Calcium, Phosphate, Renal Impairment and Coronary Artery Disease in the Cardio-renal Syndrome, The CAPRICORN-CRS Study
Calcium, Phosphate, Renal Impairment and Coronary Artery Disease in the Cardio-renal Syndrome, The CAPRICORN-CRS Study
Heart failure (HF) is a major public health problem, which affects about 5 million
 Americans.HF is when the heart muscle does not pump as much blood as the body needs. As a
 result of this,the body has difficulties in keeping an optimal fluid status. The fluid status
 of the body is regulated by both the heart and the kidneys. Due to the strong interaction
 between the heart and the kidneys, heart failure can result in a slight decreased kidney
 function as well.

 It is known that people who primarily suffer from chronic kidney disease (CKD) have a higher
 risk of developing arterial calcifications. Calcification of the arteries is caused by
 deposits of calcium within the walls of the blood vessels. Calcifications of the arteries may
 result in a loss of elasticity of the blood vessels. Recent research studies have shown that
 people with CKD have stiffer blood vessels which in these people, is associated with a higher
 chance of developing cardiovascular diseases.

 However, it is not known whether a decrease in kidney function in people with HF results in
 arterial calcification as well. In addition, it is not known whether this is also associated
 with a higher risk of developing cardiovascular diseases (diseases of the heart and blood
 vessels.) We are asking you to take part in this study because you have HF combined with some
 decrease in your kidney function.

 The purpose of this study is to see whether people with HF and a decrease in kidney function
 do have a higher chance of developing arterial calcifications. We will do this by comparing
 the results of the following; 1) several blood tests, 2) pictures taken of your heart by
 echocardiogram and computed tomography (CT) scan, and 3) measurements of the elasticity of
 your arteries. All of these tests are routinely used in clinical care. However, there have
 not been any research studies that have compared these results to see how they relate to
 arterial calcification in people with HF who have a decrease in kidney function.

 We also want to see whether people with HF and a decreased kidney function are at a higher
 risk of developing cardiovascular diseases. This study is being performed at Massachusetts
 General Hospital (MGH), in Boston Massachusetts. We expect to enroll a total of 150 subjects
 at MGH.
The interaction between cardiac and renal (dys)function has been a highly relevant, yet
 poorly understood phenomena to both clinicians and scientists. More than 50% of the heart
 failure patients suffers from renal impairment, defined as a creatinine clearance < 60
 ml/min,while renal impairment is one of the most powerful predictors of outcome in heart
 failure.However, the complex mechanism why renal insufficiency is associated with a worse
 outcome, is still not fully elucidated.

 It was presumed that in the setting of acute heart failure, cardiac output reduces, which is
 counteracted by systemic and other responses such as a decrease in renal blood flow, in order
 to retain circulating fluid and restore cardiac output.Yet, heart failure patients with
 deterioration in renal function are not necessarily those with the poorest ventricular
 function, lowest cardiac output or the lowest blood pressures.It is therefore hypothesized
 that renal impairment is not merely a marker of end-stage heart failure, but is associated
 with a myriad of pathophysiological processes which may influence prognosis.

 One of the consequences of renal insufficiency that usually remains unnoticed by
 cardiologists, is a disregulation in the calcium and phosphate homeostasis. Yet, especially
 hyperphosphatemia is present in 50% of the pre-dialysis patients and is an important
 independent predictor of cardiovascular morbidity and mortality in this population.

 The pathophysiological mechanisms behind this process are intensively studied. In vitro
 studies show that elevated phosphate concentrations induce differentiation of vascular smooth
 muscle cells (VSMC) via Cbfa1 to osteoblast-like cells. These osteoblast-like cells are
 capable of producing bone matrix proteins, which may subsequently regulate mineralization.
 Once mineralization is initiated, increased Ca x PO4 product from (ab)normal bone metabolism,
 secondary hyperparathyroidism, or excessive calcium intake may accelerate this process
 leading to vascular calcification.

 Serum phosphate concentrations are regulated by fibroblast growth factor 23 (FGF-23), a
 circulating protein which may protect the transition of VSMC into osteoblast-like cells by
 lowering phosphate concentrations.Studies with FGF-23 null mice revealed extensive vascular
 calcification of the media layer in arteries.FGF-3 was also strongly related to vascular
 calcification in patients with end stage renal disease (ESRD), while there was no association
 found with atherosclerosis in subjects with normal renal function.

 Fetuin-A, also a circulatory protein, inhibits the de novo formation and precipitation of
 mineral basic calcium phosphate, but does not dissolve it once the basic calcium phosphate is
 formed. Therefore, fetuin-A can prevent undesirable calcification in the circulation without
 inhibiting bone mineralization. Serum levels of fetuin-A in individual dialysis patients are
 indeed inversely correlated to coronary artery calcification on CT scan.

 Matrix-carboxyglutamic acid protein (MGP), a calcification inhibitor, is a
 vitamin-K-dependent protein synthesized by chondrocytes and VSMC.MGP knockout mice develop
 severe calcifications of the arterial media layer.However, only carboxylated MGP seems to
 inhibit the process of calcification and the inhibition of MGP carboxylation by the vitamin K
 antagonist warfarin resulted in extensive calcification of arteries in vitro as well as in
 vivo.This is explained by the fact that during warfarin treatment undercarboxylated MGP
 (uc-MGP) is synthesized, which is inactive. It was recently found that uc-MGP serum
 concentrations were negatively associated with phosphate levels and positively with fetuin-A
 and intact parathyroid hormone (iPTH) concentrations, suggesting that low uc-MGP
 concentrations may be a marker of active calcification.Besides, low uc-MGP concentrations are
 inversely related to both the aortic augmentation index, a marker of arterial stiffness, as
 well as to coronary artery calcification diagnosed on CT.

 Interestingly, the process of vascular calcification in renal impairment seems not to be a
 process of accelerated atherosclerosis, i.e plaque (de)formation, but of more severe
 calcification besides existing atherosclerosis. It is shown in autopsy specimens from ESRD
 patients and matched controls that the plaque area and volume were not different in the two
 groups, but the plaque was more calcified in the ESRD population. Furthermore, intimal
 thickness was not different between the two groups as well, whereas medial thickness was
 significantly greater in the ESRD patients. In addition,a 2- to 5-fold increase in coronary
 artery calcification is found in dialysis patients compared with age-matched non-dialysis
 patients with angiographically proven coronary artery disease.

 An elegant, new diagnostic technique which seems to be ideal for imaging coronary
 calcification, is the coronary artery calcification score (CAC-score) as measured by
 electron-beam computed tomography (EBCT).This technique enables to objectify coronary artery
 calcification without the application of any nephrotoxic contrast agent. Although this would
 be an ideal tool for diagnosing coronary artery disease in patients where classical contrast
 agents could potentially be harmful, there is debate about the role of CAC determination in
 cardiovascular medicine. Indeed, recently an AHA/ACC panel of experts stated that the role of
 CAC is still undetermined. Because of the variability of reported data and the large variance
 of calcium scores in the asymptomatic population, a clear definition of a CAC score threshold
 for application to the general population is problematic. For a cutoff threshold in the
 100-200 range of Agatston score, most population studies have found that although the
 negative predictive value is very high (0.95-0.99), the positive predictive value is rather
 low (0.02-0.13).

 Although there is a positive correlation between the site and the amount of coronary artery
 calcium and the percent of coronary luminal narrowing at the same anatomic site, the relation
 is nonlinear and has large confidence limits.The relation of arterial calcification, like
 that of angiographic coronary artery stenosis, to the probability of plaque rupture is
 unknown and there is a broad variation in the correlation between CAC and angiographically
 proven coronary artery disease in patients without renal impairment. Interestingly however,
 it was found that CAC on EBCT correlated well with serum concentrations of calcium and
 phosphate in ESRD patients.

 While there is uncertainty about the exact association with plaque instability, vascular
 calcification does lead to arterial stiffness.Arterial stiffness can be objectified by
 functional parameters such as the pulse wave velocity (PWV) or the augmentation index
 (AIx).It has been previously demonstrated that CAC strongly correlates with these parameters
 of arterial stiffness.Interestingly, it was found that PWV is an independent predictor of
 future coronary events, while patients undergoing a percutaneous coronary intervention who
 have an increased AIx, are at the highest risk for a future coronary event.Furthermore, in a
 population of patients with renal impairment it was found that PWV significantly correlates
 with both vascular calcification on CT as well as serum phosphate concentrations.

 Via an increase of pressure throughout systole and a decrease in pressure throughout
 diastole, arterial stiffness results in an increase of cardiomyocyte oxygen demand. While an
 acute increase in load increases tension-time index and acute oxygen demand, chronic increase
 enhances basal oxygen requirements. This process of increased coronary blood flow
 requirements, associated with a decreased ability to supply, develops independently of
 coronary narrowing.

 Although small studies indeed suggest that heart failure patients have higher serum phosphate
 concentrations, the prevalence and prognostic role of hyperphosphatemia or any disturbances
 in the calcium and phosphate balance of heart failure patients with renal impairment have
 never been the specific subject of investigation in a larger population. The correlation
 between coronary artery calcification, arterial stiffness and coronary events in this
 population is unknown as well.

 We designed this study in order to investigate the prevalence of calcium and phosphate
 disturbances and their correlates with other markers such as fetuin-A, uc-MGP and FGF-23,
 vascular calcification on EBCT and functional parameters of arterial stiffness.Secondly, we
 want to optimize the application of the CAC score in this population, where classical
 contrast agents are contra-indicated, by adding serological and or functional parameters to
 this score. Thirdly, we aim to study the prognostic role of all these parameters.
Inclusion Criteria:

 -  Men and women of 18 years old or older

 -  history and clinical findings of heart failure for at least three months before
 screening

 -  Patients have to be in New York Heart Association (NYHA) class II, III, or IV and
 clinically stable

 -  Left ventricular ejection fraction <50%

 -  GFR ≤ 40 ml/min/1.73m² as calculated the abbreviated MDRD formula

 Exclusion Criteria:

 -  pregnancy as determined by urine test for reproductive-aged females

 -  current or past renal replacement therapy

 -  current treatment for hyperphosphatemia

 -  a history of renal transplantation or CABG

 -  Symptoms consistent with Canadian Cardiovascular Society > class 1 angina

 -  Inability to comprehend or unwillingness to sign informed consent

 -  chronic atrial fibrillation