CMR detects decreased myocardial deformation in asymptomatic patients at risk for heart failure

AimsThe main management strategy of heart failure with preserved ejection fraction (HFpEF) is prevention since HFpEF is associated with many cardiovascular (CV) risk factors, especially since HFpEF is linked to a high risk for both mortality and recurrent heart failure (HF) hospitalizations. Therefore, there is a need for new tools to identify patients with a high risk profile early. Regional strain assessment by CMR seems to be superior in describing deformation impairment in HF. The MyoHealth score is a promising tool to identify cardiac changes early.Methods and resultsHeart failure patients irrespective of LVEF and asymptomatic controls were recruited, and CMR based measures were obtained. For this analysis the asymptomatic control group (n = 19) was divided into asymptomatic subjects without CV co-morbidities or evidence of cardiac abnormalities and (n = 12) and asymptomatic subjects with CV co-morbidities or evidence of cardiac abnormalities (n = 7) as well as patients with HFpEF (n = 19). We performed CMR scans at rest and during a stress test using isometric handgrip exercise (HG). Assessing the MyoHealth score at rest revealed preserved regional strain in 85 ± 9% of LV segments in controls, 73 ± 11% in at Risk subjects and 73 ± 8% in HFpEF patients. During stress the MyoHealth score was 84 ± 7% in controls, 83 ± 7 in at risk subjects and 74 ± 11 in HFpEF patients.ConclusionIn summary, we show for the first time that asymptomatic subjects with increased CV risk present with HFpEF like impaired myocardial deformation at rest, while they show results like controls under HG stress. The potential of preventive treatment in this group of patients merits further investigation in future.Clinical trial registration[https://drks.de/search/de/trial/DRKS00015615], identifier [DRKS00015615]

CMR detects decreased myocardial deformation in asymptomatic patients at risk for heart failure

Aims: The main management strategy of heart failure with preserved ejection fraction (HFpEF) is prevention since HFpEF is associated with many cardiovascular (CV) risk factors, especially since HFpEF is linked to a high risk for both mortality and recurrent heart failure (HF) hospitalizations. Therefore, there is a need for new tools to identify patients with a high risk profile early. Regional strain assessment by CMR seems to be superior in describing deformation impairment in HF. The MyoHealth score is a promising tool to identify cardiac changes early. Methods and results: Heart failure patients irrespective of LVEF and asymptomatic controls were recruited, and CMR based measures were obtained. For this analysis the asymptomatic control group (n = 19) was divided into asymptomatic subjects without CV co-morbidities or evidence of cardiac abnormalities and (n = 12) and asymptomatic subjects with CV co-morbidities or evidence of cardiac abnormalities (n = 7) as well as patients with HFpEF (n = 19). We performed CMR scans at rest and during a stress test using isometric handgrip exercise (HG). Assessing the MyoHealth score at rest revealed preserved regional strain in 85 +/- 9% of LV segments in controls, 73 +/- 11% in at Risk subjects and 73 +/- 8% in HFpEF patients. During stress the MyoHealth score was 84 +/- 7% in controls, 83 +/- 7 in at risk subjects and 74 +/- 11 in HFpEF patients. Conclusion: In summary, we show for the first time that asymptomatic subjects with increased CV risk present with HFpEF like impaired myocardial deformation at rest, while they show results like controls under HG stress. The potential of preventive treatment in this group of patients merits further investigation in future

Plasma Biomarker Profiling in Heart Failure Patients with Preserved Ejection Fraction before and after Spironolactone Treatment: Results from the Aldo-DHF Trial

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapeutic strategies are lacking. This study aimed to identify plasma proteins with pathophysiological relevance in HFpEF and with respect to spironolactone-induced effects. We assessed 92 biomarkers in plasma samples from 386 HFpEF patients—belonging to the Aldo-DHF trial—before (baseline, BL) and after one-year treatment (follow up, FU) with spironolactone (verum) or a placebo. At BL, various biomarkers showed significant associations with the two Aldo-DHF primary end point parameters: 33 with E/e’ and 20 with peak VO2. Ten proteins including adrenomedullin, FGF23 and inflammatory peptides (e.g., TNFRSF11A, TRAILR2) were significantly associated with both parameters, suggesting a role in the clinical HFpEF presentation. For 13 proteins, expression changes from BL to FU were significantly different between verum and placebo. Among them were renin, growth hormone, adrenomedullin and inflammatory proteins (e.g., TNFRSF11A, IL18 and IL4RA), indicating distinct spironolactone-mediated effects. BL levels of five proteins, e.g., inflammatory markers such as CCL17, IL4RA and IL1ra, showed significantly different effects on the instantaneous risk for hospitalization between verum and placebo. This study identified plasma proteins with different implications in HFpEF and following spironolactone treatment. Future studies need to define their precise mechanistic involvement

Diagnostik und Früherkennung von Herzinsuffizienz mit erhaltener Auswurffraktion (HFpEF): Von der Validierung der Diagnose zur Entwicklung innovativer Deformitätsanalysen mittels Kardio-MRT

Diese Arbeit untersucht Herzinsuffizienz, insbesondere HFpEF, und zeigt innovative Kardio- MRT-Methoden für Diagnostik und Präventions- sowie Behandlungsstrategien auf. HFpEF ist eine Erkrankung mit limitierten Behandlungsmöglichkeiten und komplexer Diagnostik und Risikostratifizierung. Der HFA-PEFF-Algorithmus verspricht eine adäquate Diagnosestellung der HFpEF. Dass dieser Algorithmus zuverlässige Prognosen für Morbidität und Mortalität bei HFpEF-Patient*innen bietet, wurde untersucht und bestätigt. Aufgrund der limitierten therapeutischen Maßnahmen steht hier vor allem die Prävention im Vordergrund der Behandlungsstrategie. Die Notwendigkeit eines besseren Managements von HFpEF ergibt sich auch aus den gesundheitsbezogenen Kosten der ambulanten HFpEF-Patient*innen der ALDO-DHF-Studie, bei denen Krankenhausaufenthalte die Hauptkostenfaktoren sind. Um eine Risikostratifizierung für HFpEF zu etablieren, wurde die Myokarddeformation im Kontraktionsablauf mittels Kardio-MRT in höherer Granularität untersucht, wobei einzelne myokardiale Segmente und das resultierende Verteilungsmuster der Deformationsveränderung ausgewertet wurden. Mit dieser Methode können Proband*innen mit kardiovaskulären Risikofaktoren von denen ohne Risikofaktoren unterschieden werden, da sie in Ruhe ein Verteilungsmuster wie HFpEF-Patient*innen und unter Belastung ein Muster wie Gesunde zeigen. Zudem konnte der Trend identifiziert werden, dass dieser Verteilungsparameter auch die funktionale Kapazität von HI-Patientinnen abbildet, selbst wenn die LVEF erhalten ist. Die gewonnenen Erkenntnisse könnten dazu beitragen, die Versorgung von Patient*innen mit HI zu verbessern, indem sie neue Wege zur Identifizierung von Risikopatient*innen und verbesserte Diagnosemethoden aufzeigen, die zu präventiven Behandlungsstrategien führen können. Die Validierung der prognostischen Bedeutung von HI-Parametern des Kardio-MRT in Interventionsstudien bildet den nächsten Schritt, da neben Validierung auch eine klinische Konsequenz prospektiv mit den Methoden verbunden und untersucht wird. Diese Kombination verspricht, die Behandlung von HFpEF-Patient*innen zu optimieren und dem Kardio-MRT einen angemessenen Stellenwert im Management-Prozess der Erkrankten und der von HI Bedrohten zu verleihen

Synkopen – Risikofaktor bei Herzinsuffizienz?

Einleitung: Synkopen sind ein häufiges Symptom bei PatientInnen mit kardiovaskulären Erkrankungen. Sie sind gemeinhin definiert als vorübergehende Bewusstlosigkeit aufgrund einer cerebralen Minderperfusion mit plötzlichem Beginn, kurzer Dauer und vollständigem Rückgang der Symptomatik. Faktoren, die mit Synkopen einhergehen und diese bedingen, schließen kardiale Arrhythmien, vegetative Dysregulation und hämodynamische Inbalancen ein. Diese sind insbesondere bei PatientInnen mit Herzinsuffizienz (HI) vorhanden. Daher glauben wir, dass eine Synkopen-Anamnese prädiktiv hinsichtlich der Gesamtmortalität sowie der Zeit bis zur nächsten Hospitalisierung bei HI-PatientInnen ist. Methoden: Wir haben Daten prospektiver, bundesweiter und multizentrischer Studien des Kompetenznetzwerkes Herzinsuffizienz (KNHI) zusammengeführt. Das KNHI schloss 11.335 StudienteilnehmerInnen ein, hierunter befanden sich PatientInnen mit Herzinsuffizienz, PatientInnen mit bekannten Risikofaktoren und auch gesunde StudienteilnehmerInnen. Aus diesem Datenpool haben wir alle Studien mit einer Beobachtungszeit kürzer als 10 Jahre sowie StudienteilnehmerInnen mit fehlenden Kernparametern ausgeschlossen. StudienteilnehmerInnen mit der Diagnose einer HI wurden in HI mit reduzierter Auswurffraktion (EF, HFrEF), mit mittelgradig eingeschränkter EF (HFmrEF) sowie mit erhaltener EF (HFpEF) eingeteilt. StudienteilnehmerInnen ohne HI werteten wir als Kontrollgruppe. Als Endpunkte wurden die Zeit bis zum Tod jeglicher Genese sowie die Zeit bis zur ersten allgemeinen Hospitalisierung definiert. Ergebnisse: Es wurden 3.594 StudienteilnehmerInnen analysiert, hiervon entfielen 2130 auf PatientInnen mit HI (HFrEF: n = 1564, HFmrEF: n = 314 und HFpEF: n = 252) und 1464 auf PatientInnen ohne HI, die wir als Kontrollgruppe deuteten. 14,6% der 3.594 analysierten Studienteilnehmer hatten bei Studieneinschluss eine Synkope in der Anamnese. PatientInnen mit HI zeigten häufiger eine Synkope als die Kontrollgruppe (p < 0,001). StudienteilnehmerInnen mit Synkope, unabhängig von HI, starben früher als diejenigen ohne Synkope [2,4% vs. 37,9%, hazard ratio (HR) = 1,21; 99% Konfidenzintervall (KI; 0,99; 1,46); p = 0,04], sie verlebten auch eine kürzere Zeit bis zur ersten Hospitalisierung [HR = 1.39, 99% KI (1.18, 1.64), P < 0.001]. Die HI-Subgruppen einzeln betrachtend, konnte dieser Effekt bei HFrEF auch gezeigt werden (Überleben: HR = 1,40; 99% KI (1,12; 1,74), P < 0,001), bei HFmrEF und HFpEF allerdings nicht. Die weiterführenden multivariaten Analysen zeigten, dass HFrEF-PatientInnen mit Synkope ein erhöhtes Risiko aufzeigten und häufiger an weiteren kardiovaskulären Risikofaktoren litten, sodass der Effekt der Synkope sich durch diese erklären ließ. Zusammenfassung: In einer großen HI-Population konnte gezeigt werden, dass eine stattgehabte Synkope ein klinischer, einfach zu erfassender Prädiktor für sowohl das Gesamtüberleben als auch das Hospitalisierungs-freie Überleben der PatientInnen mit HFrEF ist.Background: Syncopal episodes are a frequent complication of cardiovascular disorders, including heart failure (HF). Syncopes are defined as a transient loss of consciousness due to a cerebral hypoperfusion characterized by a rapid onset, short duration, and spontaneous complete recovery. Factors associated with syncopes include cardiac arrhythmias, autonomic dysfunction and hemodynamic disturbances. These factors are also associated with heart failure (HF). Therefore, we hypothesized that presence of a history of syncope (HoS) has an impact on overall and hospitalization-free survival in patients suffering from HF. Methods: We pooled the data of prospective, nationwide, multicentre studies conducted within the framework of the German Competence Network for Heart Failure including 11 335 subjects. These subjects include patients with heart failure, patients without heart failure but known risk factors and healthy subjects. We excluded studies with follow-up periods <10 years as well as patients with missing key parameters or follow-up data. Patients with HF were grouped by the ESC HF entities HF with reduced ejection fraction (EF) which include HF with reduced EF (HFrEF), HF with mid-range EF (HFmrEF) and HF with preserved EF (HF), subjects without HF were considered as controls. The endpoints were defined as time to mortality from any cause or time to first hospitalization (hospitalization-free survival). Results: Finally, we analyzed 3594 eligible subjects, including 2130 patients with HF (HFrEF: n = 1564; HFmrEF: n = 314; HFpEF: n = 252) and 1464 subjects without HF considered as controls. Of all the subjects, 14.6% reported a HoS. HoS was more frequent in the overall cohort of patients with HF compared with controls (P < 0.001). Subjects with HoS showed a worse overall survival [42.4% vs. 37.9%, hazard ratio (HR) = 1.21, 99% confidence interval (0.99, 1.46), P = 0.04] and less days alive until the first hospitalization [HR = 1.39, 99% confidence interval (1.18, 1.64), P < 0.001] compared with subjects without HoS – independent of HF. Patients with HFrEF with HoS died earlier [30.3% vs. 41.6%, HR = 1.40, 99% confidence interval (1.12, 1.74), P < 0.001] and lived fewer days out of hospital than those without HoS. We could not find these changes in mortality and hospital-free survival in the HFmrEF and HFpEF cohorts. HoS represented a clinically high-risk profile within the HFrEF group – combining different risk factors. Further analyses showed that among patients with HFrEF with HoS, known cardiovascular risk factors were more prevalent. In a large cohort of patients with HF these constellations of the risk factors explained the effect of HoS in a multivariable Cox regression models. Conclusion: In a large HF population, it is shown that HoS was found to be a clinically and easily accessible predictor of both overall and hospitalization-free survival in patients with HFrEF and should thus routinely be assessed

Economic impact of heart failure with preserved ejection fraction: insights from the ALDO‐DHF trial

Aims Although heart failure (HF) with preserved ejection fraction (HFpEF) is a leading cause for hospitalization, its overall costs remain unclear. Therefore, we assessed the health care-related costs of ambulatory HFpEF patients and the effect of spironolactone. Methods and results The aldosterone receptor blockade in diastolic HF trial is a multicentre, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2011 at 10 sites in Germany and Austria that included 422 ambulatory patients [mean age: 67 years (standard deviation: 8); 52% women]. All subjects suffered from chronic New York Heart Association (NYHA) class II or III HF and preserved left ventricular ejection fraction of 50% or greater. They also showed evidence of diastolic dysfunction. Patients were randomly assigned to receive 25 mg of spironolactone once daily (n = 213) or matching placebo (n = 209) with 12 months of follow-up. We used a single-patient approach to explore the resulting general cost structure and included medication, number of general practitioner and cardiologist visits, and hospitalization in both acute and rehabilitative care facilities. The average annual costs per patient in this cohort came up to euro1, 118 (± 2,475), and the median costs were euro332. We confirmed that the main cost factor was hospitalization and spironolactone did not affect the overall costs. We identified higher HF functional class (NYHA), male patients with low haemoglobin level, with high oxygen uptake (VO(2)max) and coronary artery disease, hyperlipidaemia, and atrial fibrillation as independent predictors for higher costs. Conclusions In this relatively young, oligosymptomatic, and with regard to the protocol without major comorbidities patient cohort, the overall costs are lower than expected compared with the HFrEF population. Further investigation is needed to investigate the impact of, for example, comorbidities and their effect over a longer period of time. Simultaneously, this analysis suggests that prevention of comorbidities are necessary to reduce costs in the health care system

The diagnostic and prognostic value of galectin‐3 in patients at risk for heart failure with preserved ejection fraction: results from the DIAST‐CHF study

Aims: Galectin-3 (Gal-3) predicts long-term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal-3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal-3 and clinical manifestations of HFpEF, the relationship between Gal-3 and all-cause mortality, or the composite of cardiovascular hospitalization and death. Methods and results: The observational Diast-CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal-3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non-cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut-off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal-3, and the diagnostic power to detect HFpEF was superior to N-terminal pro-brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal-3 was associated with risk factors for HF (P < 0.001). Higher levels of Gal-3 predicted incident HFpEF (P < 0.05), adjusted all-cause mortality (P < 0.001), and the adjusted composite of cardiovascular hospitalization and death (P < 0.001), both independent from N-terminal pro-brain natriuretic peptide. Conclusions: Gal-3 differentiated patients with HFpEF from an overall cohort of well-characterized patients with risk factors for HFpEF. Independent of other factors, baseline Gal-3 levels were associated with a higher risk for incident HFpEF, mortality, or the composite of cardiovascular hospitalization and death over 10 year follow-up. In conjunction with clinical parameters, Gal-3 adds a statistically significant value for the diagnosis of HFpEF within this study, yet the clinical relevance remains debatable

Multilayer myocardial strain improves the diagnosis of heart failure with preserved ejection fraction

Aims: The diagnostic and treatment of patients with heart failure with preserved ejection fraction (HFpEF) are both hampered by an incomplete understanding of the pathophysiology of the disease. Novel imaging tools to adequately identify these patients from individuals with a normal cardiac function and respectively patients with HF with reduced EF are warranted. Computing multilayer myocardial strain with feature tracking is a fast and accurate method to assess cardiac deformation. Our purpose was to assess the HFpEF diagnostic ability of multilayer strain parameters and compare their sensitivity and specificity with other established parameters. Methods and results: We included 20 patients with a diagnosis of HFpEF and, respectively, 20 matched controls. We assessed using feature-tracking cardiac magnetic resonance longitudinal and circumferential myocardial strain at three distinct layers of the myocardium: subendocardial (Endo-), mid-myocardial (Myo-), and subepicardial (Epi-). Comparatively, we additionally assessed various others clinical, imaging, and biochemical parameters with a putative role in HFpEF diagnostic: left ventricular end-diastolic volume (LVEDV), left ventricular mass (LVM), interventricular septum (IVS) wall thickness and free wall thickness, left atrial volume and strain, septal and lateral mitral annular early diastolic velocity (e`), E/e' ratio, and plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Global longitudinal strain (GLS) is significantly impaired at Endo (-20.8 ± 4.0 vs. -23.2 ± 3.4,P = 0.046), Myo- (-18.0 ± 3.0 vs. -21.0 ± 2.5,P = 0.002), and Epi- (-12.2 ± 2.0 vs. -16.2 ± 2.5,P < 0.001) levels. Compared with any other imaging parameter, an Epi-GLS lower than 13% shows the highest ability to detect patients with HFpEF [area under the curve (AUC) = 0.90 (0.81-1),P < 0.001] and in tandem with NT-proBNP can diagnose with maximal sensibility (93%) and specificity (100%), patients with HFpEF from normal, composed variable [AUC = 0.98 (0.95-1),P < 0.001]. In a logistic regression model, a composite predictive variable taking into account both GLS Epi and NT-proBNP values in each individual subject reached a sensitivity of 89% and a specificity of 100% with an AUC of 0.98 (0.95-1),P < 0.001, to detect HFpEF. Conclusions: Epi-GLS is a promising new imaging parameter to be considered in the clinical assessment of HFpEF patients. Given its excellent specificity, in tandem with a highly sensitive parameter such as NT-proBNP, Epi-GLS holds the potential to greatly improve the current diagnostic algorithms

Plasma Biomarker Profiling in Heart Failure Patients with Preserved Ejection Fraction before and after Spironolactone Treatment: Results from the Aldo-DHF Trial

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapeutic strategies are lacking. This study aimed to identify plasma proteins with pathophysiological relevance in HFpEF and with respect to spironolactone-induced effects. We assessed 92 biomarkers in plasma samples from 386 HFpEF patients—belonging to the Aldo-DHF trial—before (baseline, BL) and after one-year treatment (follow up, FU) with spironolactone (verum) or a placebo. At BL, various biomarkers showed significant associations with the two Aldo-DHF primary end point parameters: 33 with E/e’ and 20 with peak VO2. Ten proteins including adrenomedullin, FGF23 and inflammatory peptides (e.g., TNFRSF11A, TRAILR2) were significantly associated with both parameters, suggesting a role in the clinical HFpEF presentation. For 13 proteins, expression changes from BL to FU were significantly different between verum and placebo. Among them were renin, growth hormone, adrenomedullin and inflammatory proteins (e.g., TNFRSF11A, IL18 and IL4RA), indicating distinct spironolactone-mediated effects. BL levels of five proteins, e.g., inflammatory markers such as CCL17, IL4RA and IL1ra, showed significantly different effects on the instantaneous risk for hospitalization between verum and placebo. This study identified plasma proteins with different implications in HFpEF and following spironolactone treatment. Future studies need to define their precise mechanistic involvement