Role of Comorbidities in Chronic Heart Failure (RoC-HF) Study
Conditions: Heart Failure, Comorbidity, Osteoporosis, Pulse Wave Analysis, Blood Pressure Monitoring, Ambulatory, Osteoporotic Fractures
Sponsor: Medical University of Graz

Role of Comorbidities in Chronic Heart Failure (RoC-HF) Study 
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Studien ID 01/2016/RoC-HF/KANV 
 
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Role of Comorbidities in Chronic Heart Failure  
(RoC-HF) Study – Study Protocol 
 
EC-No: 28-467 ex 15/16 
 
ClinicalTrials.gov Identifier: NCT02922478 
Version: 6.0 
 
 
Date: 07th Aug 2018 
Prinicipal Investigators: 
KLEMENS ABLASSER, MD* 
Department of Cardiology, Medical University Graz, Auenbruggerplatz 15, 8036 
Graz, email: klemens.ablasser@medunigraz.at 
NICOLAS VERHEYEN, MD 
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 
Graz, email: nicolas.verheyen@medunigraz.at 
*klinischer Prüfarzt 
 
Heart Failure Outpatient Clinic, Department of Cardiology 
FRITZ FRUHWALD, MD, PROF 
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 
Graz, email: fritz.fruhwald@medunigraz.at 
 
X-Ray, Department of Radiology 
JOHANNES SCHMID, MD 
Department of Radiology, Medical University of Graz, Auenbruggerplatz 9, 8036 
Graz, email: Johannes.schmid@meduingraz.at 
 
Osteoporosis Outpatient Clinic, Division of Endocrinology 

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ASTRID FAHRLEITNER-PAMMER, MD 
Division of Endocrinology, Department of Internal Medicine, Medical University of Graz, 
Auenbruggerplatz 15, 8036 Graz, email: astrid.fahrleitner@medunigraz.at 
 
Department of Cardiology 
DIRK von LEWINSKI, MD, PROF 
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 
Graz, email: dirk.von-lewinski@medunigraz.at 
 
Contribution to Study Design 
ANDREAS TOMASCHITZ, MD 
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 
Graz, email: andreas.tomaschitz@medunigraz.at 
 
STEFAN PILZ, MD, PhD, PROF 
Division of Endocrinology, Department of Internal Medicine, Medical University of Graz, 
Auenbruggerplatz 15, 8036 Graz, email: stefan.pilz@medunigraz.at 
 
 

Role of Comorbidities in Chronic Heart Failure (RoC-HF) Study 
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Table of Contents  
 
Table of Contents .................................................................................................................................... 3 
Abbreviations .......................................................................................................................................... 5 
1. 
Protocol Synopsis ............................................................................................................................ 6 
2. 
Introduction ..................................................................................................................................... 8 
3. 
Study aims ..................................................................................................................................... 10 
4. 
Relevance ...................................................................................................................................... 10 
5. 
Study population ........................................................................................................................... 11 
a. 
Recruitment ............................................................................................................................... 11 
b. 
Inclusion criteria ........................................................................................................................ 11 
c. 
Exclusion criteria ....................................................................................................................... 11 
d. 
Premature discontinuation of study participation .................................................................... 12 
6. 
Investigational Plan ....................................................................................................................... 12 
a. 
Study design .............................................................................................................................. 12 
b. 
Study schedule .......................................................................................................................... 13 
c. 
Study visits ................................................................................................................................. 13 
Visit 1 ............................................................................................................................................. 13 
Visit 2 ............................................................................................................................................. 14 
d. 
Study procedures ...................................................................................................................... 14 
Blood/urine sampling – immediate determination....................................................................... 14 
Blood/urine sampling – biobanking .............................................................................................. 17 
Echocardiography .......................................................................................................................... 18 
ECG ................................................................................................................................................ 18 
Assessment of medical history ...................................................................................................... 18 
Assessment of medication history ................................................................................................ 19 
Pregnancy test ............................................................................................................................... 20 
Physical examination ..................................................................................................................... 20 
Questionnaires .............................................................................................................................. 20 
24-hours ambulatory blood pressure monitoring (ABPM) ........................................................... 20 
X-ray of the spine .......................................................................................................................... 21 
Vital signs (office blood pressure and heart rate) ......................................................................... 22 
Hand Grip Strength ........................................................................................................................ 22 

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4-meter Gait Speed test ................................................................................................................ 22 
PWA ............................................................................................................................................... 23 
PWV ............................................................................................................................................... 23 
DXA-scan ........................................................................................................................................ 23 
6. 
Study medication ........................................................................................................................... 24 
7. 
Randomization............................................................................................................................... 24 
8. 
Ethical considerations/safety ........................................................................................................ 24 
9. 
Sample size calculation .................................................................................................................. 25 
10. 
Statistical analyses ..................................................................................................................... 26 
11. 
Data processing ......................................................................................................................... 26 
12. 
Data access ................................................................................................................................ 27 
13. 
Responsibilities and competences ............................................................................................ 27 
14. 
Literature ................................................................................................................................... 27 
 
 
 
 

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Abbreviations 
ABPM, ambulatory blood pressure monitoring 
CI, clinical investigator 
DXA, dual energy X-ray absorptiometry 
PWA, pulse wave analysis 
PWV, pulse wave velocity 
HFpEF, heart failure with preserved ejection fraction 
HFrEF, heart failure with reduced ejection fraction 
 
 

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1. Protocol Synopsis 
Studien ID: 01/2016/ROC-HF/KANV 
Version: 6.0 
Date: 07. Aug 2018 
 
Study title: 
Role of Comorbidities in Chronic Heart Failure (RoC-HF) Study 
Study aims: 
Aims:  
 
To quantify the prevalence of osteoporosis in HFrEF  (primary aim) 
 
To quantify the prevalence of vertebral fractures in HFrEF (primary aim) 
 
To quantify the 24-hour central blood pressure in HFrEF (secondary aim) 
 
To quantify arterial stiffness in HFrEF (secondary aim) 
Exploratory aims:  
 
To elucidate the role of the bone-vascular axis in HFrEF 
o Relationship between bone metabolism and cardiac systolic function in dependence 
of vascular status 
o Relationship between bone metabolism and cardiac diastolic function in dependence 
of vascular status 
 
To elucidate the role of central arterial pressures and cardiac function in HFrEF  
 
To elucidate the relationship between arterial stiffness and cardiac stiffness in HFrEF 
 
To find or apply novel blood- or urine-derived biomarkers that may improve our 
understanding of mechanisms linking heart and bone pathologies. 
Study design: 
Longitudinal, prospective, single-center, epidemiological cohort study. 
Study procedures will be performed at the Medical University of Graz, Graz, Austria: Division of 
Endocrinology (DXA scans), Department of Radiology (X-ray) and Department of Cardiology (all other 
procedures). 

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Duration of active study participation: 2 x 4 hours on two separate days, follow-up visits planned as 
part of a separate protocol 
Study population: 
Male or female subjects with stable chronic heart failure with reduced ejection fraction 
Number of participants: 205, 
Inclusion criteria:  
1. 
Age >= 18 
2. 
NYHA class II-IV symptoms 
3. 
Left ventricular ejection < 50% at Visit 1 
4. 
Treatment according to current Heart Failure Guidelines of the European Society of 
Cardiology 
5. 
Willingness and ability to provide signed informed consent form (ICF) prior to participation in 
any study-related procedures 
6.  
Previous diagnosis of heart failure with reduced ejection fraction defined as symptomatic left 
ventricular ejection fraction < 40% requiring optimization of heart failure therapy 
 
Exclusion criteria: 
1. 
Unplanned hospitalization within 1 month prior to the Baseline Visit. 
2. 
Discontinuation or initiation of a pharmacologic or device treatment for HFrEF within 1 
month prior to the baseline visit. 
3. 
Coronary or peripheral revascularization procedures, valvular procedures, OR any major 
surgical procedure within 3 months prior to the Screening Visit. 
4. 
Acute coronary syndrome (ACS), stroke or transient ischemic attack (TIA) within 3 months 
prior to the Screening Visit. 
5. 
Any acute illness 
6. 
Disease reducing life expectancy to <1 year, except HFrEF 
7. 
Recipient of any organ transplant 
8. 
Primary significant valve disease (at least moderate to severe valve disease) 
 
 

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2. Introduction 
Chronic Heart failure with reduced ejection fraction (HFrEF) is a major health problem, due to high 
and increasing prevalence with high morbidity and mortality (1). Currently, approximately 250.000 to 
300.000 people in Austria have a diagnose of heart failure, a disease with a two-year mortality that is 
higher than in most patients with cancer (2). Around 50% of all patients hospitalized with heart 
failure have a serious event within 60 days of discharge (3). Patients with HFrEF are exposed to a 
death rate of up to 141 deaths per 1000 patient-years. After hospitalization for heart failure reported 
median survival range between 1.3 and 2.4 years (4); Ninety percent of heart failure patients die 
from cardiovascular causes; it is, however, important to acknowledge that co-morbidities crucially 
contribute to disease progression (5, 6) and the number of non-cardiac co-morbidities predicts all-
cause hospitalizations and even short-term mortality (6, 7). 
There are many etiologies leading to HFrEF and heart failure is more often considered to be a 
symptom with many co-morbidities influencing the prognosis, rather than an isolated cardiac 
dysfunction. The most common etiology leading to HFrEF is coronary artery disease (CAD). In 
randomized clinical heart failure trails 68% of patients presented with ischemic cardiomyopathy (8). 
In Europe the ischemic cardiomyopathy is believed to be the primary etiology in 41 % of chronic 
heart failure patients (9). Classic Risk factors for CAD include arterial hypertension, diabetes, 
smoking, obesity and hypercholesteremia. Central hemodynamic markers, such as central blood 
pressure, and measurements of arterial stiffness have shown independent and additive prognostic 
value for cardiovascular risk in the general population (10, 11), in patients with arterial hypertension 
(12, 13) and in patients with HFpEF (14). However this has not been shown in HFrEF patient.  
The second most common reported HFrEF is dilative cardiomyopathy attributed to about 25% of 
chronic heart failure patients. Dilative cardiomyopathy is a descriptive term and has several 
underlying causes including inflammatory cardiomyopathy or toxic associated cardiomyopathy. CAD 
is often not present and does not significantly contribute to the progression of the disease. Arterial 
hypertension is thought to be risk factor for the development and progression of dilative 
cardiomyopathy. However little is known about the central blood pressures or arterial stiffness in this 
subset of patients. 
 
HFrEF is associated with altered bone metabolism and novel evidence from our research group 
strongly suggests that bone metabolism interferes with cardiac function. However, the prevalence of 
altered bone metabolism and osteoporosis as well as the link with cardiac function has not been 
analyzed in patients with chronic heart failure. Given that bone metabolism in patients with HFrEF 
responds to hemodynamic changes (15), vascular function may play a mediating role in the bone-

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heart axis. However, epidemiological studies totally lack to disentangle these complex relationships 
in HFrEF. 
The role of bone disease in this context has attracted increasing attention. Experience of a hip 
fracture doubles the mortality rate in heart failure patients (16) Moreover, treatment of osteoporosis 
after hip fracture reduced mortality in the HORIZON trial (17). Bone strength is crucially determined 
by bone metabolism. The role of bone metabolism in HFrEF is, however, completely unknown.  
 
Figure 1: Risk for all-cause hospitalization as a function of number of non-cardiac co-morbidities in 
patients with heart failure (7).  
Increasing evidence suggests that bone should be regarded as an endocrine organ. Of note, novel 
cross-sectional data from our research group and others point towards an independent link between 
bone metabolism and cardiac function. Proposed mechanistic links include cardiovascular effects of 
bone-derived peptides that are increasingly secreted in the course of HFrEF. These include effects on 
blood pressure, glucose metabolism or vascular calcification which may further promote cardiac 
remodeling and deterioration of cardiac function. The clinical relevance of these mechanistic links for 
cardiovascular outcomes in HFrEF remains elusive in large parts. This is due to the fact that available 
longitudinal analyses are limited by their retrospective approach and, importantly, the lack of 
profound profiling of study participants: studies on HFrEF patients lack important baseline 
information on bone characteristics such as bone mineral density or prevalence of vertebral 
fractures. Thus, current evidence is insufficient to fully enlighten the role of disturbed bone 
metabolism and bone status in HFrEF. The current “Role of Co-morbidities in Heart Failure”(RoC-HF 
study) is therefore designed to address the question whether disturbances in bone metabolism affect 
cardiac function and cardiovascular outcomes in a highly standardized cohort of HFrEF patients with 
comprehensive assessment of bone/ mineral metabolism, fracture status and bone mineral density 
at baseline. 

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Sample size calculation: 
Based on previous epidemiological studies we expect a prevalence of osteoporosis in RoC-HF of 20 % 
(95% confidence interval: 14 -26). Calculating with a significance level of 5% and a two-sided P-value 
leads to a number of 171 participants to be analyzed. Calculating with 20% unavailable data due to 
invalid ABPM, missing laboratory values or other missing parameters, we will need to enroll 205 
subjects in total. 
3. Study aims 
This study aims to create a large and previously unavailable database of patients with stable HFrEF 
with comprehensive assessment of bone, skeletal and vascular status. RoC-HF will facilitate cross-
sectional and, eventually, longitudinal mechanistic epidemiological analyses to disentangle the role 
of the bone- vascular axis in HFrEF. 
Aims:  
 
To quantify the prevalence of osteoporosis in HFrEF  
 
To quantify the 24-hour central blood pressure in HFrEF 
 
To quantify arterial stiffness in HFrEF 
Exploratory aims:  
 
To elucidate the role of the bone-vascular axis in HFrEF 
o Relationship between bone metabolism and cardiac systolic function in dependence 
of vascular status 
o Relationship between bone metabolism and cardiac diastolic function in dependence 
of vascular status 
 
To elucidate the role of central arterial pressures and cardiac function in HFrEF  
 
To elucidate the relationship between arterial stiffness and cardiac stiffness in HFrEF 
 
To find or apply novel blood- or urine-derived biomarkers that may improve our 
understanding of mechanisms linking heart and bone pathologies. 
4. Relevance 
HFrEF is associated with altered bone metabolism and fractures increase mortality risk in patients 
with HFrEF (16). Yet. bone disease is not even listed among relevant co-morbidities in international 
HFrEF guidelines . Therefore, bone disease in HFrEF is underdiagnosed and undertreated. 

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Retrospective analyses indicate that osteoporosis as the manifestation of altered bone metabolism is 
present in approximately 1 of 5 patients with HFrEF (see Table 5). However, prospective studies lack 
to quantify the burden of osteoporosis in HFrEF. Given that some studies even indicated a mortality 
reduction by osteoporosis therapy (17) is it of critical importance to fill this gap in evidence. The RoC-
HF study will prospectively determine the prevalence of osteoporosis, fractures and altered bone 
metabolism and the link with cardiac function in a well-standardized cohort of HFrEF patients. RoC-
HF will thus provide novel and important evidence on the relevance of bone disease in HFrEF. It is the 
final aim of RoC-HF to establish bone disease as a relevant co-morbidity in international HFrEF 
guidelines and, thus, to improve medical treatment of these patients. 
5. Study population 
Male or female subjects with stable chronic heart failure with reduced ejection fraction. 
Number of participants: 205 
a. Recruitment 
Patients will be recruited from the Department of Cardiology or the Department of Internal Medicine 
and will be contacted personally. 
b. Inclusion criteria 
1. 
Age >= 18 
2. 
NYHA class II-IV symptoms 
3. 
Left ventricular ejection < 50% at Visit 1 
4. 
Treatment according to current Heart Failure Guidelines of the European Society of 
Cardiology 
5. 
Willingness and ability to provide signed informed consent form (ICF) prior to participation in 
any study-related procedures 
6.  
Previous diagnosis of heart failure with reduced ejection fraction defined as symptomatic left 
ventricular ejection fraction < 40% requiring optimization of heart failure therapy 
c. Exclusion criteria 
1.  
Unplanned hospitalization within 1 month prior to the Baseline Visit. 

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2. 
Discontinuation or initiation of a pharmacologic or device treatment for HFrEF within 1 
month prior to the baseline visit. 
3. 
Coronary or peripheral revascularization procedures, valvular procedures, OR any major 
surgical procedure within 3 months prior to the Screening Visit. 
4. 
Acute coronary syndrome (ACS), stroke or transient ischemic attack (TIA) within 3 months 
prior to the Screening Visit. 
5. 
Any acute illness 
6. 
Disease reducing life expectancy to < 1 year, except HFrEF 
7. 
Recipient of any organ transplant 
8. 
Primary significant valve disease (at least moderate to severe valve disease) 
d. Premature discontinuation of study participation 
Subjects may be discontinued for the following reasons: 
 
CI decision for any reason 
 
Subject Decision: The subject or the subject’s designee, (e.g., parents or legal guardian), 
requests to be withdrawn from the study.  
 
The subject is lost to follow-up 
6. Investigational Plan 
a. Study design 
Longitudinal, prospective, single-center, epidemiological cohort study. 
Study procedures will be performed at the Medical University of Graz, Graz, Austria:  
- 
Division of Endocrinology (DXA scan) 
- 
Department of Radiology (X-ray) 
- 
Department of Cardiology (all other procedures). 
Duration of active study participation: 3 (+2) days, follow-up visit planned 
Study duration: 2 years for cross-sectional part, follow-up planned 

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b. Study schedule 
Patients hospitalized at the Department of Internal Medicine/Department of Cardiology or who are 
consulting the Outpatient Clinic of the Department of Cardiology, will be screened for coherence 
with in/exclusion criteria either by a clinical investigator (CI) or by a study nurse. If a patient fulfills 
in/exclusion criteria, he or she will be informed by a CI about the possibility to participate at the RoC-
HF study. If the patient is found to be eligible for study participation by a CI and agrees to participate, 
Visit 1 will be scheduled. All study-related procedures will only be initiated when the patient has 
signed the written informed consent form. Every study participant will be assigned a unique ID 
number. The first study participant will be assigned the study ID 001 and every further ID will 
increase by 1 with every new participant. All study IDs will be documented in the RoC-HF study book 
which will be kept locked safely at a place only accessible by the CIs. Study procedures include blood 
sampling (65 ml), spot urine sampling (12 mL), physical examination, assessment of vital signs, 
assessment of medication and medical history, echocardiography, electrocardiography, pulse wave 
analysis (PWA), pulse wave velocity (PWV), DXA-scan, 24-hours ambulatory blood pressure 
monitoring and X-ray of the spine. 
NV will routinely assess the results of X-ray examinations and DXA scans following European 
Guidelines for diagnosis and management of osteoporosis (18). If found pathologies require initiation 
of medical treatment, the participant will be informed and an appointment at the Outpatient Clinic 
of the Division of Endocrinology will be scheduled. 
c. 
Study visits 
Visit 1 
Visit 1 will be scheduled on the day of Screening or at a separate day. Study procedures will include 
the following: 
1. Signing of informed consent forms (possible already during screening): General form, 
form of the Biobank Graz, separate form for data generation from stored samples. 
2. Assessment of medical history 
3. Assessment of medication history 
4. Physical examination 
5. ECG 
6. Echocardiography 
7. Spot urine pregnancy test for women of child-bearing age 
8. 24-hours ambulatory blood pressure monitoring (ABPM).  

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9. Scheduling of visit 2, at least 2 days after visit 1 to facilitate performance of 24-hours 
ABPM. The patient will be advised to remove and switch off the ABPM device 24 hours 
after attaching. The patient will be advised to attend visit 2 as fasting and non-smoking 
over the preceding night. 
Visit 2 
Visit 2 will take place at least 2 days after visit 1 to facilitate performance of 24-hours ABPM. Visit 2 
will take place in the Clinical Studies Outpatient Clinic of the Department of Cardiology. The 
participant should be fasting and should not have smoked over the previous night. Following study 
procedures will be performed: 
1. X-ray of the thoracic and lumbar spine. Women of child-bearing age will not perform X-
ray in case of a positive pregnancy test during visit 1. 
2. Re-obtainment of ABPM device. If ABPM was unsuccessful it can be repeated once, if the 
patient agrees. 
3. Vital signs (office blood pressure and heart rate) 
4. Hand Grip 
5. 4m Gait Speed 
6. Sampling of blood (65 mL) and spot urine (12 mL) 
7. PWA 
8. PWV 
9. Questionnaires 
10. DXA-scan. Women of child-bearing age will not perform DXA in case of a positive 
pregnancy test during visit 1. 
 
d. 
Study procedures 
Blood/urine sampling – immediate determination 
32mL of blood and 8mL-of spot urine will be processed directly after collection for the purpose of 
immediate determination of parameters, at the Clinical Institute of Medical and Chemical Laboratory 
Diagnostics (18mL) and at the Laboratory platform of Division of Endocrinology (14mL). An oversight 
is provided in Table 1 and Table 2. 

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Table 1: Endo lab parameters from blood (14 mL). 
3mL EDTA-plasma (on ice) 
8mL Serum (room temperature) 
Parathyroid Hormone 
TSH 
Osteocalcin 
fT3 
FGF-23 
fT4 
CTX 
25-hydroxy-vitamin D 
 
bALP 
3mL EDTA-plasma (room temperature) 
P1NP 
Aldosterone (plasma aldosterone 
concentration) 
P3NP 
Renin (plasma renin concentration) 
TRAP 
 
IGF-1 
FGF-23, fibroblast growth factor-23; TSH, thyroid stimulating hormone; fT3, triiodothyronine; 
fT4, tetraiodothyronine; bALP. bone-specific alkaline phosphatase; P1NP, intact N-terminal 
propeptide of procollagen type 1; P3NP, amino-terminal propeptide of type III procollagen; 
TRAP, active isoform 5b of the tartrate-resistant acid phosphatase; IGF-1, Insulin-like growth 
factor 1. 
 

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Table 2: KIMCL parameters from blood (18mL) and urine (8 mL) 
Hematology (3mL EDTA plasma): 
Clinical Chemistry (8mL Li-Hep plasma): 
Hemoglobin 
Sodium (Na+) 
Hematocrit 
Potassium (K+) 
Erythrocyte count (RBC) 
Chloride (Cl-) 
Leukocytes (WBC) 
Total calcium (Ca2+) 
Neutrophils, segmented 
Phosphate 
Lymphocytes 
Magnesium (Mg2+) 
Monocytes 
Total bilirubin 
Eosinophils 
Alkaline phosphatase (AP) 
Basophils 
Alanine aminotransferase (ALT) 
Platelets 
Aspartate aminotransferase (AST) 
HbaA1c 
-glutamyl-transferase (GGT) 
Coagulation (3mL sodium citrate) 
Urea 
International normalized ratio (INR) 
Creatinine 
Prothrombin time (PZ) 
Calcium 
Activated partial thromboplastin time (aPTT) 
Glucose 
Urinalysis (8mL spot urine): 
Albumin 
Sodium (Na+) 
Total protein  
Potassium (K+) 
Total cholesterol 
Chloride 
HDL/LDL (Friedewald formula) 
Total calcium (Ca2+) 
Trigylcerides 
Creatinine 
eGFR (CKD EPI equation) 
Magnesium 
Iron (Fe2+) 
Phosphate 
Transferrin 
Protein 
Ferritin 
Albumin 
C-reactive protein 
Venous blood (1mL syringe) 
Creatine-kinase (CK) 
Blood gas analysis 
Creatine kinase myoglobin isoform (CK-MB) 
Sodium (Na+) 
Lactate dehydrogenase (LDH) 
Potassium (K+) 
hsTroponin T 
Chloride (Cl-) 
NT-proBNP 
Ionized calcium (Ca2+
ion) 
Interleukin-6 
Glucose 
Coagulation (3mL sodium citrate) 

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Lactate 
 
 
Von Willebrand factor (vWF) 
HbA1c, glycated hemoglobin A1c; NT-proBNP, n-terminal pro-brain B-type natriuretic peptide, 
hs, high sensitive. 
 
Blood/urine sampling – biobanking 
Immediately after collection, 36 mL of blood and 4 mL of spot urine will be transferred to the 
biobanking facility of the Biobank Graz, located at the Department of the Clinical Institute of Medical 
and Chemical Laboratory Diagnostics (Auenbruggerplatz 15, first floor). A list of stored sampled is 
provided in Table 3. Subjects will be asked to sign the informed consent of the Biobank Graz. 
Table 3: Blood and urine samples for biobanking (36mL + 4mL) 
Collected volumes 
Aliquoted volumes 
Total aliquoted volume (sum) 
3x8mL serum 
14*235 µL/aliquot  
14* 580µL/aliquot 
11.410 µL serum 
2x6mL EDTA plasma 
10*580µL/aliquot 
1* 235µl buffy coat/aliquot 
5.800 µL EDTA plasma 
235µL buffy coat 
1x4mL spot urine 
4*580 µL/aliquot 
2.320 µL spot urine 
 
Analyses of gene mutations that may predispose for the development of heart failure or for 
cardiovascular risk factors will be analyzed. These analyses will be conducted from buffy coat that 
will be frozen to -80°C as part of the blood plasma sampling (see Attachment 3). An overview on 
genes to be analyzed is provided in Table 4. 

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Table 4: Genes to be analyzed in genetic testing 
Gene name 
Location 
Expressed protein 
Function of protein 
MYBPC3 
11.p11.2 
Cardiac myosin binding 
protein C (cardiac MyBP-C) 
Cardiac myocyte 
contractility 
TTN 
2q31.2 
Titin 
Myocyte contractility 
MYH7 
14q11.2 
Myosin heavy chain beta 
(MHC-) 
LMNA 
1q22 
Lamin A and C 
Cytoskeleton stability 
DES 
2q35 
Desmin 
CYP11B2 
8q22 
Aldosterone synthase 
Regulates aldosterone 
concentration 
CaSR 
3q21 
Calcium sensing receptor 
Regulates parathyroid 
hormone concentration 
Analyses of gene mutations that are not currently known to increase the risk of heart failure but 
may be identified in the future. 
 
Echocardiography 
Echocardiographic examination will be performed with a Vivid 7 or Vivid 9 (GE Healthcare, Chalfont 
St Giles, UK). For acquisition of images in the parasternal view the participant will be placed in the 
steep left-lateral decubitus position. The participant’s left arm will be raised. Images will be acquired 
during quiet respiration. Image rate will be set at least at 70 frames per second. Echocardiographic 
examination will be outlined in a separate SOP. 
ECG 
A 12-lead ECG will be obtained in supine position. 
ECG intervals (PR, QRS, QT, QTc), heart rate and pathologies (rhythm abnormalities, AV block, 
pathological Q, branch block, repolarization abnormalities) will be recorded for each subject. 
Assessment of medical history 
Detailed medical history (including dates): 
 
Any surgery 
 
Any cardiovascular interventions 
 
Smoking history (pack years) 

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 
Cardiovascular events: stroke, myocardial infarction (STEMI, NSTEMI), other embolic or 
thrombotic event, cardiac decompensation, hospitalization for heart failure, peripheral 
vascular disease 
 
Cardiovascular disease: arterial hypertension, atrial fibrillation, heart failure signs (ankle 
edema, elevated jugular venous pulse) and symptoms (NYHA classification, angina pectoris, 
dizziness, syncope, palpitations) 
 
Chronic renal failure 
 
Pulmonary disease (COPD, asthma) 
 
Any other relevant illness 
 
Previous fractures?- traumatic/minor injuries/non traumatic 
 
Previous vertebral trauma 
 
Previous nephrolithiasis? 
 
Child-bearing potential? If yes, spot urine pregnancy test will be performed. 
 
Assessment of medication history 
Devices or drugs: names (INNs), dosing scheme (if applicable), date and indication of 
implantation/first prescription of regularly or intermittently taken drugs. Particular care will be taken 
to ask for treatment of: 
1.  Heart failure (medical): levosimendane, loop diuretics, ACE-inhibitors, angiotensin II 
receptor I blockers, mineralocorticoid receptor antagonists, neprilysin inhibitors, beta-
blockers, ivabradine, digitalis or digoxin, amiodarone, other 
2. Heart failure (devices): ICD, CRT 
3. Coronary artery disease: aspirin, PY12 inhibitors, anti-anginal drugs (nitrates or similar) 
4. Bone therapy: treatment for osteoporosis including PTH analogues, bisphosphonates, 
RANKL-antagonists, strontium-ranelate, estrogen receptor antagonists, vitamin D or 
analogues 
5. Others: Pacemaker, oral anticoagulation, heparin, thiazide diuretics, other antihypertensive 
medication, drugs for psychiatric disorders 

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Pregnancy test 
Women of child-bearing age will be asked to perform a routine spot urine pregnancy test. If the test 
result is positive, the participant will not perform X-ray and DXA during visit 2. 
Physical examination 
Lung auscultation, heart auscultation, assessment of peripheral edema, assessment of jugular venous 
pulse height, weight, height, height at 20 years of age. Further examinations will be symptom-
oriented. 
Questionnaires 
 
Minnesota Living with Heart Failure (MLWHF) questionnaires 
 
SF-36 questionnaire 
 
Physical Activity Questionnaire (IPAQ) 
 
Calcium questionnaire (CaQ, 19) 
 
Pedigree questionnaire 
24-hours ambulatory blood pressure monitoring (ABPM) 
The ABPM device will be attached by a study nurse in the Outpatient Clinic of the Department of 
Cardiology at Visit 1, before X-ray and after all other procedures of Visit 1 have been performed. 
ABPM will be performed using the brachial, oscillometric, automated self-measurement mobil-O-
Graph device (I.E.M. GmbH, Stolberg, Germany) with integrated ARCSolver®-Software (Austrian 
Institute of Technology Wien). The device was validated according to the criteria of the British 
Hypertension Society (20). The range of measurement is 70–260mmHg for systolic blood pressure, 
45–180mmHg for diastolic blood pressure, and 40–240/min for heart rate. Before measurement arm 
circumferences will be measured and recorded to allow correct choice of cuff size. Measurements of 
blood pressure and heart rate will be performed every 30 minutes between 22:00h and 6:00h and 
every 20 minutes between 6:00h and 22:00h. Daytime will be defined as from 09:00 to 21:00, 
nighttime will be defined as from 01:00 to 06:00 and evening will be defined as from 21:00 to 01:00 
according to the ESC position paper 2013 on ambulatory blood pressure monitoring (21). If the 
ambulatory recordings will be longer than 24 hours, only the first 24 hours will be used for analysis 
starting the 24 hours timeframe from the first valid recorded measurement. The ARCSolver®-method 
allows the calculation of PWA values and PWV with each blood pressure measurement.  
The ABPM device will be placed on the non-dominant upper arm, except if the office blood pressure 
measurements reveals more than 20mmHg systolic or more than 10mmHg diastolic difference 
between the two arms.  In that case the arm with the higher blood pressure will be used. The patient 

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will be instructed on proper handling of the ABPM including resting the arm at the level of the heart 
during the measurements. Patients will be informed that they should conduct normal daily activities, 
however they should restrain from strenuous sports. 
If less than 70% of the measurements over 24 hours are invalid the ABPM will be considered as 
unsuccessful and will be redone.  
X-ray of the spine 
Women of child-bearing age will not perform X-ray in case of a positive pregnancy test during visit 1. 
X-ray examination, performed at the Department of Radiology, will be the first study procedure 
performed at visit 2. Afterwards, the participant will be transported to the Cardiology Outpatient 
Clinic 
X-rays of thoracic and lumbar spine will be performed in anterior-posterior and lateral projections. 
The procedure will take approximately 5 minutes in total. All images will be analyzed by one 
radiologist (JS) who will be blinded to all patient-specific data. Unclear findings will be reassessed by 
a second radiologist and a consensus result will be reported. Fractures will be graded according to 
Genant Score (GS). Parameters will be collected according to Table 5.  
Table 5: Parameters to be determined from X-ray of the vertebral spine. 
 
Thoracic 
Lumbar 
Genant Score: 
1: 20-25% height reduction 
2: 25-40% height reduction 
3: >40% height reduction 
0: no fracture according to GS 
NA: not assessible 
deformity:  
w: wedge 
b: biconcave 
c: crush 
n: no deformity 
1. 
 
 
7. 
 
 
1. 
 
 
2. 
 
 
8. 
 
 
2. 
 
 
3. 
 
 
9. 
 
 
3. 
 
 
4. 
 
 
10.  
 
4. 
 
 
5. 
 
 
11.  
 
5. 
 
 
6. 
 
 
12.  
 
(6.)  
 
Sum of fractures 
 
Sum of fractures > GS 1 
 
Severe scoliosis (0/1) 
 
Degeneration (mild/moderate/severe) 
 
 
Other pathologies 
 
If found pathologies require initiation of medical treatment according to (18), the participant will be 
informed and an appointment at the Outpatient Clinic of the Division of Endocrinology will be 
scheduled. 

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Vital signs (office blood pressure and heart rate) 
The office blood pressure and heart rate will be measured according to the current ESH/ESC 
guidelines (22). A validated semi-automatic blood pressure monitor will be used to measure the 
blood pressure on both upper arms. The arm with the higher measured value will be used for the 
further measurements. In one-minute intervals the blood pressure will be recorded two more times. 
The first measurement will be ignored and the average of the second and third blood pressure 
measurement will be recorded in the CRF as office blood pressure and the average of the two heart 
rates will be recorded as office heart rate. 
Hand Grip Strength 
The hand grip strength will be determined as a measure of “weakness” to calculate the 
“Cardiovascular Health Study Frailty Screening Scale” (23) a recommended tool to assess frailty (24). 
The JAMAR Hydraulic Hand Dynamometer (Model J00105) (Lafayette Instrument Company, USA) will 
be used, a current gold standard to measure hand grip strength (25). The recording will be done 
according to the Southampton protocol, a well-established protocol for measurement of grip 
strength in epidemiological studies of older people, which is based on the ASHT protocol (25). The 
patients are seated comfortably in a standard chair with legs, back support and armrests. They will 
rest their forearms on the arms of the chair with their wrist just over the end of the arm of the chair 
in a neutral position with thumb facing upwards. The handgrip dynamometer will be demonstrated 
to the patient. The instrument is positioned so that the thumb is round one side of the handle and 
the four fingers are around the other side. The handgrip dynamometer has to sit comfortably in the 
hand for the patient, otherwise the position will be slightly altered. The base of the hand grip 
instrument will have to rest on the palm of the investigator, to support the weight, but care has to be 
taken to not restrict the movement. The patient will be encouraged to squeeze the handgrip 
dynamometer as long and tightly as possible until the needle of the instruments stops rising. The 
result will be documented to the nearest 1kg. First the right hand strength then the left hand 
strength will be examined and this will be repeated twice to get six overall measurements. The 
highest hand grip strength recording out of all six measurements will be documented and used for 
the study. 
4-meter Gait Speed test 
As a measurement of “slowness” to calculate the “Cardiovascular Health Study Frailty Screening 
Scale” (23) the 4 meters gait speed test will be conducted. Gait speed will be measured over a 4 
meters. Subjects will begin the test from a standing position and are instructed to walk at their usual 

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pace a distance of 4 meters. The time will be recorded. A slow gait speed is considered with a walking 
speed <0.8 m/s (26, 27). 
PWA 
The pulse wave analysis (PWA) will be performed using the SphygmoCor® (AtCor Medical, Sydney, 
Australia), which allows a noninvasive central blood pressure assessment. The patient will have to lie 
in a supine position for 15 minutes before the start of the measurements and care will be taken to 
assure a quite environment. Initially the brachial blood pressure will be recorded in supine position 
and the SphygmoCor® will be calibrated using this measurement. Using the technique of the radial 
applanation tonometry the pulse wave analysis will be performed with the SphygmoCor® to measure 
at least two PWA recordings. Only recordings with a quality index above 80% will be accepted and 
otherwise the measurements will have to be repeated. If there are major differences between the 
parameters, such as an augmentation index difference of more than 4%, a third measurement will be 
done. The PWA results in which the measured values are closer to each other will be used. 
PWV 
The carotid-femoral pulse wave velocity (PWV) will be determined using the SphygmoCor® (ATCOR 
Medical, Sydney, Australia) immediately after performing the PWA in supine position. It is considered 
the noninvasive gold standard to determine the PWV and is approved by the Federal Drug 
Administration (FDA) (28). The recordings will be performed at the carotid artery and at the femoral 
artery. The distances from the palpable carotid pulse to the suprasternal notch (fossa jugularis 
sternalis) as well as the distances from the palpable femoral pulse to the suprasternal notch will be 
determined by measuring tape (29). To calculate the PWV the “Intersecting Tangents” algorithm will 
be chosen. The recording will be done twice. If the two results differ by more than 1,5 m/sec, a third 
measurement will be taken. The two PWV measurements, which are closer to each other, will be 
used and the other one discarded. 
DXA-scan 
Women of child-bearing age will not perform DXA in case of a positive pregnancy test during visit 1. 
The participant will be transported/accompanied by the study nurse to the Outpatient Clinic of the 
Division of Endocrinology. DXA scan will be performed and will include scan of lumbar spine, femoral 
neck, distal radius and full size for the purpose of estimating percentage body fat according to the 
departmental Standard Operating Procedure. Body regions are defined using standard anatomical 
partitions. Scan areas are analysed to determine lean mass, fat mass, bone mineral content, and total 
body composition. If found pathologies require initiation of medical treatment according to 
European Guidelines for diagnosis and management of osteoporosis (18), the participant will be 

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informed and an appointment at the Outpatient Clinic of the Division of Endocrinology will be 
scheduled. 
If repetition of any study procedures is not necessary, DXA-scan will be the last procedure of Visit 2. 
Pacemaker,  ICD or CRT interrogation 
Most chronic heart failure patients have, according to current guidelines, an ICD (implantable 
cardioverter-defibrillator) or CRT (cardiac resynchronization therapy) implanted. Those Devices can 
record arrhythmias and deliver therapeutic actions if necessary. Standard interrogation of the 
devices will be done during the study to record device parameters and recorded arrhythmic events. 
6. Study medication 
None. 
7. Randomization 
None. 
8. Ethical considerations/safety 
RoC-HF is designed as a cross-sectional, non-interventional study, with an option for longitudinal 
follow-up. Therefore, the only safety risk imposed to participants may refer from study procedures. 
None of the planned procedures will be invasive and only blood sampling will be semi-invasive. 
Particular care was taken to reduce the volume of blood samples to a minimum: many biomarkers of 
interest will be determined immediately which will save volume. Therefore, the volume of blood 
samples to be stored at the Biobank Graz will be relatively low when compared to other studies. 
Nevertheless, it will be crucially important to perform biobanking because this will facilitate 
achievement of one the major goals of the RoC-HF study: to biochemically disentangle the complex 
relationships between these co-morbidities (bone disease, vascular disease) with each other and 
with cardiac function in HFrEF. Radiation exposure should be mentioned as another safety issue: 
Patients will undergo X-Ray examinations of the spine and DXA scans (femur, distal forearm, 
vertebral spine), which pose a certain radiation exposure. However the total radiation dose 
(depending on body constitution a maximum of 1.5 mSv for X-ray and approx. 0.3 mSv for DXA; in 
total <0.01% increased cancer mortality risk per patient) seems acceptable. Given that osteoporosis 
is largely underdiagnosed in HFrEF populations, participation in the RoC-HF study may turn out 

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beneficial for a significant proportion of participants as the comprehensive assessment of the 
patients’ bone and mineral status may lead to consecutive initiation of preventive treatment by an 
experienced osteologist if indicated (AF, KA, SP). Of note, osteoporosis treatment reduces mortality 
and thus, performance of X-ray/DXA scan may, in fact, turn out to be beneficial for the participant. 
Women of child-bearing age will not perform X-ray and DXA in case of a positive pregnancy test 
during visit 1. 
To conclude, the safety risk of participation in the RoC-HF is minimal; on the other hand, diagnosis 
and treatment of previously undiagnosed osteoporosis will be beneficial for many participants. 
Therefore, we consider the conduct of the RoC-HF study to be ethically justifiable. 
9. Sample size calculation 
The sample size calculation of RoC-HF is based on data from previous analyses that reported 
prevalence data of osteoporosis among patients with HFrEF leading to an expected prevalence of 
osteoporosis in RoC-HF of 20%. Osteoporosis is defined as a T-Score < -2.5 (measured by DXA), and 
severe osteoporosis is defined as a T-Score < -2.5 and presence of a fragility fracture, e.g., a vertebral 
fracture. In most of available studies on patients with HFrEF, data from DXA scans were not available. 
Therefore, presence of a vertebral fracture was commonly used as a criterion of osteoporosis. Thus, 
these studies likely underestimated the real prevalence of osteoporosis, because presence of a 
fracture may constitute only the “tip of the iceberg”. Taken together, previous studies reported on 
prevalences of osteoporosis of 12 – 16% (see Table 6). 
Table 6: Prevalence of osteoporosis as reported in previous heart failure cohorts 
Study 
Patient number 
Heart failure definition 
LVEF in % 
Data 
Lyons et al (30) 
623 
Listed for transplant 
32 +/- 16 
12% with vertebral 
fractures 
Mazziotti et al 
(31) 
1031  
(430 vs 601 
healthy controls) 
ICD + revision of clinical 
records 
27 (15-45) 
16.1% with 
vertebral fracture 
Youn et al (32) 
65 
Acute decompensated 
heart failure 
28 +/- 12 (males) 
36 +/- 16 (females) 
15% with  
T-Score < -2.5 
Given that the RoC-HF study procedures comprise DXA scan as well as X-ray of both the thoracic and 
lumbar spine, we expect a prevalence of osteoporosis in RoC-HF of 20 % (95% confidence interval: 14 
-26). Calculating with a significance level of 5% and a two-sided P-value leads to a number of 171 

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participants to be analyzed. Calculating with 20% unavailable data due to invalid ABPM, missing 
laboratory values or other missing parameters, we will need to enroll 205 subjects in total. 
Support in sample size calculation was provided by the Institute for Medical Informatics, Statistics 
and Documentation of the Medical University of Graz (Regina Riedl, MSc). 
10. 
Statistical analyses 
Data will be illustrated by descriptive statistics using numbers and percentages for categorical 
variables and means and standard deviation or medians and interquartile range for continuous 
variables, respectively, as appropriate.  
To test our primary hypotheses, the correlation between a bone formation marker or central arterial 
systolic pressure (independent variable, respectively) with LV systolic function (dependent variable) 
will be analyzed using multivariate linear regression analyses, with adjustment for age, sex, blood 
lipids, blood glucose, kidney function and other potentially confounding variables. 
Differences of echocardiographic and other variables between patients with and without 
osteoporosis or other categorical variables will be compared using student’s t-test, Mann-Whitney U 
test or analysis of variance (ANOVA), as appropriate. These differences will also be analyzed using 
multivariate analyses of covariance (ANCOVA), with osteoporosis (yes/no) as fixed factor, 
echocardiographic or other continuous variables dependent variable and age, sex, blood pressure, 
blood lipids, blood glucose, kidney function and other potentially confounding variables as 
covariates. Also other categorical variables of interest and their association with continuous outcome 
variables will be analyzed in the same manner. 
Statistical analyses of the RoC-HF study will be the responsibility of the PIs or persons who received 
the permission by the PIs to perform statistical analyses. The PIs have published more than 15 
original manuscripts in the field of epidemiological research, partly as first authors, and have thus 
proven their expertise to conduct statistical analyses. Support in statistical analyses will also be 
provided by Prof. Stefan Pilz or PD Andreas Tomaschitz who have authored more than 100 peer-
reviewed original manuscripts in the field of epidemiological research. 
11. 
Data processing 
All generated data will be recorded in case report forms (CRF) and will be transcribed into Excel or 
SPSS datasets. In electronic datasets participating subjects can only be identified by their unique 
study ID, name and surname will not be recorded. 

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12. 
Data access 
All CIs will have unlimited access to the dataset. 
13. 
Responsibilities and competences 
Only the principal investigators (Klemens Ablasser, Nicolas Verheyen) will have unlimited access to 
study data and will have the right to nominate co-authorships and the position of co-authors, on 
publications that originate from data of the RoC-HF study. Forwarding of anonymized RoC-HF data 
may only occur with permission of both the PIs. 
14. 
Literature 
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