by high-volume CTO operators in tertiary university hospital. Successful CTO-PCI was performed in 3906 patients, failed CTO-PCI in 1479 patients, 412 patients underwent CABG surgery and 833 patients were treated with OMT. During the 5-year follow-up period, 1019 (15%) patients died. Kaplan-Meier analysis unveiled a significantly improved long-term outcome for CTO patients undergoing revascularization either by PCI or by CABG compared to patients with failed CTO-PCI or OMT alone (log-rank P 0.001). In the multivariate Cox-regression analysis successful CTO-PCI was associated with significantly improved long-term outcome compared to patients under OMT (adj. HR 0.39, 95%CI 0.33-0.45, P 0.001) or CABG (adj. HR 0.68, 95%CI 0.53-0.86, P = 0.002) independent of clinical confounders encompassing age, BMI, diabetes, kidney function and left ventricular function.This study showed an improved long-term outcome for CTO revascularization compared to optimal medical therapy, independent from revascularization mode, with the highest survival rate in patients undergoing successful CTO-PCI.

Aims Concomitant cardiac amyloidosis (CA) in severe aortic stenosis (AS) is difficult to recognize, since both conditions are associated with concentric left ventricular thickening. We aimed to assess type, frequency, screening parameters, and prognostic implications of CA in AS. Methods and results A total of 191 consecutive AS patients (81.2 ± 7.4 years; 50.3% female) scheduled for transcatheter aortic valve replacement (TAVR) were prospectively enrolled. Overall, 81.7% underwent complete assessment including echocardiography with strain analysis, electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), 99mTc‐DPD scintigraphy, serum and urine free light chain measurement, and myocardial biopsy in immunoglobulin light chain (AL)‐CA. Voltage/mass ratio (VMR; Sokolow–Lyon index on ECG/left ventricular mass index) and stroke volume index (SVi) were tested as screening parameters. Receiver operating characteristic curve, binary logistic regression, and Kaplan–Meier curve analyses were performed. CA was found in 8.4% of patients (n = 16); 15 had transthyretin (TTR)‐CA and one AL‐CA. While global longitudinal strain by echo did not reliably differentiate AS from CA‐AS [area under the curve (AUC) 0.643], VMR as well as SVi showed good discriminative power (AUC 0.770 and 0.773, respectively), which was comparable to extracellular volume by CMR (AUC 0.756). Also, VMR and SVi were independently associated with CA by multivariate logistic regression analysis (P = 0.016 and P = 0.027, respectively). CA did not significantly affect survival 15.3 ± 7.9 months after TAVR (P = 0.972). Conclusion Both TTR‐ and AL‐CA can accompany severe AS. Parameters solely based on ECG and echocardiography allow for the identification of the majority of CA‐AS. In the present cohort, CA did not significantly worsen prognosis 15.3 months after TAVR.

Objectives The aim of the present long-term study was to assess the incidence and mode of valve hemodynamic deterioration (VHD) of bioprosthetic aortic valves, as well as associated factors. Background Modern definitions of bioprosthetic valve deterioration recommend the use of echocardiography for the assessment of transprosthetic gradients and valvular regurgitation. Methods A total of 466 consecutive patients (mean age 73.5 ± 7.5 years, 56.0% women) underwent surgical bioprosthetic aortic valve replacement between 1994 and 2014. Clinical assessment, transthoracic echocardiography, and laboratory testing were performed at baseline and follow-up. VHD was defined as mean transprosthetic gradient ≥30 mm Hg and/or at least moderate valvular regurgitation on echocardiography. Patient-prosthesis mismatch was defined as an effective orifice area indexed to body surface area ≤0.8 cm2/m2. Results Patients were followed for a median of 112.3 months (interquartile range: 57.7 to 147.7 months). Among patients with complete follow-up (n = 383), 70 subjects (18.3%; 4.8% per valve-year) developed VHD after a median of 32.4 months (interquartile range: 12.9 to 87.2 months; stenosis, n = 45; regurgitation, n = 16; both, n = 9). Factors associated with VHD by multivariate regression analysis were serum creatinine >2.1 mg/dl (hazard ratio [HR]: 4.143; 95% confidence interval [CI]: 1.740 to 9.866; p = 0.001), porcine tissue valves (HR: 2.241; 95% CI: 1.356 to 3.706; p = 0.002), arterial hypertension (HR: 3.022; 95% CI: 1.424 to 6.410; p = 0.004), and patient-prosthesis mismatch (HR: 1.931; 95% CI: 1.102 to 3.384; p = 0.022). By Kaplan-Meier analysis, elderly subjects showed faster development of VHD (age 80 years, 100.3 months [95% CI: 63.6 to 136.9 months]; p = 0.023). By multivariate Cox regression, age, diabetes, concomitant coronary artery bypass grafting, creatinine, and VHD (p Conclusions On the basis of echocardiography, every fifth patient developed VHD after surgical bioprosthetic heart valve replacement. VHD was associated with renal impairment, the use of porcine tissue valves, arterial hypertension, and patient-prosthesis mismatch. Patients younger than 70 years were not affected by faster VHD.

Background Left atrial (LA) function is related with outcome in heart failure with preserved ejection fraction (HFpEF). However, how LA function contributes to outcome in the context of atrial fibrillation (AF) versus sinus rhythm (SR) remains unclear. Purpose To determine the prognostic impact of LA size and phasic function in patients with HFpEF in SR vs. AF. Methods We enrolled consecutive HFpEF patients and assessed indexed LA volumes (LAVi) and emptying fractions (LA-EF) on cardiac magnetic resonance (CMR) imaging. We prospectively followed patients and used Cox regression models to determine the association of LA size and function with a composite endpoint of heart failure hospitalization and cardiovascular death. Results A total of 188 patients (71% female, 70±8 y/o) were included of whom 92 (49%) were in persistent AF (Figure 1A). Patients in persistent AF were older (p=0.017) and had a worse NYHA functional class (p=0.003). Compared to SR, peak and minimal LAVi were increased and LA-EF impaired (each p A total of 65 patients reached the combined endpoint during a follow-up of 31 (9–57) months. Multivariate Cox regression adjusted for established risk factors revealed that LA-EF was significantly associated with outcome in patients in SR (adj.HR 2.14; 95% CI [1.32–3.47] per 1-SD decline, p=0.002). In persistent AF, however, no LA imaging parameter was related to outcome (Figure 1B). By receiver operating characteristic curve and restricted cubic spline- analyses, we identified an LA-EF ≥40% as best indicator for favorable outcomes in patients with HFpEF and SR (Figure 2B). Persistent AF carried a similar risk for adverse outcome compared to impaired LA-EF ( Conclusions In HFpEF patients in SR, impaired LA-EF is independently associated with worse cardiovascular outcome, which is similar to persistent AF. With disease progression including development of persistent AF, LA parameters lose their prognostic ability and thus, are not helpful for further risk stratification. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Aims Increased afterload to the right ventricle (RV) has been shown to induce myocardial fibrosis at the RV insertion points (RVIPs). Such changes can be discrete but potentially detected by cardiac magnetic resonance (CMR) T1-mapping. Whether RVIP fibrosis is associated with prognosis in heart failure with preserved ejection fraction (HFpEF) is unknown. Methods and results We prospectively investigated 167 consecutive HFpEF patients, a population frequently suffering from post-capillary pulmonary hypertension, who underwent CMR including T1-mapping. About 92.8% also underwent right heart catheterization for haemodynamic assessment. Native T1 times were 995 ± 73 ms at the anterior and 1040 ± 90 ms at the inferior RVIP. By Spearman’s rank order testing, RVIP T1 times were significantly correlated with pulmonary artery pressure (mean PAP, r = 0.313 and 0.311 for anterior and inferior RVIP), pulmonary artery wedge pressure (r = 0.301 and 0.251) and right atrial pressure (r = 0.245 and 0.185; P for all Conclusion Interstitial expansion of the anterior RVIP as detected by CMR T1-mapping reflects haemodynamic alterations, and is independently related with prognosis in HFpEF.

The renin-angiotensin system plays an important role in the development and progression of heart failure (HF). In addition to the classical renin-angiotensin pathway, an alternative pathway produces Angs (angiotensins), which counteract the negative effects of Ang II. We hypothesized that Ang profiling could provide insights into the pathogenesis and prognosis of HF with preserved ejection fraction. We aimed to investigate the effects of Angs on outcome in HF with preserved ejection fraction. Consecutive patients were included into a prospective single-center registry. Clinical, laboratory, and imaging parameters were assessed and serum samples were taken at baseline and measured by mass spectroscopy. Serum equilibrium levels were analyzed in regard to the combined clinical end point of cardiovascular death or HF hospitalization. In total, 155 patients were included during a median follow-up time of 22.5 (interquartile range, 4.0–61.0) months, 52 individuals (34%) reached the combined end point. We identified higher levels of Ang 1–7 and Ang 1–5 as predictors for poor outcome. After adjusting for potential confounding factors, Ang 1–5 remained predictive for poor outcome. In addition to Ang 1–7 and Ang 1–5, the novel ACE (angiotensin-converting enzyme) independent Ang composite marker [Ang 1–7+Ang 1–5] was shown to predict adverse events. We conclude that Angs of the alternative renin-angiotensin system seem to play a role in HF with preserved ejection fraction and are linked to outcome in patients with HF and preserved ejection fraction. Ang 1–5 and the alternative renin-angiotensin system composite marker [Ang 1–7+Ang 1–5] are independent predictors of outcome.

Objectives This study investigated the diagnostic and prognostic value of cardiac magnetic resonance (CMR) imaging in chronic aortic regurgitation (AR). Background Accurate quantification of AR severity by echocardiography frequently remains difficult. CMR is recommended as the complementary method; however, its accuracy and prognostic utility remain unknown. Methods A total of 232 consecutive patients (34.5% were females 55.5 ± 19.8 years of age) with chronic AR (including 40 with moderate to severe and 44 with severe AR on echocardiography) underwent CMR within 4 weeks of echocardiography. CMR included phase-contrast velocity-encoded imaging for the measurement of regurgitant volume and fraction at the sinotubular junction and assessment of holodiastolic retrograde flow (HRF) in the descending aorta. Significant AR was defined as the presence of HRF on CMR. Patients were followed prospectively, and multivariate Cox regression was applied for outcome analysis using a combination of heart failure, hospitalization, and cardiovascular death as primary endpoint. Results AR severity on the basis of echo was reclassified in a significant number of patients according to CMR: 6.8% with mild AR on echo had HRF on CMR, whereas 34.1% with severe AR on echo did not have HRF on CMR and were reclassified as having nonsignificant AR. In 40 patients with uncertain AR severity (moderate to severe) on echo, 45.0% had HRF on CMR, indicating severe AR. Patients were followed for 35.3 ± 26.6 months. During that period, 63 patients (27.2%) reached the combined endpoint, including 43 (18.5%) with heart failure hospitalizations and 20 (8.6%) with cardiovascular deaths. By multivariate regression analysis, including clinical as well as imaging parameters, only N-terminal pro–B-type natriuretic peptide concentration (hazard ratio: 2.184 [95% confidence interval: 1.468 to 3.248]; p Conclusions In chronic AR, CMR has the potential to add important diagnostic and prognostic information.

Objectives Decision making in severe aortic stenosis (AS) requires a comprehensive pre-operative evaluation of the risk-to-benefit ratio. The aim of this study was to assess whether certain pre-operative symptoms are associated with outcome after surgical aortic valve replacement (SAVR). Background The cardinal symptoms of AS indicating a need for intervention are angina, symptoms of heart failure, and syncope. Nevertheless, it remains unknown whether the presence of these more advanced symptoms conveys an increased risk after SAVR and whether the detection of early symptoms in patients with asymptomatic AS should be emphasized more in routine clinical practice. Methods A total of 625 patients with isolated severe AS undergoing elective SAVR were prospectively enrolled in this long-term observational study. Results Patients experiencing syncope had significantly smaller left ventricular diameters (p = 0.02), left atrial diameters (p = 0.043), right ventricular diameters (p = 0.04), and right atrial diameters (p = 0.001), smaller aortic valve areas (p = 0.048), and lower indexed stroke volumes (p = 0.043) compared with patients without syncope. Syncope conveyed an increased risk for mortality after SAVR that persisted after multivariate adjustment for a bootstrap-selected confounder model, with an adjusted hazard ratio of 2.27 (95% confidence interval: 1.04 to 4.95; p = 0.04) for 1-year short-term mortality and an adjusted hazard ratio of 2.11 (95% confidence interval: 1.39 to 3.21; p Conclusions This long-term observational study in a large contemporary cohort of patients with AS for the first time demonstrates that syncope represents an underestimated threat in aortic stenosis, associated with poor prognosis after SAVR. Importantly, other primary indications for SAVR (i.e., dyspnea, angina, and decreased left ventricular function) were associated with significantly better post-operative outcomes than syncope. Patients experiencing syncope displayed a specific pathophysiologic phenotype characterized by a smaller aortic valve area, smaller cardiac cavities, and lower stroke volumes.

Aim: Peak oxygen uptake (peakVO2) is one of the strongest predictors of survival in patients with valvular heart disease. The purpose of this study was to determine whether endurance training improves peakVO2 and endurance capacity in patients with moderate-severe aortic and mitral valve disease.Methods: 30 patients with moderate-severe valvular heart disease were randomly assigned to 12 weeks of endurance training (TG) (n = 16) or standard care (SC) (n = 14). PeakVO2 and maximum working capacity (Wattmax) were assessed by cardiopulmonary exercise testing, as well as submaximal endurance test at 80% of peakVO2 at baseline and after 12 weeks.Results: There was a significant improvement in peakVO2 from 27.2 ± 5.9 ml/kg to 30.4 ± 6.3 ml/kg (P < 0.001) in TG compared to the SC (peakVO2 from 24.6 ± 4.4 to 24.7 ± 3.8) and in the Wattmax from 151.8 ± 41.0 Watt to 171.2 ± 49.7 Watt in the TG compared to the SC (152.9 ± 35.6 Watt to 149.2 ± 28.4 Watt). The endurance capacity increased significantly from 17.0 ± 9.4 min to 32.8 ± 16.8 min (p = 0.003) in the TG compared to the SC (11.7 ± 6.2 min to 11.2 ± 7.6 min). The heart rate during the endurance test decreased in the TG from 154 ± 14 b/min to 142 ± 20 b/min for the same workload. No changes could be seen in the SC.Conclusion: Endurance training in patients with moderate to severe valvular heart disease increased significantly the peakVO2 as well as the endurance capacity.

Background: Left ventricular (LV) dilatation is a key compensatory feature in patients with chronic aortic regurgitation (AR). However, sex-differences in LV remodeling and outcomes in chronic AR have been poorly investigated so far. Methods: We performed cardiovascular magnetic resonance imaging (CMR) including phase-contrast velocity-encoded imaging for the measurement of regurgitant fraction (RegF) at the sinotubular junction, in consecutive patients with at least mild AR on echocardiography. We assessed LV size (end-diastolic volume indexed to body surface area, LVEDV/BSA) and investigated sex differences between LV remodeling and increasing degrees of AR severity. Cox-regression models were used to test differences in outcomes between men and women using a composite of heart failure hospitalization, unscheduled AR intervention, and cardiovascular death. Results: 270 consecutive patients (59.6% male, 59.8 &plusmn, 20.8 y/o, 59.6% with at least moderate AR on echocardiography) were included. On CMR, mean RegF was 18.1 &plusmn, 17.9% and a total of 65 (24.1%) had a RegF &ge, 30%. LVEDV/BSA was markedly closer related with AR severity (RegF) in men compared to women. Each 1-SD increase in LVEDV/BSA (mL/m2) was associated with a 9.7% increase in RegF in men and 5.9% in women, respectively (p-value for sex-interaction &lt, 0.001). Based on previously published reference values, women&mdash, in contrast to men&mdash, frequently had a normal LV size despite severe AR (e.g., for LVEDV/BSA on CMR: 35.3% versus 8.7%, p &lt, 0.001). In a Cox-regression model adjusted for age, LVEDV/BSA and RegF, women were at significantly higher risk for the composite endpoint when compared to men (adj. HR 1.81 (95%CI 1.09&ndash, 3.03), p = 0.022). Conclusion: In patients with chronic AR, LV remodeling is a hallmark feature in men but not in women. Severity of AR may be underdiagnosed in female patients in the absence of LV dilatation. Future studies need to address the dismal prognosis in female patients with chronic AR.

Aims Right ventricular dysfunction (RVD) on echocardiography has been shown to predict outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). However, a comparison with the gold standard, RV ejection fraction (EF) on cardiovascular magnetic resonance (CMR), has never been performed. Methods and results Consecutive patients scheduled for TAVR underwent echocardiography and CMR. RV fractional area change (FAC), tricuspid annular plane systolic excursion, RV free-lateral-wall tissue Doppler (S’), and strain were assessed on echocardiography, and RVEF on CMR. Patients were prospectively followed. Adjusted regression analyses were used to report the strength of association per 1-SD decline for each RV function parameter with (i) N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, (ii) prolonged in-hospital stay (>14 days), and (iii) a composite of heart failure hospitalization and death. Two hundred and four patients (80.9 ± 6.6 y/o; 51% female; EuroSCORE-II: 6.3 ± 5.1%) were included. At a cross-sectional level, all RV function parameters were associated with NT-proBNP levels, but only FAC and RVEF were significantly associated with a prolonged in-hospital stay [adjusted odds ratio 1.86, 95% confidence interval (CI) 1.07–3.21; P = 0.027 and 2.29, 95% CI 1.43–3.67; P = 0.001, respectively]. A total of 56 events occurred during follow-up (mean 13.7 ± 9.5 months). After adjustment for the EuroSCORE-II, only RVEF was significantly associated with the composite endpoint (adjusted hazard ratio 1.70, 95% CI 1.32–2.20; P Conclusion RVD as defined by echocardiography is associated with an advanced disease state but fails to predict outcomes after adjustment for pre-existing clinical risk factors in TAVR patients. In contrast, RVEF on CMR is independently associated with heart failure hospitalization and death.

Aims Cardiac amyloidosis (CA) leads to signs and symptoms of heart failure (HF). The mechanisms of biventricular dysfunction and their impact on outcome in subtypes of CA are poorly understood. Our aim was to compare right ventricular (RV) and left ventricular (LV) parameters in patients with light chain (AL) and wild-type transthyretin amyloidosis (ATTRw) and evaluate their ability to predict cardiac outcome. Methods and results We included patients with CA into a prospective registry. Baseline assessment included biventricular 2D speckle tracking imaging parameters. Patients were followed-up in regular intervals. The composite endpoint was defined as cardiovascular death, heart transplantation or ventricular assist device implantation, and HF hospitalization. We included 122 patients with CA. Sixty-two of these patients (50.8%) were diagnosed with ATTRw and 60 (49.2%) with AL. In ATTRw, parameters of RV size and function correlated well with symptom severity and only morphological and functional parameters of the RV predicted outcome. RV free wall strain was the only independent predictor of outcome with a hazard ratio (HR) of 1.185 [95% confidence interval (CI) 1.047-1.342, P = 0.007]. In AL on the other hand, RV function correlated well with symptoms but was not associated with outcome. In contrast, global longitudinal strain of the LV (LV-GLS) was predictive for outcome. After adjusting in a multivariable model, LV-GLS remained predictive with a HR of 1.180 (95% CI 1.032-1.348, P = 0.015). Conclusion Our data suggest that mechanisms underlying HF differ between ATTRw and AL. This may have substantial implications in particular in light of emerging therapies for both subtypes of CA.

Purpose Cardiovascular disease and foremost coronary heart disease (CHD) are the worldwide leading causes of death. The aim of this study was to use non-invasive, multimodel retinal imaging to define microvascular features in patients with and without coronary angiography (CA)-confirmed CHD. Methods In this prospective, cross-sectional pilot study we included adult patients who presented to a tertiary referral center for elective CA due to suspected CHD. All patients underwent widefield fundus photography for retinopathy grading. Optical coherence tomography angiography was used to measure vessel density (VD) of the individual capillary plexuses in 6 × 6-mm macular volume scans. Adaptive optics imaging was performed to assess the first-order arteriolar lumen diameter (LD), total diameter (TD), wall-to-lumen ratio (WLR), and wall cross-section area, as well as to qualitatively describe vessel morphology. Results Of the included 45 patients (13 females; 65 ± 10 years old), 27 were confirmed with CHD in elective CA. The most prevalent retinal vascular pathologies were arteriovenous nickings, focal arterial narrowings, and microaneurysms. VD in the superficial capillary plexus, deep capillary plexus, and choriocapillaris was lower in CHD patients, although the odds ratios were not significantly different from 1 (P = 0.06-0.92). Median arterial LD, TD, and WLR values were 98.3 µm (interquartile range [IQR] = 13.0), 122.9 µm (IQR = 17.6), and 0.26 µm (IQR = 0.07), respectively, with a trend toward a higher WLR in CHD patients. Conclusions In a cardiovascular risk population, high-resolution quantitative and qualitative microvascular phenotyping in the retina may provide valuable subclinical indicators for coronary artery impairment, although larger clinical trials are needed. Translational relevance Subclinical retinal microvascular changes may serve as non-invasive, cost-effective biomarkers for risk stratification of patients with CHD.

Most heart failure with preserved ejection fraction (HFpEF) patients, at some point, present to an emergency department with typical symptoms of volume overload. Clinically, most respond well to standard diuretic therapy, sometimes at the cost of renal function. The study sought to define the prognostic significance of fluid status versus renal function in patients with HFpEF.One hundred sixty-two consecutive patients with HFpEF were enrolled in our prospective registry. Twelve patients with clinically overt decompensation were excluded. Fluid status at baseline was determined by bioelectrical impedance spectroscopy. The primary outcome measure was a combined end point consisting of hospitalization for heart failure and/or death for cardiac reason.Mean age was 74.4±8.4years. Ninety-one (61%) patients were hypo- or normovolemic (relative fluid overload [Rel. FO] -0.7±5.7%) while 59 (39%) patients presented with fluid overload (Rel. FO 11.5±2.7%). During a median follow-up of 24.3months (interquartile range: 19.8-33.2), 34% of patients reached the combined end point. Multivariate Cox hazard analysis identified fluid overload (hazard ratio: 3.09; 95% confidence interval: 1.68-5.68; p0.001) as an independent predictor of adverse outcome. Patients with fluid overload and normal renal function showed a worse event-free survival compared to the subgroup with normohydration and impaired renal function (log-rank: p=0.042).HFpEF patients with measurable fluid overload face a dismal prognosis as compared to euvolemic patients. Our data, while preliminary, suggest that patients with fluid overload may face a better outcome under continued fluid removal irrespective of changes in eGFR.

In cardiac amyloidosis (CA), extracellular deposition of amyloid fibrils within the myocardium significantly expands the extracellular volume (ECV). Affected patients develop severe heart failure and face a dismal prognosis. Cardiac magnetic resonance (CMR) T1 mapping allows ECV measurement [(1)][1

Previous studies suggested an association between heart failure (HF) and hepatic disorders. Liver function parameters have been shown to predict outcome in HF with reduced ejection fraction, but their impact in HF with preserved ejection fraction (HFpEF) has not yet been investigated. Between January 2011 and February 2017, 274 patients with confirmed HFpEF were enrolled (age 71.3 ± 8.4 years, 69.3% female) in a prospective registry. During a median follow-up of 21.5 ± 18.6 months, 97 patients (35.4%) reached the combined endpoint defined as hospitalization due to HF and/ or death from any cause. By multivariable cox regression, serum gamma-glutamyltransferase (GT) was independently associated with outcome (Hazard Ratio (HR) 1.002, p = 0.004) along with N-terminal pro brain natriuretic peptide (HR 2.213, p = 0.001) and hemoglobin (HR 0.840, p = 0.006). Kaplan-Meier analysis showed that patients with serum gamma-GT levels above a median of 36 U/L had significantly more events as compared to the remainder of the group (log-rank p = 0.012). By multivariable logistic regression, higher early mitral inflow velocity/ mitral peak velocity of late filling (Odds Ratio (OR) 2.173, p = 0.024), higher right atrial (RA) pressure (OR 1.139, p 36 U/L. Serum levels of gamma-GT are associated with both left and right-sided cardiac alterations and may serve as a simple tool for risk prediction in HFpEF, especially when further diagnostic modalities are not available.

Background Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). While this might be suggestive of a sign of right heart failure, it is not known, whether effusions correlate with right ventricular (RV) function in patients with CA. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce. Methods Patients with cardiac transthyretin (ATTR) and light chain (AL) amyloidosis were included in a clinical registry at our dedicated CA outpatient clinic. CA was diagnosed according to current guidelines. All patients underwent a comprehensive transthoracic echocardiography (TTE) exam at the time of study inclusion. The TTE protocol included standard and advanced parameters describing left ventricular and RV function, including speckle-tracking imaging to assess global longitudinal left ventricular and RV free wall (RV-FW) strain. The presence of pericardial and pleural effusion was determined in every patient and was verified by cardiac magnetic resonance imaging when present. The size of pericardial effusion was measured at the point of its maximum extension. The clinical endpoint was defined as all-cause death. Results Between March 2012 and February 2019, 177 patients were included in our CA registry, however, TTE image quality was only sufficient for analysis in 143 patients. Of these, 83 patients (59.4%) were diagnosed with ATTR and 60 patients (42.0%) with AL. In total, 23 patients (16.1%) presented with isolated pericardial effusion and 36 (25.2%) with isolated pleural effusion. In 17 patients (11.9%) both pericardial and pleural effusion were found and in 66 patients (46.2%) no effusion was present at baseline. Overall, there was no significant difference in the type of effusion between patients with AL and ATTR. In general, pericardial effusions were small (median diameter 7.1 mm (IQR 5.2–9.7) and none were hemodynamically compromising. Interestingly, the presence of pleural effusion correlated well with poor RV function, measured by RV-FW strain (p=0.034). However, no such correlation could be found for pericardial effusion and RV-FW strain (p=0.319). Kaplan Meier analysis showed that patients presenting with pleural effusion had a worse prognosis compared to patients with pericardial effusion alone or no effusion at baseline (p=0.001, Figure 1). Figure 1 Conclusion More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function, we were not able to detect this association with pericardial effusion. In addition, patients with pleural effusions had an exceptionally poor prognosis compared to patients with pericardial effusions or no effusion at baseline.

Background Intracardiac filling and pulmonary arterial pressures play a central role in various heart failure entities, as they are strong predictors of outcome. However, their role in patients with cardiac amyloidosis (CA) is less clear. Purpose We aimed to characterize hemodynamic profiles of CA patients and assess their association with outcomes. Methods The present study was conducted within a prospective, national CA registry. Patients underwent invasive hemodynamic, clinical, laboratory, and echocardiography assessment, as well cardiac magnetic resonance imaging with T1-mapping. The main outcome measure was a combined endpoint consisting of hospitalization for heart failure or cardiovascular death. Results Between March 2012 and October 2018, 63 consecutively recruited CA patients underwent invasive hemodynamic profiling. Of those, 36 had cardiac transthyretin amyloidosis (ATTR) and 25 cardiac light-chain amyloidosis (AL). In two patients amyloid subtyping was not possible. Median age of the study population was 74.0 years and the majority were male (61.9%). Almost half of the patients were in New York Heart Association (NYHA) class ≥III (47.6%) and showed elevated N-terminal prohormone of brain natriuretic peptides (NT-proBNP) with a median of 3222 pg/mL. In comparison to AL, cardiac TTR patients were older (75.0 years versus 69.0 years, p=0.004), more often male (80.6% versus 40.0%, p=0.001), less symptomatic (NYHA class ≥III: 38.9% versus 64.0%, p=0.021), and had lower NT-proBNP values (2324pg/mL versus 5151pg/mL, p=0.004). Hemodynamic profiling revealed significantly increased intracardiac as well as pulmonary arterial pressures (PAP). On an average, pulmonary artery wedge pressure was 20.0mmHg [interquartile range (IQR): 17.0–25.0], mean PAP (mPAP) was 30.0mmHg (IQR: 25.0–37.0), and mean right atrial pressure (mRAP) was 11.0mmHg (IQR: 7.0–16.0). No differences between ATTR and AL patients could be detected (p=0.148, p=0.398, p=0.620). During a median follow-up of 63.0 weeks, 28 study participants (44.4%) reached the combined endpoint. Moreover, cardiac AL patients had significantly more events as their ATTR counterparts (72.0% versus 27.8%, p=0.001). In cardiac ATTR patients, mPAP was significantly associated with outcome [hazard ratio (HR): 1.083, p=0.034, Figure 1A], which was not the case in the AL group (HR: 1.024, p=0.186, Figure 1B). Cardiac output and pulmonary vascular resistance were not associated with outcome. Neither in the ATTR (p=0.144; p=0.063) nor in AL cohort (p=0.420; p=0.115). Figure 1 Conclusion Despite differences in the severity of symptoms between cardiac AL and cardiac ATTR patients, no differences with regards to hemodynamic profiles could be detected. Furthermore, intracardiac filling and pulmonary arterial pressures seem to be of greater clinical importance in cardiac ATTR as compared to cardiac AL, as these parameters were associated with outcome in the first, but not the latter group.

Background Transthyretin amyloid cardiomyopathy (ATTR-CA) is caused by deposition of amyloid fibrils in the myocardium. The deposition occurs when transthyretin (TTR) becomes unstable and misfolds. Tafamidis is a kinetic stabilizer of TTR that prevents tetramer dissociation and amyloidogenesis by TTR. Methods Eighteen patients with diagnosis of ATTR-CA (hATTR or wtATTR) from our national amyloidosis registry were treated with 20 mg of tafamidis for a period of six months. In our explorative analysis we aimed to evaluate the effects of tafamdis by changes from baseline of the serum NT-proBNP concentration, 6-minute walking distance, as well as cardiac structure and function. Results The exploratory analysis showed a decrease in serum NT-proBNP concentration in tafamidis treated patients, compared to increase in untreated patients (median difference, −481.0 pg/mL). Tafamidis improved the walking distance during the 6-minute walk test at month six, compared to baseline (mean, 31.25 m). Echocardiographic findings revealed an improvement of the global longitudinal strain (mean, 0.77%), a decrease in left atrial size (mean, −1.65 mm) and a decrease in left ventricular size (mean, −4.13 mm) in tafamidis treated patients compared to untreated patients. Due to insufficient power the results did not differ significantly between tafamidis treated patients and untreated patients. Change from baseline Tafamidis No treatment Treatment Difference p-value Cardiac Biomarkers n=18 n=15 NT-proBNP, ng/L Baseline, median 2740.0 2835.0 CFB to 6 months, median −207.0 274.0 −481.0 0.329 Functional Status n=8 n=7 6MWT, m Baseline, mean 441.00 420.50 CFB to 6 months, mean 31.25 −16.50 +47.75 0.373 Echocardiogram n=17 n=15 LA, mm Baseline, mean 63.41 61.33 CFB to 6 months, mean −1.65 0.60 −2.25 LV, mm Baseline, mean 44.13 41.80 CFB to 6 months, mean −4.13 0.33 −4.46 0.075 LV wall thickness, mm Baseline, mean 22.06 18.47 CFB to 6 months, mean 0.68 −0.60 +1.28 0.055 Longitudinal strain, % Baseline, mean −10.66 −12.42 CFB to 6 months, mean 0.77 −1.03 +1.80 0.652 MRI n=7 n=6 ECV, % Baseline, mean 52.26 44.22 CFB to 6 months, mean 0.81 3.70 − 2.89 0.493 LV mass, g Baseline, mean 187.71 170.33 CFB to 6 months, mean 24.29 19,67 +4.62 0.612 Conclusion Treatment with tafamidis for a period of six months in patients with ATTR-CA leads to positive effects on NT-proBNP level, 6-minute walking distance, as well as cardiac structure and function compared to untreated patients.

Background Apical sparing describes a reduced longitudinal strain in the basal segments and preserved or supranormal longitudinal strain in the apical segments of the left ventricular (LV) myocardium. This pattern has been described as a typical finding in patients with cardiac amyloidosis (CA) and restrictive cardiomyopathy. However, apical sparing is not a quantitative parameter and is fairly subjective to the echocardiographer's judgement. It is not known, if a certain degree of apical sparing is also present in patients with only mild LV hypertrophy and diastolic dysfunction such as it is present in heart failure with preserved ejection fraction (HFpEF). Methods Patients with cardiac transthyretin and light chain amyloidosis and patients with HFpEF were included in a clinical registry at our outpatient clinic. CA was diagnosed according to current guidelines. All patients underwent a comprehensive transthoracic echocardiography (TTE) exam at the time of study inclusion. The TTE protocol included standard and speckle-tracking imaging to assess the presence of apical sparing as well as the basal to apical strain gradient. Patients with known coronary artery disease were excluded. Results In total 115 patients were included in this study. Of these, 87 (75.7%) were diagnosed with CA and 28 (24.3%) with HFpEF. Not surprisingly, apical sparing was found in a majority (86.2%) of patients with CA, however mild forms of this phenomenon were also present in 67.9% of patients with HFpEF (p=0.029, Figure 1). Median basal longitudinal strain was significantly more impaired in patients with CA (p Figure 1 Conclusion Mild forms of apical sparing can be found in patients without CA. Gradual reduction in strain from base to apex could be an unspecific pathophysiologic mechanism which is remarkably pronounced in patients with CA.

Aims. Two thirds of patients with heart failure and preserved ejection fraction (HFpEF) have an indication for oral anticoagulation (OAC) to prevent thromboembolic events. However, evidence regarding the safety of OAC in HFpEF is limited. Therefore, our aim was to describe bleeding events and to find predictors of bleeding in a large HFpEF cohort. Methods and Results. We recorded bleeding events in a prospective HFpEF cohort. Out of 328 patients (median age 71 years (interquartile range (IQR) 67&ndash, 77)), 64.6% (n = 212) were treated with OAC. Of those, 65.1% (n = 138) received vitamin-K-antagonists (VKA) and 34.9% (n = 72) non-vitamin K oral anticoagulants (NOACs). During a median follow-up time of 42 (IQR 17&ndash, 63) months, a total of 54 bleeding events occurred. Patients on OAC experienced more bleeding events (n = 49 (23.1%) versus n = 5 (4.3%), p &lt, 0.001). Major drivers of events were gastrointestinal (GI) bleeding (n = 18 (36.7%)]. HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score (hazard ratios (HR) of 2.15 (95% confidence interval (CI) 1.65&ndash, 2.79, p &lt, 0.001)) was the strongest independent predictor for overall bleeding. In the subgroup of GI bleeding, mean right atrial pressure (mRAP: HR of 1.13 (95% CI 1.03&ndash, 1.25, p = 0.013)) and HAS-BLED score (HR of 1.74 (95% CI 1.15&ndash, 2.64, p = 0.009)] remained significantly associatiated with bleeding events after adjustment. mRAP provided additional prognostic value beyond the HAS-BLED score with an improvement from 0.63 to 0.71 (95% CI 0.58&ndash, 0.84, p for comparison 0.032), by C-statistic. This additional prognostic value was confirmed by significant improvements in net reclassification index (61.3%, p = 0.019) and integrated discrimination improvement (3.4%, p = 0.015). Conclusion. OAC-treated HFpEF patients are at high risk of GI bleeding. High mRAP as an indicator of advanced stage of disease was predictive for GI bleeding events and provided additional risk stratification information beyond that obtained by HAS-BLED score.

Background Atrial fibrillation (AF) is a frequent finding in HFpEF. However, its association with invasive haemodynamics, imaging parameters and outcome in HFpEF is not well established. Furthermore, the relevance of AF subtype with regard to outcome is unclear. This study sought to investigate the prognostic impact of paroxysmal and persistent AF in a well‐defined heart failure with preserved ejection fraction (HFpEF) population. Materials and methods Between 2010 and 2016, 254 HFpEF patients were prospectively enrolled. All patients underwent echocardiography as well as left and right heart catheterization. Patients without contraindications underwent CMR including T1 mapping. Follow‐up and outcome data were collected. Patients with significant coronary artery disease were excluded. Results A total of 153 patients (60%) suffered from AF, 119 (47%) had persistent and 34 (13%) had paroxysmal AF. By multiple logistic regression analysis, persistent AF was independently associated with NT‐proBNP (P = .003), NYHA functional class (P = .040), left and right atrial size (P = .022 and

Background/Aims: Heart failure (HF) is a main cause of mortality of hemodialysis (HD) patients. While HF with reduced ejection fraction (HFrEF) is known to only affect a minority of patients, little is known about the prevalence, associations with clinical characteristics and prognosis of HF with preserved ejection fraction (HFpEF). Methods: We included 105 maintenance HD patients from the Medical University of Vienna into this prospective single-center cohort study and determined the prevalence of HFpEF (per the 2013 criteria of the European Society of Cardiology) and HFrEF (EF Results: All but 4 patients (96%) had evidence of diastolic dysfunction. 70% of the entire cohort fulfilled HF criteria (81% HFpEF, 19% HFrEF). Age, female sex, body mass index, blood pressure and dialysis vintage were predictive of HFpEF (sensitivity 86%, specificity 63%; AUC 0.87), while age, female sex, NT pro-BNP, history of coronary artery disease and atrial fibrillation were predictive of HFrEF (sensitivity 85%, specificity 90%; AUC 0.95). Compared to patients without HF, those with HFpEF and HFrEF had a higher risk of hospitalization for cardiovascular reason and/or cardiac death (adjusted HR 4.31, 95% CI 0.46-40.03; adjusted HR 3.24, 95% CI 1.08-9.75, respectively). Conclusion: Diastolic dysfunction and HFpEF are highly prevalent in HD patients while HFrEF only affects a minority. Distinct patient-specific characteristics predict diagnosis of either entity with good accuracy.

Aims Accumulation of extracellular matrix (ECM) is known to play a crucial role in the pathophysiology of heart failure (HF). However, its prognostic relevance is poorly investigated. Methods and results A total of 73 HF patients who underwent LV endomyocardial biopsy were enrolled in our study. ECM area was quantified by TissueFAXS and ImageJ software. Patients were followed-up at 6-month intervals. The study endpoint was defined as hospitalization for a cardiac reason and/or cardiac death. Furthermore, the influence of the ECM on invasively measured haemodynamic parameters was tested. During a median follow-up period of 9.0 months, 34 patients (46.6%) reached the combined endpoint. Median ECM area was 30.5%. Patients with ECM area ≥30.5% experienced significantly more events (67.6% vs. 25.0%, P < 0.001) in comparison with patients with an ECM area

Background: Concomitant left main coronary artery (LMCA) disease in patients with chronic total occlusions (CTO) commonly results in referral for coronary artery bypass grafting, although the impact of LMCA in CTO patients remains largely unknown. Nevertheless, patient selection for percutaneous coronary intervention of CTOs (CTO-PCI) or alternative revascularization strategies should be based on precise evaluation of the coronary anatomy to anticipate those patients that most likely benefit from a procedure and not on strict adherence to perpetual clinical practice. Therefore, the aim of this study was to assess the impact of LMCA disease on long-term outcomes in patients undergoing percutaneous coronary intervention for CTO. Methods: We enrolled 3860 consecutive patients undergoing PCI for at least one CTO lesion and investigated the predictive value of concomitant LMCA disease. All-cause mortality was defined as the primary study endpoint. Results: We observed that LMCA disease is significantly associated with mortality. In the Cox regression analysis, we observed a crude hazard ratio (HR) 1.59 (95% confidence interval (CI) 1.23&ndash, 2.04, p &lt, 0.001) for patients with LMCA disease as compared to patients without. Results remained unchanged after bootstrap- or clinical confounder-based adjustment. Conclusion: LMCA disease is associated with excess mortality in CTO patients. Specifically, anatomical features such as CTO of the circumflex artery represent a high risk patient population.

Current European guidelines classify heart failure (HF) patients according to left ventricular ejection fraction (LVEF) as reduced, mid-range, and preserved subtypes [(1)][1]. Although this is reasonable clinically, several aspects limit the use of LVEF as sole indicator for the severity of HF.

Objectives The purpose of this study was to prospectively investigate the diagnostic and prognostic impact of cardiac magnetic resonance (CMR) T1 mapping and validate it against left ventricular biopsies. Background Extracellular volume (ECV) expansion is a key feature of heart failure. CMR T1 mapping has been developed as a noninvasive technique to estimate ECV; however, the diagnostic and prognostic impacts of this technique have not been well established. Methods A total of 473 consecutive patients referred for CMR (49.5% female, age 57.8 ± 17.1 years) without hypertrophic cardiomyopathy, cardiac amyloidosis, or Anderson-Fabry disease were studied. T1 mapping with the modified Look-Locker inversion recovery (MOLLI) sequence was used for ECV calculation (CMR-ECV). For methodological validation, 36 patients also underwent left ventricular biopsy, and ECV was quantified by TissueFAXS analysis (TissueFAXS-ECV). To assess the prognostic value of CMR-ECV, its association with hospitalization for cardiovascular reasons or cardiac death was tested in a multivariable Cox regression model. Results TissueFAXS-ECV was 26.3 ± 7.2% and was significantly correlated with CMR-ECV (r = 0.493, p = 0.002). Patients were followed up for 13.3 ± 9.0 months and divided into CMR-ECV tertiles for Kaplan-Meier analysis (tertiles were ≤25.7%, 25.8% to 28.5%, and ≥28.6%). Significantly higher event rates were observed in patients with higher CMR-ECV (log-rank p = 0.013). By multivariable Cox regression analysis, CMR-ECV was independently associated with outcome among imaging variables (p = 0.004) but not after adjustment for clinical parameters. Conclusions CMR T1 mapping allows accurate noninvasive quantification of ECV and is independently associated with event-free survival among imaging parameters. Its prognostic value on top of established clinical risk factors warrants further investigation in long-term studies.

Background A genome wide association study has identified a robust risk locus for cardiovascular disease on 3q22.3. However, the mechanisms by which the [C]/[T] polymorphism rs9818870 increases cardiovascular risk are unknown. This forearm blood flow (FBF) study addressed the question if the genetic association with cardiovascular disease in patients is preceded by incipient vasodilator impairment in young, healthy carriers of this new risk locus on chromosome 3. Materials and methods After a pre-screening of 74 subjects 17 male healthy volunteers homozygous/heterozygous for a single nucleotide polymorphism (SNP) risk allele on 3q22.3 and a control group of 17 healthy volunteers not carrying the allele were included into this case–control study. Results Forearm vascular endothelium-dependent and -independent vasodilator responses were in the normal range in both groups, although endothelium-dependent FBF reactivity to acetylcholine was significantly higher in SNP carriers of the risk allele. Conclusion The augmented endothelium-dependent vasodilation of the forearm resistance vasculature does not support the presence of endothelial dysfunction in young SNP carriers and indicates that other mechanisms are responsible for the strong association between coronary artery diseases and the rs9818870 polymorphism, located on 3q22.3.

Aims Recent data indicate that right ventricular systolic dysfunction (RVSD) by cardiac magnetic resonance imaging (CMR) is a strong predictor of outcome in heart failure. However, the prognostic significance of RVSD by CMR in heart failure with preserved ejection fraction (HFpEF) is unknown. Methods and results We prospectively enrolled 171 HFpEF patients who underwent CMR in addition to invasive and non-invasive testing. RVSD, defined as right ventricular (RV) EF

Heart failure with preserved ejection fraction (HFpEF) affects more women than men, suggesting gender to play a major role in disease evolution. However, studies investigating gender differences in HFpEF are limited. In the present study we aimed to describe gender differences in a well-characterized HFpEF cohort. Consecutive HFpEF patients underwent invasive hemodynamic assessment, cardiac magnetic resonance imaging and exercise testing. Study endpoints were: cardiac death, a combined endpoint of HF hospitalization or cardiac death and all-cause death. 260 HFpEF patients were prospectively enrolled. Men were more compromised with regard to exercise capacity and had significantly more co-morbidities. Men had more pronounced pulmonary vascular disease with higher diastolic pressure gradients and a lower right ventricular EF. During follow-up, 9.2% experienced cardiac death, 33.5% the combined endpoint and 17.3% all-cause death. Male gender was independently associated with cardiac death, but neither with the combined endpoint nor with all-cause mortality. We detected clear gender differences in HFpEF patients. Cardiac death was more common among men, but not all-cause death. While men are more prone to develop a right heart phenotype and die from HFpEF, women are more likely to die with HFpEF.

Diffuse myocardial fibrosis is a key pathophysiologic feature in heart failure and can be quantified by cardiac magnetic resonance (CMR) T1 mapping. However, increases in myocardial free water also prolong native T1 times and may impact fibrosis quantification. Thus far, the impact of systemic patient volume status remains unclear. In this study, native T1 time by CMR was investigated in hemodialysis (HD) patients (n = 37) and compared with healthy controls (n = 35). Volume status was quantified by bioimpedance spectroscopy and correlated with CMR T1 time. While no differences between HD patients and controls were present with regard to age (p = 0.180), height (p = 0.535), weight (p = 0.559) and left ventricular (LV) ejection fraction (p = 0.273), cardiac size was significantly larger in HD patients (LV end-diastolic volume 164 ± 53 vs. 132 ± 26 ml, p = 0.002). Fluid overloaded HD patients had significantly longer native T1 times than normovolemic HD patients and healthy controls (1,042 ± 46 vs. 1,005 ± 49 vs. 998 ± 47 ms, p = 0.030). By regression analysis, T1 time was significantly associated with fluid status (r = 0.530, p = 0.009, post-HD fluid status). Our data strongly indicate that native CMR T1 time is significantly influenced by systemic volume status. As fluid overload is common in patients with cardiovascular diseases, this finding is important and requires further study.

Objectives This study sought to compare the prognostic power of left ventricular end-diastolic pressure (LVEDP) and pulmonary arterial wedge pressure (PAWP) in heart failure with preserved ejection fraction (HFpEF).

Objective Acute inflammation induced by administration of Escherichia coli lipopolysaccharide endotoxin (LPS) reduces plasma concentrations of vitamin C and impairs vascular endothelium-derived nitric oxide (NO) bioactivity. We tested the hypothesis that systemically administered high dose vitamin C restores the endogenous anti-oxidant potential and improves NO-dependent vasodilatation in the forearm vasculature. Design & setting 36 male subjects were enrolled in this balanced, placebo controlled cross-over study. Forearm blood flow (FBF) reactivity to acetylcholine (ACh) and glyceryl-trinitrate (GTN), a sensitive test for endothelial function, was assessed at baseline and 4 h after LPS-administration (20 IU/kg i.v). The effect of two different doses of intravenous vitamin C (Vitamin C-Injektopas®), 320 mg/kg and 480 mg/kg over 2 h, or placebo on forearm vascular function was studied after LPS. Main results LPS caused transient flu-like symptoms, decreased plasma vitamin C concentrations and reduced the ACh-dependent increase in FBF by up to 76%. Vitamin C at a mean plasma concentration of 3.2 or 4.9 mmol/L restored the response to ACh compared to baseline. Conclusion High dose systemic vitamin C recovers LPS-induced endothelium-dependent vasodilation in the forearm resistance vasculature. This provides a rationale for a further clinical study of the systemic vitamin C effect under inflammatory conditions.

Renin-angiotensin system inhibitors (RASi) aim to reduce the negative effects of Angiotensin (Ang) II, either by decreasing its production or by inhibiting its binding to the Ang II receptor Type 1 (AT1R) using angiotensin-converting enzyme inhibitors (ACEi) or Ang receptor blockers (ARB)

Two thirds of patients with heart failure and preserved ejection fraction (HFpEF) suffer from atrial fibrillation (AF). However, current evidence regarding safety of OAC in HFpEF is limited. We recorded bleeding events in a prospective HFpEF cohort over 8 years. Out of 328 patients (median age 71

Approximately 50% of patients presenting with clinical signs of heart failure are diagnosed with heart failure with preserved ejection fraction (HFpEF) [(1)][1]. Pulmonary hypertension (PH) is a common feature of HFpEF and predicts poor outcome. According to the diastolic pressure gradient (DPG)

Background Recent studies suggest that reduced right ventricular function is an important predictor of outcome in patients with heart failure and preserved ejection fraction (HFpEF). Because affected patients suffer from a broad spectrum of non-cardiac co-morbidities, it remains unclear, whether they actually die from right heart failure (RHF) or as a consequence of other conditions. Methods Consecutive patients with a confirmed diagnosis of HFpEF were enrolled in this prospective registry. Local and external medical records, as well as telephone interviews with relatives were used to ascertain modes of death. RHF was accepted as a mode of death, if the following criteria were met: 1. right ventricular dysfunction assessed by transthoracic echocardiography, and 2. clinical signs of right heart decompensation at the time of death. Results Out of 230 patients with complete follow-up, 16.5% ( n =38) died after a mean of 30±17months. 60.5% deaths were classified as cardiovascular and 34.2% as non-cardiovascular. In 5.3% patients, the reason for death remained unknown. Of the cardiovascular cases ( n =23), 91.4% of deaths were attributed to RHF, 4.3% died from stroke and 4.3% from sudden cardiac death. Of the non-cardiovascular deaths ( n =13), 46.2% of deaths were attributed to major infections and 38.4% deaths were related to cancer. Other reasons for death included ileus (7.7%) and major bleeding (7.7%). Conclusion In our well-characterised HFpEF cohort, more than half of all deaths could directly be attributed to RHF. The right ventricle seems to be a meaningful therapeutic target in a subset of patients.

Patients with heart failure with preserved ejection fraction have functional impairment resulting in reduced quality of life. Specific pathological mechanisms underlying symptoms have not yet been defined.The aim of this study was to identify hemodynamic and other patient-related variables that are associated with New York Heart Association (NYHA) functional class and to analyze functional class in perspective with other clinical, laboratory, imaging, and hemodynamic parameters with respect to its influence on outcomes.Between January 2011 and February 2015, 193 patients with confirmed heart failure with preserved ejection fraction were enrolled.Those in more advanced NYHA functional classes (III and IV; n = 136) were older (p = 0.008), had higher body mass indexes (p = 0.004), and had higher levels of N-terminal pro-brain natriuretic peptide (p = 0.001) compared with less symptomatic patients (NYHA class II; n = 57). Furthermore, parameters reflecting left ventricular diastolic dysfunction were more pronounced in advanced NYHA classes (early mitral inflow velocity/early diastolic mitral annular velocity; p = 0.023) as well as parameters reflecting right ventricular afterload (diastolic pulmonary artery pressure; p 0.001). By multivariate regression analysis, age (p = 0.007), body mass index (p = 0.002), N-terminal pro-brain natriuretic peptide (p 0.001), early mitral inflow velocity/mitral peak velocity of late filling (p = 0.031), and diastolic pulmonary artery pressure (p 0.001) were independently associated with advanced NYHA class. After 21.9 months of follow-up, 64 patients (33.2%) reached the combined endpoint, defined as hospitalization for heart failure and/or cardiac death. By multivariate Cox analysis, NYHA functional class was independently associated with outcome (hazard ratio: 2.133; p = 0.040), as well as N-terminal pro-brain natriuretic peptide (hazard ratio: 1.655; p 0.001) and impaired right ventricular function (hazard ratio: 2.360; p = 0.001).Symptoms of breathlessness in patients with heart failure with preserved ejection fraction are multifactorial and largely related to body mass index, left ventricular diastolic function, and the pulmonary vasculature. Clinically meaningful therapeutic interventions should target body weight, left ventricular stiffness, and concomitant pulmonary vascular disease.

Background. Asymmetric dimethylarginine (ADMA) is associated with macrovascular disease and possibly with microangiopathy in type 2 diabetes (T2DM). We tested the hypothesis that ADMA is related to diabetic retinopathy (DR) independently of macrovascular disease.Methods. This cross-sectional study included 127 T2DM patients selected to achieve equal distributions of patients with and without macrovascular disease in the groups with and without DR.Results. Patients with DR had increased ADMA, longer diabetes duration, and reduced glomerular filtration rate (GFR). ADMA correlated with GFR (; ), diabetes duration (; ), and age (; ). Logistic regression analysis revealed an association of ADMA with DR. After adjustment for macrovascular disease, this association remained significant (OR 1.48; 95% CI: 1.02–2.15; ). Inclusion of GFR and T2DM duration into the model abolished this significant relationship. GFR remained the only independent predictor for DR. A 10 mL/min/1.73 m2GFR decrease was associated with DR in a multivariate model (OR 1.30; 95% CI: 1.08–1.56; ).Conclusions. These findings indicate an association between ADMA and DR in T2DM independent of macrovascular disease. This relationship is modified by GFR, the only parameter significantly related to DR in multivariate analysis.

It is considered that the first properly controlled trial in history was performed by James Lind. This Scottish surgeon and ship’s doctor was the first who conducted a trial with an appropriately controlled design from a modern point of view. In 1747 when scurvy was a common disease among sailors James Lind administered different acidic substances to 12 sailors affected with scurvy to test who benefits most. Five pairs of the seamen were given vinegar, mustard and garlic purges, and elixir of vitriol. The sixth pair was given two oranges and one lemon per day and recovered within 6 days. Objective and reliable evaluation of appropriate treatments against diseases has become a great need in medical research especially in the last century. Today healthcare professionals are required to base their decisions on the highest level of evidence. Evidence based medicine aims to rationalize this decision process in medical treatment and legitimates a certain treatment - or rejects it. In the process of finding the best treatment available it became obvious that different kinds of clinical trials might not provide the same level of evidence and differences between study designs are more than trivial. Today clinical trials are currently seen to have the highest level of evidence and to be the “Gold Standard” in clinical research.

Background Previous work indicates that dilatation of the pulmonary artery (PA) itself or in relation to the ascending aorta (PA:Ao ratio) predicts pulmonary hypertension (PH). Whether these results also apply for heart failure with preserved ejection fraction (HFpEF) is unknown. In the present study we evaluated the diagnostic and prognostic power of PA diameter and PA:Ao ratio on top of right ventricular (RV) size, function, and septomarginal trabeculation (SMT) thickness by cardiovascular magnetic resonance (CMR) in HFpEF. Methods and Results 159 consecutive HFpEF patients were prospectively enrolled. Of these, 111 underwent CMR and invasive hemodynamic evaluation. By invasive assessment 64 % of patients suffered from moderate/severe PH (mean pulmonary artery pressure (mPAP) ≥30 mmHg). Significant differences between groups with and without moderate/severe PH were observed with respect to PA diameter (30.9 ± 5.1 mm versus 26 ± 5.1 mm, p

Background Diastolic dysfunction of the left ventricle is common but frequently under-diagnosed. Particularly in advanced stages affected patients may present with significant functional tricuspid regurgitation (TR) as the most prominent sign on echocardiography. The underlying left ventricular pathology may eventually be missed and symptoms of heart failure are attributed to TR, with respective therapeutic consequences. The aim of the present study was to determine prevalence and mechanisms underlying TR evolution in heart failure with preserved ejection fraction (HFpEF). Methods and results Consecutive HFpEF patients were enrolled in this prospective, observational study. Confirmatory diagnostic tests including echocardiography and invasive hemodynamic assessments were performed. Of the 175 patients registered between 2010 and 2014, 51% had significant (moderate or severe) TR without structural abnormalities of the tricuspid valve. Significant hemodynamic differences between patients with and without relevant TR were encountered. These included elevated pulmonary vascular resistance (p = 0.038), reduced pulmonary arterial compliance (PAC, p = 0.005), and elevated left ventricular filling pressures (p = 0.039) in the TR group. Multivariable binary logistic regression analysis revealed diastolic pulmonary artery pressure (p = 0.029) and PAC (p = 0.048) as independent determinants of TR. Patients were followed for 18.1±14.1 months, during which 32% had a cardiac event. While TR was associated with outcome in the univariable analysis, it failed to predict event-free survival in the multivariable model. Conclusions The presence of ´isolated´ functional TR should prompt the suspicion of HFpEF. Our data show that significant TR is a marker of advanced HFpEF but neither an isolated entity nor independently associated with event-free survival.

Objectives This study sought to define the prognostic significance and clinical determinants of the 6-min walk distance (6-MWD) in affected patients. Background Symptoms of exertional fatigue and dyspnea, as well as a reduced exercise tolerance, are cardinal features of pulmonary hypertension associated with heart failure and preserved ejection fraction (PH-HFpEF). Mechanisms limiting exercise capacity in this specific entity remain incompletely understood. Methods Consecutive patients with PH-HFpEF, as confirmed by right heart catheter, were enrolled in our prospective registry. Hospitalization for HF and/or death for cardiac reasons were defined as primary outcome. Multiple regression models were constructed to establish determinants of the 6-MWD. For quantification of left ventricular (LV) extracellular matrix (ECM), myocardial biopsies were taken from 18 patients. Results Between December 2010 and July 2013, 142 PH-HFpEF patients were included in the study. After a mean follow-up of 14.0 ± 10.0 months, 43 patients (30.3%) reached the combined endpoint. The 6-MWD was found to be an independent predictor of outcome and was influenced by a variety of clinical, echocardiographic, hemodynamic, laboratory, and pulmonary parameters. There was a significant inverse correlation between the 6-MWD and the extent of ECM in the LV myocardium. Conclusions Impaired exercise capacity in PH-HFpEF patients is explained by cardiac and noncardiac factors. The 6-MWD predicts outcome and may be a useful endpoint in clinical trials.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of pulmonary embolism that results from mechanical obstruction of proximal pulmonary vessels by non-resolving thromboemboli and distal arteriopahty due to non-occluded area overperfusion. Increased right ventricular (RV) afterload challenges the RV and leads to changes in its morphology and function: RV hypertrophy is followed by tricuspid regurgitation, dilatation and left-ward bowing of the interventricular septum. Sustained pressure overload results in RV failure and death.

Rationale: Asymmetric dimethylarginine (ADMA), a potent endogenous nitric oxide synthase inhibitor, is increased in pulmonary hypertension (PH), and associated with unfavorable outcome. We hypothesized that plasma ADMA may serve as a biomarker to monitor disease progression under PH-specific treatment. Methods: ADMA was measured at baseline and at least after 24 weeks of treatment in consecutive patients (pts) under advanced PH-targeted treatments. Therapy responders were defined by decrease of pulmonary vascular resistance (PVR) of at least 200dynes.cm-1.s-5, 6-minute walking distance > 380m, and improvement of WHO at follow-up and were compared with non-responders. Results: 51 consecutive patients (44 pts with pulmonary arterial hypertension and 7 patients with PH due to lung disease) were enrolled in this study. According to our definition; there were 16 non-responders, and 23 responders to treatments. 11 patients showed no change. ADMA plasma levels did not change significantly under treatment in the whole group. There was a significant drop of ADMA in responder group (p The decrease of ADMA correlated with the decrease of PVR (r=0.56, p Conclusions: ADMA parallels the hemodynamic benefit of PH-specific treatment in patients with PH of various etiologies. ADMA can serve as a biomarker for the effect of PH-specific treatments.