Felix Hofer

Purpose: A planar Perugini grade 1 scan is equivocal for transthyretin amyloid cardiomyopathy (ATTR-CM), has no dedicated management pathway and is biologically heterogeneous, spanning early or low-burden ATTR, AL amyloidosis and non-amyloid blood-pool activity. Rather than investigating grade 1 as a step toward amyloid confirmation, we characterized the clinical phenotype it marks and tested whether that phenotype, rather than amyloid, drives its prognosis. Methods: We studied 9,170 consecutive patients who underwent [ ^99m Tc]Tc-DPD bone scintigraphy between 2010 and 2020, graded on planar imaging by blinded expert consensus. Using an imaging-phenotype association (IPA) framework analogous to genome-wide association analysis, we related Perugini grade to 1,243 clinical, laboratory, echocardiographic, cardiac magnetic resonance and ICD-10 comorbidity variables from electronic health records, adjusting for age, sex and cancer history. The outcome was a composite of heart failure hospitalization or death. Results: Grade 1 occurred in 175 (1.9%) and grade ≥2 in 142 (1.6%) patients. Grade ≥2 reproduced the canonical infiltrative ATTR phenotype, with greater septal thickness, higher extracellular volume, neuropathy and atrial fibrillation, validating the framework. Grade 1 instead marked a non-infiltrative cardiometabolic phenotype dominated by hypertension, chronic ischemic heart disease, high BMI, anemia, reduced eGFR and atrial enlargement, with low extracellular volume and septal thickness arguing against meaningful infiltration. Grade 1 carried worse outcomes than grade 0 (adjusted HR 1.30, 95% CI 1.07 to 1.59). Within grade 1, a cardiometabolic phenotype defined by hypertension, high BMI and low hematocrit, with or without chronic ischemic heart disease, identified patients whose risk matched or exceeded that of grade ≥2 (median HR 2.46 versus HR 1.76), indicating that grade 1 prognosis is driven substantially by comorbid cardiometabolic disease rather than amyloid burden. Conclusions: Perugini grade 1 is neither uniform early amyloid nor a benign artifact but a mixed-etiology, predominantly non-infiltrative cardiometabolic phenotype that carries clinically meaningful risk. A simple cardiometabolic phenotype stratifies this risk, supporting reinterpretation of grade 1 and a management focus on cardiorenal comorbidity alongside selective amyloid workup. The IPA framework provides a scalable approach to characterizing cardiovascular imaging biomarkers.

Background: In the era of personalized medicine, tools for risk stratification after cardiovascular interventions are crucial to reduce mortality and morbidity, especially in the aging population. Biomarker-based approaches, in particular, have gained significant importance. Mid-regional pro-adrenomedullin (MR-proADM) represents an easily assessable biomarker that mirrors cardiac function and fibrosis. Therefore, we aimed to investigate the prognostic potential of MR-proADM in patients undergoing elective cardiac surgery. Methods: Patients undergoing elective cardiac bypass and/or valve surgery were prospectively enrolled between May 2013 and August 2018. The primary endpoint was the composite of hospitalization for heart failure (HHF) or cardiovascular (CV) mortality. Results: In total, 500 patients (146 female [29.2%]; median age 69.8 years (IQR 60.6–75.5 years) were included. Individuals were stratified into risk categories based on their MR-proADM values (Low Risk ≤ 0.63 nmol/L, Intermediate Risk > 0.63 and ≤0.84, High Risk > 0.84). A significant increase in 5-year event rates for HHF/CV mortality in patients in the high-risk category (Low Risk 8.6% vs. High Risk 37.7%, p < 0.001) was observed. MR-pro ADM showed an independent association with HHF/ CV mortality (adjusted HR of 3.43, 95% CI 1.83–6.42; p < 0.001 comparing the High-Risk group to the Low-Risk group). Conclusions: MR-pro ADM was found to be a strong and independent predictor for HHF/CV mortality in patients undergoing elective cardiac surgery. Considering a personalized diagnostic and prognostic work-up, a standardized preoperative evaluation of MR-proADM levels might help to identify patients at risk for major adverse events and early re-hospitalization.

Felix Hofer, Andreas Hammer, Eva Steinacher, Ulrike Baumer, Niema Kazem, Lorenz Koller, Bernhard Richter, Christian Hengstenberg, Patrick Sulzgruber, Alexander

Background: Fibroblast growth factor 23 (FGF‐23) is crucial in regulating phosphate and vitamin D metabolism and is moreover associated with an increased cardiovascular risk. The specific objective of this study was to investigate the influence of FGF‐23 on cardiovascular outcomes, including hospitalization for heart failure (HHF), postoperative atrial fibrillation, and cardiovascular death, in an unselected patient population after cardiac surgery. Methods and Results: Patients undergoing elective coronary artery bypass graft and/or cardiac valve surgery were prospectively enrolled. FGF‐23 blood plasma concentrations were assessed before surgery. A composite of cardiovascular death/HHF was chosen as primary end point. A total of 451 patients (median age 70 years; 28.8% female) were included in the present analysis and followed over a median of 3.9 years. Individuals with higher FGF‐23 quartiles showed elevated incidence rates of the composite of cardiovascular death/HHF (quartile 1, 7.1%; quartile 2, 8.6%; quartile 3, 15.1%; and quartile 4, 34.3%). After multivariable adjustment, FGF‐23 modeled as a continuous variable (adjusted hazard ratio for a 1‐unit increase in standardized log‐transformed biomarker, 1.82 [95% CI, 1.34–2.46]) as well as using predefined risk groups and quartiles remained independently associated with the risk of cardiovascular death/HHF and the secondary outcomes, including postoperative atrial fibrillation. Reclassification analysis indicated that the addition of FGF‐23 to N‐terminal pro‐B‐type natriuretic peptide provides a significant improvement in risk discrimination (net reclassification improvement at the event rate, 0.58 [95% CI, 0.34–0.81]; P P <0.001). Conclusions: FGF‐23 is an independent predictor of cardiovascular death/HHF and postoperative atrial fibrillation in individuals undergoing cardiac surgery. Considering an individualized risk assessment, routine preoperative FGF‐23 evaluation may improve detection of high‐risk patients.

Background: The study investigated the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing cardiac surgery and calculated a simplified biomarker score comprising suPAR, N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and age.Methods and Results: Biomarkers were assessed in a cohort of 478 patients undergoing elective cardiac surgery. After a median follow‐up of 4.2 years, a total of 72 (15.1%) patients died. SuPAR, NT‐proBNP and age were independent prognosticators of mortality in a multivariable Cox regression model after adjustment for EuroScoreII. We then calculated a simplified biomarker score comprising age, suPAR and NT‐proBNP, which had a superior prognostic value compared to EuroScoreII (Harrel's C of 0.76 vs. 0.72; P for difference = 0.02). Besides long‐term mortality, the biomarker score had an excellent performance predicting one‐year mortality and hospitalization due to heart failure.Conclusion: The biomarker suPAR and NT‐proBNP were strongly and independently associated with mortality in patients undergoing cardiac surgery. A simplified biomarker score comprising only three variables (age, suPAR and NT‐proBNP) performed better than the established EuroScoreII with respect to intermediate and long‐term outcome as well as hospitalization due to heart failure. As such, integration of established and upcoming biomarkers in clinical practice may provide improved decision support in cardiac surgery.

Aims: The study investigated the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) patients undergoing cardiac surgery and calculated a simplified biomarker score comprising suPAR, N-terminal pro B-type natriuretic peptide (NT-proBNP) and age. Methods and results: Biomarkers were assessed in a cohort of 478 patients undergoing elective cardiac surgery. After a median follow-up of 4.2 years a total of 72 (15.1%) patients died. SuPAR, NT-proBNP and age were independent prognosticators of mortality in a multivariable Cox regression model after adjustment for EuroScoreII. We then calculated a simplified biomarker score comprising age, suPAR and NT-proBNP, which had a superior prognostic value compared to EuroScoreII (Harrel's C of 0.76 vs 0.72; P for difference = 0.02). Besides long-term mortality, the biomarker score had an excellent performance predicting one-year mortality and hospitalization due to heart failure. Conclusion: The biomarker suPAR and NT-proBNP were strongly and independently associated with mortality in patients undergoing cardiac surgery. A simplified biomarker score comprising only 3 variables (age, suPAR and NT-proBNP) performed better than the established EuroScoreII with respect to intermediate and long-term outcome as well as hospitalization due to heart failure. As such, integration of established and upcoming biomarkers in clinical practice may provide improved decision support in cardiac surgery. Funding Acknowledgement: Type of funding sources: None.

Although a strong association of cardiogenic shock (CS) with in-hospital mortality in patients with acute coronary syndrome (ACS) is well established, less attention has been paid to its prognostic influence on long-term outcome. We evaluated the impact of CS in 1173 patients undergoing primary percutaneous coronary interventions between 1997 and 2009. Patients were followed up until the primary study endpoint (cardiovascular mortality) was reached. Within the entire study population, 112 (10.4%) patients presented with CS at admission. After initial survival, CS had no impact on mortality (non-CS: 23.5% vs. CS: 24.0%; p = 0.923), with an adjusted hazard ratio of 1.18 (95% CI: 0.77–1.81; p = 0.457). CS patients ≥ 55 years (p = 0.021) with moderately or severely impaired left ventricular function (LVF; p = 0.039) and chronic kidney disease (CKD; p = 0.013) had increased risk of cardiovascular mortality during follow-up. The present investigation extends currently available evidence that cardiovascular survival in CS is comparable with non-CS patients after the acute event. CS patients over 55 years presenting with impaired LVF and CKD at the time of ACS are at increased risk for long-term mortality and could benefit from personalized secondary prevention.

Aims: We aim to explore the relationship of heart failure (HF) and diabetes with cardiovascular (CV) death or hospitalization for HF (HHF) and to study the clinical utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected patient population with atrial fibrillation (AF). Methods and results: Patients with AF admitted to a tertiary academic center between January 2005 and July 2019 were identified through a search of electronic health records. We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, coronary artery disease, hypertension, smoking, C-reactive protein, and low-density lipoprotein cholesterol. To select the most informative variables, we performed a least absolute shrinkage and selection operator Cox regression with 10-fold cross-validation. In total, 7412 patients (median age 70 years, 39.7% female) were included in this analysis and followed over a median of 4.5 years. Both diabetes [adjusted (Adj.) HR 1.87, 95% CI 1.55–2.25] and HF (Adj. HR 2.57, 95% CI 2.22–2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared with patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all-cause death. NT-proBNP showed good discriminatory performance (area under the curve 0.78, 95% CI 0.77–0.80) and the addition of NT-proBNP to the covariates used for adjustment resulted in a significant area under the curve improvement (Δ = 0.04, P < 0.001). With least absolute shrinkage and selection operator, the strongest associations for CV death/HHF were obtained for NT-proBNP [HR 1.91 per 1-SD in log-transformed biomarker], HF (HR 1.72), and diabetes (HR 1.56). Conclusions: Diabetes and HF were independently associated with an increased risk of CV death/HHF in an unselected AF patient population, and NT-proBNP improved risk assessment. These findings suggest that AF patients with diabetes and/or HF should be managed not only for their risk of stroke and systemic embolic events but also for CV death/HHF.

Background: Left ventricular thrombus (LVT) is a rare but dreaded complication during the acute phase of acute coronary syndrome (ACS). However, profound data on long‐term outcome and associated antithrombotic treatment strategies of this highly vulnerable patient population are scarce in current literature.Methods: Patients presenting with ACS were screened for presence of LVT and subsequently included within a prospective clinical registry. All‐cause mortality and the composite of major adverse cardiac events (MACE) and thromboembolic events were defined as primary and secondary endpoint.Results: Within 43 patients presenting with LVT, thrombus resolution during patient follow‐up was observed in 27 individuals (62.8%). Patients that reached a resolution of LVT experienced lower incidence rates of death (−23.9%; p = .022), MACE (−37.8%; p = .005), and thromboembolic events (−35.2%; p = .008). Even after adjustment for clinical variables, thrombus resolution showed an independent inverse association with all‐cause death with a hazard ratio (HR) of 0.14 (95% CI: 0.03–0.75; p = .021) and as well with MACE with a HR of 0.22 (95% CI: 0.07–0.68; p = .008) and thromboembolic events with a HR of 0.22 (95% CI: 0.06–0.75; p = .015). Triple antithrombotic therapy (TAT) with ticagrelor/prasugrel showed a strong and independent association with thrombus resolution with an adjusted HR of 3.25 (95% CI: 1.22–8.68; p = .019) compared to other strategies.Conclusion: The presented data indicate a poor outcome of ACS patients experiencing LVT. In terms of a personalized risk stratification, thrombus resolution has a strong protective impact on both all‐cause death and MACE with the potential to tailor treatment decisions—including an intensified antithrombotic treatment approach—in this patient population.

Background: Fibroblast growth factor 23 (FGF-23) participates in phosphate and vitamin D metabolism and proved to be associated with an increased risk for fatal events in individuals presenting with cardiovascular disease. In the era of personalized medicine and individualized prognostication, the identification of novel risk markers seems of major importance in terms of state-of-the-art patient care. Since data on the prognostic potential of FGF-23 in individuals undergoing cardiac valve and/or coronary artery bypass graft (CABG) surgery remain scarce, we aimed to investigate the impact of FGF-23 on cardiovascular (CV) death in an unselected patient population after cardiac surgery. Methods: Within the present investigation, patients undergoing elective cardiac valve and/or CABG surgery were prospectively enrolled at the Department of Cardiac Surgery of our Medical University. Preoperative blood values were assessed immediately before the surgical intervention. FGF-23 concentrations were measured via FGF Quantikine ELISA Kit (R&D Systems, Minneapolis, USA). Patients were followed prospectively until the primary study endpoint (CV death) was reached. Cox regression models were calculated and adjusted for age, sex, diabetes, heart failure, body mass index, prior myocardial infarction, hypertension and coronary artery disease. Results: In total, 462 patients were included in the present analysis and followed over a median of 3.9 years. During follow-up 67 (14.5%) patients died. The patients' median age was 70 years (interquartile range [IQR] 60 to 75) and 133 (28.8%) were female. The median FGF level in the entire study population was 1.9 pmol/L (IQR 1.2 to 3.5). After stratification into tertiles (T) of FGF-23 (median FGF-23 T1: 0.95 pmol/L [IQR 0.65 to 1.19], T2: 1.93 pmol/L [IQR 1.64 to 2.28] T3: 4.80 pmol/L [IQR 3.54 to 8.09]), patients in the highest FGF-23 tertile had highest rates of CV death (T1: 4.8%, T2: 6.8%, T3: 19.1%; P-logrank <0.001; Figure A). Moreover, there was a strong association between FGF-23 and CV death (Adj. hazard ratio for 1-unit increase in standardized log-transformed biomarker 1.44, 95% CI: 1.19 to 1.75; P-value <0.001). The risk of CV death increased within higher tertiles of FGF-23 (T3: adj. HR 3.59 [95% CI 1.48–8.71], P-value= 0.005) (T1 was chosen as reference). FGF23 also showed good discriminatory performance (area under the curve [AUC] 0.69, 95% CI 0.61–0.77). Conclusion: FGF-23 proved to be a strong and independent predictor for CV death in individuals undergoing elective cardiac valve and/or CABG surgery. This biomarker may provide improved risk assessment and fosters individualized patient care in this highly vulnerable patient population in the era of personalized medicine. Funding Acknowledgement: Type of funding sources: None. Figure 1. Kaplan Meier curves