Cardiovascular Biomarker Assessment Across Glycemic Status

Chapter 21

Cardiovascular Biomarker Assessment Across Glycemic Status Daniel Y. Li, BSc1 and W.H. Wilson Tang, MD2,3 1

Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA, 2Department of Cardiovascular Medicine,

Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA, 3Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

Chapter Outline A Review of Macrovascular Results in Past Major Clinical Trials Involving Glucose Control University Group Diabetes Program DCCT, EDIC, and UKPDS ACCORD and ADVANCE Veterans Affairs Diabetes Trial Summary: Insufficient Understanding of Macrovascular Risk Overview of Current Clinical Biomarkers for Cardiovascular Risk C-Reactive Protein CRP and Diabetes Current Clinical Considerations of CRP

246 246 246 246 248 248 249 249 251 252

Currently in the United States, nearly 26 million individuals have diabetes mellitus (DM), and by year 2025 this number is estimated to double to over 53 million [1,2]. Epidemiological studies have demonstrated the risk of cardiovascular disease (CVD), independent of other factors, to be increased two- to threefold in individuals with type 2 diabetes mellitus (T2DM) [3]. CVD accounts for the highest percentage of deaths in people with diabetes even when risk factors such as smoking, hyperlipidemia, and hypertension are considered. However, despite the decreasing incidence of cardiovascular events in the general population, there has been an increase in the CVD burden of T2DM on the population [4]. Therefore, it is more crucial than ever to focus our efforts on learning how to best diagnose, control, and prevent macrovascular disease in these high-risk patients. Glycemic control has long been the golden standard for diabetes management. This metabolic disorder is principally characterized by raised blood glucose levels along with microvascular and cardiovascular complications. In the past Glucose Intake and Utilization in Pre-Diabetes and Diabetes. © 2015 Elsevier Inc. All rights reserved.

Myeloperoxidase Cardiac Troponins cTns as a Prognostic Tool Diabetes and cTns B-Type Natriuretic Peptide BNP in the Prevention of Subclinical CVD Albuminuria Perspectives on Biomarkers for Cardiovascular Risk Multi-Biomarker Profiles for Prognostics Conclusion References

252 254 255 256 256 257 258 259 259 260 261

three decades, many landmark diabetes studies have confirmed the importance of tight glucose control in the prevention of general complications in individuals with T2DM. Cohort studies such as the Diabetes Intervention Study, the San Antonio Heart Study, and the Framingham Study have all observed two- to fourfold increase in CVD risk associated with increased glycosylated hemoglobin or fasting glucose [5 7]. This has led to the current recommendations by the American Diabetes Association to achieve a normal or near normal glycosylated hemoglobin (HbA1c) level of ,7% for most diabetic individuals [8]. Clinical investigators in the Diabetes Control and Complications Trial (DCCT) and the similar but smaller Stockholm Diabetes Intervention Study have demonstrated the unequivocal benefits of glycemic control to decrease rates of microvascular diseases such as nephropathy, neuropathy, and retinopathy [9,10]. However, mere reduction of blood glucose levels does not alleviate the many other symptoms diabetics exhibit, which contribute to cardiovascular risk. Although 245

246 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

the emphasis of glycemic control in treatment guidelines will remain a golden standard, increasing evidence suggests the insufficiency of primarily focusing on glucose monitoring to reduce diabetes-related complications such as adverse cardiovascular events. Clinical trials have shown us that HbA1c is a poor marker of CVD and is indicative only for microvascular disease in diabetes patients (Table 21.1). This paradoxical trend compels us to reconsider the continuum of diabetic vascular disease. Although there are recommendations of multi-risk factor reduction for the secondary prevention of macrovascular disease, the development of novel biomarkers to measure specific and indicative processes associated with the development of CVD in stable patients would greatly aid the risk assessment and prevention of macrovascular disease.

A REVIEW OF MACROVASCULAR RESULTS IN PAST MAJOR CLINICAL TRIALS INVOLVING GLUCOSE CONTROL University Group Diabetes Program One of the first randomized controlled trials to evaluate the effects of glycemic control in T2DM patients was completed in 1969. The University Group Diabetes Program (UGDP) consisted of 823 patients randomly assigned to placebo, sulfonylurea, and insulin treatment groups to assess the benefits of using a hypoglycemic agent to reduce vascular complications [17]. The patients in the sulfonylurea group demonstrated increased cardiovascular mortality (12.7% vs. 4.9%). Disappointingly, this study failed to demonstrate any cardiovascular risk benefits with use of hypoglycemic agents. In fact, the study was one of the first to raise concerns of glycemic control and its impact on increased cardiovascular death rates. At the time of the UGDP study, HbA1c was not yet available for measuring chronic glycemia.

DCCT, EDIC, and UKPDS The landmark glycemic intervention trials DCCT as well as the UK Prospective Diabetes Study (UKPDS) followed up on the observations from UGDP [10,11,13]. These studies set the cornerstone for the importance of HbA1c control in the reduction of eye, kidney, and nerve disease in individuals with both T1DM and T2DM. The HbA1c levels for those in the intensive glycemic control group of DCCT and UKPDS were 7.4% and 7.0%, respectively, compared to those in conventional control who had HbA1c levels of 9.1% and 7.9%. However, neither trial was able to demonstrate significant benefit of glycemic intervention on cardiovascular events. DCCT saw a 41% reduction in the rate of all cardiovascular and peripheral vascular events

that was nonsignificant (P 5 0.08), whereas UKPDS saw a 16% reduction in the risk of myocardial infarction (MI) that was also nonsignificant (P 5 0.052). Extended posttrial follow-up was conducted for both DCCT and UKPDS. In the DCCT follow-up, Epidemiology of Diabetes Interventions and Complications (EDIC), those undergoing conventional therapy were placed into intensive treatment [10]. By the end of the 11-year follow-up, the HbA1c levels between the original conventional treatment group and the intensive treatment group equalized from 9.1% versus 7.4% to 7.9% versus 7.8%. EDIC observed decreased cardiovascular events during the follow-up period in the original intensive treatment group (0.38 vs. 0.80 events per 100 patient-years). These results suggest that the original sustained period of glycemic control in the DCCT intensive treatment group conferred lasting benefits in reducing cardiovascular morbidity and mortality in T1DM patients. Similarly, the UKPDS follow-up observed similar trends in this “legacy” effect [18]. After the completion of UKPDS, the participants were followed for an additional 10 years [12]. The HbA1c level differences also disappeared between the intensive and standard treatment groups from the UKPDS follow-up in the first year. However, nonsignificant benefits in cardiovascular events observed in the intensive group became significant. There was a 15% relative risk reduction for MI and a 13% reduction for death of any cause. Although these trials shed light on the different avenues with which intensive glucose-lowering therapies can be of benefit in decreasing macrovascular risk, the proposition to use HbA1c as a marker of macrovascular disease is further diminished. In the initial phases, a lower HbA1c was unable to show a significant increase in macrovascular benefits. However, as HbA1c levels of the different treatment groups became the same during follow-up, there were differences in cardiovascular outcomes despite a similar HbA1c. This lack of association between the biological gradient and outcome demonstrates the weakness of using HbA1c to quantify the extent of macrovascular disease. Though the possible “legacy” effects of intensive glucose-lowering therapy is an important outcome to consider as we decide on the appropriate levels of glucose control to aim for, this data also suggests that measurements of glycemic status may be at best an unresponsive and nonmodifiable risk factor. The search for an appropriate biomarker of diabetes cardiovascular risk is required, as HbA1c levels do not seem to reflect the quantitative risk of macrovascular disease after intensive glycemic control.

ACCORD and ADVANCE The Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Pretax and Diamicron Modified Release Control

TABLE 21.1 Summary of Major Glucose Control Trials and Macrovascular Results Study

N

Mean Age (years)

Diabetes Duration (years)

Hx of Macrovascular Disease (%)

HbA1c Goal (%)

Followup (years)

Risk for Primary Outcome (CI 95%)

Risk for Total Mortality (CI 95%)

Risk for CV Mortality (CI 95%)

Refs.

UKPDS

3867

53.3

Newly diagnosed

6

FPG ,108 mg/dL

10

RR any diabetesrelated endpoint 0.88 (0.79 0.99)

RR 0.94 (0.8 1.1)

NS as combined endpoint

[11]

UKPDS follow-up

3277

DCCT

1441

EDIC

1397

ACCORD

10,251

27

62.2

6

10

0

35

,6.05

,6

6

3.4

ACCORD follow-up ADVANCE

11,140

65.8

8

32

# 6.5

VADT

1791

60.4

11.5

40

,6 (action if .6.5)

5

Metformin: After 17.7 years, 33% risk reduction in MI, 27% reduction from death of any cause Sulfonylurea: After 16.8 years, 15% risk reduction for MI, and 13% risk reduction from death of any cause

[12]

Nonsignificant 41% macrovascular risk reduction

[10,13]

After 17 years, 42% reduction in first CV event rate

[10]

HR 0.90 (0.78 1.04)

[14]

HR 1.22 (1.01 1.46)

HR 1.35 (1.04 1.76)

After 5 years, reduced nonfatal MIs but increased 5-year mortality

[14]

HR 0.90 (0.82 0.98)

HR 0.93 (0.83 1.06)

HR 0.88 (0.74 1.04)

[15]

HR 0.88 (0.74 1.05)

HR 1.07 (0.81 1.42)

HR 1.32 (0.81 2.14)

[16]

ACCORD, Action to Control Cardiovascular Risk and Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Pretax and Diamicron Modified Release Control Evaluation; CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; FPG, fasting plasma glucose; HR, hazard ratio; MI, myocardial infarction; NS, nonsignificant; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veteran Affairs Diabetes Trial.

248 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

Evaluation (ADVANCE) trials were specifically designed to assess even greater glycemic controls compared to UKPDS in T2DM patients and determine if reducing blood glucose and utilizing HbA1c as a marker will decrease the risk of cardiovascular events [14,15]. In these trials, ACCORD set the intensive control group for ,6.0% HbA1c whereas ADVANCE set their control point for ,6.5%. Both trials enrolled more than 10,000 patients, over double that of UKPDS, in hope of providing enough power for a randomized trial to conclusively understand the optimal target control in HbA1c levels. In ACCORD, the primary outcome was a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular cause. The baseline patient population had a mean age of 62 with a longstanding history of diabetes (B10 years). These patients either had a history of CVD or at least two risk factors for vascular disease. After 1 year of beginning glucose-lowering therapy, the median HbA1c levels in the intensive group had reached 6.4% compared to 7.5% in the conventional therapy patients, and by 2 years, early differences in mortality had already been observed. Compared to the conventional therapy, the intensive therapy resulted in a significant relative increase in mortality by 22%. This higher finding led to the premature termination of intensive therapy (mean treatment time 3.5 years). There was no observed risk reduction in the intensive therapy group. Although a 24% decrease in nonfatal MI was observed (HR 5 0.76, P 5 0.004), there was an increase in death from cardiovascular causes (HR 5 1.35, P 5 0.02) and no change in the overall composite of primary outcomes. Following the study termination, those on intensive therapy were switched to conventional therapy. After this transition, the original intensive group’s HbA1c rose from 6.4% to 7.2%, comparable to that of the conventional therapy group at 7.6% [19]. At the end of the 5-year follow-up, the overall rate of nonfatal MI in the intensive therapy group remained lower than the conventional therapy at HR 5 0.82, P 5 0.01. However, they also exhibited a 19% higher death rate from any cause (HR 5 1.19, P 5 0.02). Death from cardiovascular causes continued to be elevated (HR 5 1.29, P 5 0.02), and there remained no change in the overall composite of primary cardiovascular outcomes. The study concluded that use of intensive therapy to target a lower HbA1c level resulted in increased mortality and did not significantly reduce cardiovascular events. ADVANCE further compared the use of intensive and standard therapies in patients with longstanding T2DM. The patient population had a mean age of 66 with original diagnosis of diabetes occurring after age 30. These patients either had a history of CVD or at least one risk factor for vascular disease. After a median treatment follow-up of 5 years, the mean HbA1c levels were 6.5%

and 7.3% for the intensive and standard treatment groups, respectively. Overall, there was a significant 10% reduction in combined major macro- and microvascular events for the intensive group. However, this was greatly attributed to the 21% decreased incidence of new or worsening nephropathy (microvascular disease) for the intensive group. In contrast with ACCORD, the intensive therapy also did not result in an increase in overall (HR 5 0.93, P 5 0.28) or cardiovascular-caused mortality (HR 5 0.88, P 5 0.12).

Veterans Affairs Diabetes Trial On the heels of the publication of ADVANCE and ACCORD, the Veterans Affairs Diabetes Trial (VADT) also aimed to compare the effects of glucose control on cardiovascular events. This trial enrolled 1791 patients who had a longstanding history of diabetes, 40% of whom had already suffered from a first cardiovascular event [16]. The trial’s primary endpoint was a composite of cardiovascular events and the results showed no significant difference between intensive and standard glucose control for any component of the primary endpoint after a 5-year follow-up (HR 5 1.07, P 5 0.62).

Summary: Insufficient Understanding of Macrovascular Risk It is possible that the presented studies, though large, are still insufficiently powered and thus fail to provide definitive results. Therefore, they can be combined in a meta-analysis to better understand relevant factors that could remain unexplored because of statistical reasons. However, recent large meta-analyses have not demonstrated positive effects from these glucose control trials. An analysis from Turnbull et al. using the four large trials, UKPDS, ACCORD, ADVANCE, and VADT, observed a modest reduction of major macrovascular events through intensive therapy, but also noted an increase in severe hypoglycemia in T2DM patients, which is a known contributor to cardiovascular mortality [20]. Furthermore, another large meta-analysis from Boussageon et al., which reviewed 13 past studies to determine the relationship between glucose control and cardiovascular mortality, also concluded limited benefits of intensive glucose-lowering treatment on deaths from cardiovascular causes [21]. Finally, in a 2014 meta-analysis by the Emerging Risk Factors Collaboration, an analysis of 73 prospective studies of individuals without known CVD or diabetes found that HbA1c contributed little incremental benefit for the risk assessment of CVD [22]. The presented trials have generally pointed toward disappointing results in the ability of HbA1c to quantify the

Chapter | 21 Cardiovascular Biomarker Assessment Across Glycemic Status 249

risk of macrovascular disease. However, as a whole, the differences in these studies must also be acknowledged when summarizing their results. For example, the patient populations of ACCORD and VADT were more advanced in their progression of diabetes. Their entry level of HbA1c was also high (ACCORD 8.1%, VADT 9.4%) despite having a large number of the participants entering the trials already on insulin. On the healthier spectrum, patients from UKPDS were newly diagnosed with diabetes and had relatively good HbA1c values at 7.1% without the use of any glucose control medication. Finally, the ADVANCE study population was more reflective of an in-between group. Though the median duration of diabetes in ADVANCE was similar to those of ACCORD and VADT, the entry level of HbA1c was at 7.5% with very few patients taking insulin. The lack of improvement from glucose control on mortality in meta-analysis could be driven by some of the larger studies, such as ACCORD, which saw increased mortality in patients. Furthermore, it is also possible that although studies such as ACCORD, ADVANCE, and VADT saw little benefits to intensive glucose control, their study sample is also exposed to the widespread use of statins, which can change the ability of glucose control to further reduce cardiovascular risk. Nonetheless, it is clear that as a marker, HbA1c has been unable to demonstrate value as a prognostic or therapeutic marker for CVD. The assumption that has prevailed in diabetes in which control of hyperglycemia can reduce macrovascular risk is no longer sustainable. Therefore, new biomarkers will be essential to stratify risk among diabetes patients for their macrovascular risk.

OVERVIEW OF CURRENT CLINICAL BIOMARKERS FOR CARDIOVASCULAR RISK Current CVD risk assessments are limited to identify individuals with high risk and offer little additional information for individuals such as diabetics who are already considered to be in the highest adverse risk category. The inclusion of clinical laboratory tests for screening and risk calculation will provide better real-time estimates of an individual’s current risk. In order to screen the general population for CVD risk, biomarkers with established prognostic value will be crucial for predicting the shortand long-term cardiac risk profile of patients as well as the necessity to provide pharmacologic and nonpharmacologic interventions. Circulating biomarkers in the body include a wide variety of molecules such as traditional protein-based markers, for example, hormones, prohormones, structural proteins, and various enzymes. On the other hand, novel biomarker development focuses on expression profiles and signatures

through simultaneous measurement of multiple proteins, metabolites, or RNAs in a high throughput “-omics” approach. Novel clinically available biomarkers for CVD are still focused on the traditional protein markers [23]. With the recent shift in focus of utilizing biomarkers for prognostic purposes, there still has not been enough time to determine if the addition of these new biomarkers can absolutely affect the current clinical risk reclassification. Fortunately, there is optimistic evidence to suggest that although many of these traditional markers were developed to focus on patients with a variety of cardiovascular pathologies, these markers can also contribute quantitative information about the state of cardiovascular health across a continuum of disease ranging from heart failure to chronic and acute CVDs, and to the general population.

C-Reactive Protein Discovered over 80 years ago by scientists studying the inflammatory response, C-reactive protein (CRP) is the prototype of acute phase reactants, a protein that increases or decreases by at least 25% during inflammatory states [24]. However, despite having the name “acute,” these responses are often found in chronic diseases such as arthritis or cancer [25]. Structurally, CRP is a pentraxin consisting of five identical, noncovalently associated subunits that are arranged symmetrically around a central pore [26]. CRP is produced mainly from the liver through signals from cytokines such as IL-1, IL-6, and TNF-α, and its primary effect is believed to be anti-inflammatory [27]. CRP is also involved in a host of other responses in the setting of inflammation such as complement activation and apoptotic cell clearance [28 30]. Since the 1990s, evidence has accumulated to target inflammatory processes as significant contributors to the development of atherosclerosis and heart disease [31,32]. Of the many markers studied as noninvasive methods to detect underlying atherosclerosis, CRP is one of the most extensively studied of its class. Assays for CRP have evolved from crude measures for detection of active infection, tissue injury, or acute inflammation to detection of subclinical levels of CRP through high sensitivity methods. CRP is relatively stable as a frozen sample, has a long half-life of 19 h, and is easily measured in a laboratory standardized assay [33,34]. While an ideal value that can be equated to high serum high-sensitivity C-Reactive Protein (hsCRP) and high cardiovascular risk has not been clearly defined, a 2003 statement from the Centers for Disease Control and Prevention and the American Heart Association (AHA) recommended low-, average-, and high-risk cardiovascular risk estimation values to be ,1, 1 3, and .3 mg/L, respectively [35]. These values correspond to approximate tertiles in the population; for a value above 10 mg/L, initiating a search for a source of inflammation or infection is recommended.

250 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

The short-term variability in hsCRP can be significant. An examination of a National Health and Nutrition Survey (NHANES) subset saw that 32% of individuals initially reported with elevated hsCRP to have a normal values after a second check [36]. Therefore, most experts recommend having patients retested 2 weeks apart, to confirm stable values and eliminate the possibility of other underlying inflammatory processes before taking therapeutic actions. Between ethnicities, large population studies have found the highest levels of CRP in African Americans, followed by Hispanics, South Asians, Caucasians, and East Asians, respectively, with geometric means ranging from 1.0 to 2.6 mg/L [37]. These data are a reminder that a uniform cutoff for hsCRP should not be applied, as many factors such as genetics and lifestyle can lead to significantly different baseline values. Clinical interpretations must be performed in the context of the individual. Although measurement of CRP is often performed in the clinic, it is still under debate whether CRP is a nonspecific marker associated only with atherogenesis, or if it has a causative role in the underlying pathology that subclinical inflammation plays in atherosclerosis. The possible mechanistic role of CRP in atherogenesis is complex. Experiments to date have demonstrated that CRP may facilitate monocyte adhesion and transmigration into the blood vessel walls. These processes may enhance the local inflammatory response and increase plaque formation through recruitment of additional lymphocytes and monocytes [38,39]. CRP catalyzes the M1 macrophage polarization, which leads to macrophage infiltration of atherosclerotic lesions and adipose tissue [40]. These processes mediated by CRP represent key steps in the atherogenic process. In humans, CRP has been found in atherosclerotic lesions, particularly regions with monocytemediated inflammatory activity or within the lipid microdomains of endothelial cells [41]. Furthermore, statin therapies reduce circulating CRP levels and early evidence suggested that the decreased CRP may mediate the concurrent reduction of cardiovascular events independent of LDL-C [42,43]. To tie these studies and observations to the general population, transgenic models of CRP were established in mice and rabbits. Unfortunately, there was no observed difference of plaque burden [44 46]. Furthermore, genome-wide assay studies (GWAS) in the population found marked differences in individual CRP levels at the different loci associated with serum CRP but no association with coronary heart disease (CHD) [47]. Meta-analysis of CRP-related genotypes and risk of CHD compared to traditional risk factors alone indicated a null association [48]. These results challenge the idea that CRP plays a causative role in atherogenesis. Despite being a possible nonspecific marker of inflammation, over 30 large epidemiological studies have confirmed the association between serum CRP levels and

prevalence of underlying macrovascular disease. hsCRP and associated CVD risk have been noted in large observational studies not only categorically for men, women, and the elderly, but also in the general population. For men, large trials such as the Multiple Risk Factor Intervention Trial (MRFIT) paved way to connect hsCRP and mortality from CHD in high-risk middle-aged men [49]. Similarly, hsCRP was also able to further provide prognostic value in apparently healthy male patients [50]. For women, the Women’s Health Study compared LDL-C, an established causative marker of atherosclerosis, with hsCRP. An 8-year follow-up of over 28,000 women led to the result that hsCRP was an even stronger predictor of cardiovascular (CV) events than LDL-C after adjustment for age and conventional risk factors [51]. For the elderly, a study of 4000 men and women over the age of 65 with no previous incidence of vascular disease revealed that 26% of the individuals had an elevated hsCRP of .3 mg/L, which translated to a higher risk of MI or cardiac death (RR 5 1.82) [52]. Finally, in the general population, many observational studies have supported the significant relationship between baseline CRP and CHD or CV events [53 56]. A 2009 meta-analysis of 65,000 patients from 22 prospective studies for the United States Preventive Services Task Force (USPSTF) saw a higher rate of incident CHD (RR 5 1.60) in patients at the higher tertile compared to the lowest tertile [57]. The Emerging Risk Factors Collaboration followed with meta-analysis of 160,000 patients from 54 prospective studies evaluating outcomes based on baseline CRP and another metaanalysis of 240,000 patients without prior CVD from 52 prospective studies [58,59]. Both studies observed modest increases in the relative risk assessment when CRP is added to traditional factors. The total of observational studies for CRP suggests that serum hsCRP can act as an independent predictor of CVD. However, other reviews from prominent databases such as NHANES suggested that hsCRP did not add significantly to traditional risk factors as a prognostic screening tool [60]. In order to answer some of the uncertainties following the observational studies, the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was a landmark study that aimed to provide direct evidence that lowering CRP alone can help improve cardiovascular risk. This trial assigned 17,802 healthy men and women with an LDL-C level below 130 mg/L and a CRP level of 2.0 mg/L to treatment with 20 mg of rosuvastatin or placebo daily [42]. After a median of 1.9 years follow-up, the trial was stopped due to the large benefit observed in the primary outcome of CV events. There was a 37% reduction in CRP in the statin-treated group and a large reduction in primary outcome (HR 5 0.56, P , 0.00001). However, because the trial did not include individuals with previously low

Chapter | 21 Cardiovascular Biomarker Assessment Across Glycemic Status 251

TABLE 21.2 Summary of Selected Trials Using hsCRP for Risk-Guided Therapy Study

N

Follow-up (Weeks/ Months/Years)

Statin Therapy

CRP predicting Response to Treatment?

Refs.

JUPITER

17,802

1.9 years

Rosuvastatin 20 mg once daily vs. placebo

Yes

[42]

CARE

782

5 years

Pravastatin 40 mg vs. placebo

Yes

[61]

PROVE-IT-TIMI 22

3745

2 years

Atorvastatin 80 mg vs. pravastatin 40 mg

Yes

[62]

A-to-Z

3813

4 months

Simvastatin 80 mg vs. 20 mg

Yes

[63]

MIRACL

2926

16 weeks

Atorvastatin 80 mg once daily vs. placebo

Yes

[64]

REVERSAL

502

1.5 years

Pravastatin 40 mg or atorvastatin 80 mg

Yes

[65]

ASCOT

643

5.5 years

Atorvastatin 10 mg vs. placebo

No

[66]

Heart Protection Study

20,536

5 years

Simvastatin 40 mg vs. placebo

No

[67]

ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; A-to-Z, Aggrastat to Zocor; CARE, Cholesterol and Recurrent Events; JUPITER, Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; MIRACL, Myocardial Ischemia Reduction with Acute Cholesterol Lowering; PROVE-IT-TIMI, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction; REVERSAL, Reversal of Atherosclerosis with Aggressive Lipid Lowering.

hsCRP levels, it is not clear if the benefit is directly from CRP, the 50% LDL reduction that was also observed in the individuals, or both. Several other prospective studies (Table 21.2) such as PROVE-IT-TIMI, CARE, and REVERSAL came to similar conclusions that CRP levels predicted response to treatment [61 65,68,69]. However, other large studies, such as the Heart Protective Study, which also followed a large cohort of 20,000 patients over a period of 5 years, did not see a relationship between baseline hsCRP levels and the effect of statins on incidence of vascular events [67]. It is important to note that in this study, the sample cohort included many high-risk patients with manifested CVD. Therefore, it could not be seen as a primary prevention trial as JUPITER was. Further post hoc analysis and studies by other groups, such as the FDA and the Anglo-Scandinavian Cardiac Outcome Trial Lipid Lowering Arm, also came to differing conclusions, which leaves the evidence for experimental benefits of hsCRP less than consistent [66,70].

CRP and Diabetes A unique feature of CRP that distinguishes it from classical markers such as LDL-C is that an ongoing acute phase response or low-grade inflammation plays an important role in the development of diabetes. CRP levels not only correlate with a variety of risk factors such as triglycerides,

obesity, blood pressure, and fasting but also with insulin sensitivity and endothelial dysfunction [53]. Based on this association, it is not surprising that the cardiac event-free survival is similar for those with CRP levels above or below 3.0 mg/L and for those with and without the metabolic syndrome, respectively [71]. However, additional experimental evidence leans toward the possibility that CRP can also add independent prognostic information on risk at all levels of severity of the metabolic syndrome. Some of the very first data from Ridker et al. from the Women’s Health Initiative demonstrated that CRP levels of ,1, 1 3, and .3 mg/L can differentiate between low, moderate, and high risk for cardiac event-free survival even in individuals already defined as having metabolic syndrome [71]. This use of CRP demonstrated that metabolic syndrome is a heterogeneous condition and suggested CRP will also add additional prognostic information of CVD even for those with T2DM. Though the data on prognostic value of CRP in diabetic patients has so far been limited, several subsequent studies observing the prognostic value of CRP in patients with T2DM have yielded generally positive results. Observational study from National Health and Nutrition Examination Survey (NHNES) (OR 5 6.01) in diabetics with intermediate CRP levels as well as prospective cohort trials with relatively long-term follow-up such as Prevention of Events With Angiotensin-Converting Enzyme Inhibition

252 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

Trial (PEACE) (hsCRP .3 mg/L: HR 5 1.52), Schulze et al. (CVD RR 5 2.62 in the highest quartile), Soinio et al. (RR 5 1.72 for patients with CRP .3 mg/L) have shown optimistic results [72 75]. The population-based Casale Monferrato Study observed no improvement in individual risk assessment after inclusion of all wellknown risk factors, but overall saw a 5-year 44% increased cardiovascular mortality in diabetic patients with CRP .3 mg/L and even a significant 64% increased risk of cardiovascular mortality in normo-albuminuric patients [76]. Finally, meta-analysis of 52 prospective trials by the Emerging Risk Factors Collaboration saw a modest increased in the co-occurrence index (C-index) by 0.0026, which, although statistically significant, was less than the C-index of 0.0042 obtained if information of CRP was added to a model with nondiabetic patients [58].

Current Clinical Considerations of CRP Though much new knowledge has been uncovered regarding the potentials of CRP as a prognostic biomarker for CVD risk prediction, the overall weight of positive epidemiological studies is not to be ignored. There is an abundance of persuasive data, but the overall inconclusiveness of hsCRP clinical utility is reflected in the writings of professional guidelines. Professional society recommendations generally emphasize the lack of conclusive data to establish a causal relationship for CRP and CVD, but also suggest the usefulness of CRP for patients in an intermediate risk category. As previously mentioned, in 2003, the CDC and the AHA concluded that CRP may be used at the discretion of the physician as part of a global assessment of cardiovascular risk. In 2007, the European Society of Cardiology described the incorporation of CRP assessment into standard models for the prediction of cardiovascular risk as “premature” [77]. In 2009, the Canadian Cardiovascular Society recommended CRP assessment in patients at “intermediate risk,” which was defined as the predicted risk of a cardiovascular event between 10% and 20% over a subsequent 10 years [78]. Also in 2009, the National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines came to the conclusion that the measurement of CRP levels might be useful for the stratification of patients at intermediate risk for a cardiovascular event, whereas the USPSTF concluded that there was insufficient evidence to support the role of hsCRP in preventative screening of asymptomatic patients [79,80]. This was followed by a 2010 report by the American College of Cardiology Foundation (ACCF)—AHA Task Force on Practice Guidelines, which states that assessment of CRP levels is reasonable for patients at intermediate risk [81]. Finally, an updated recommendation from the European Society of Cardiology in 2012 recommended

screening for patients with a moderate or unusual CVD risk profile [82,83]. It is expected that future guidelines regarding biomarkers such as CRP will continue to emerge as updated guidelines are integrated into the guidelines on cardiovascular risk reduction.

MYELOPEROXIDASE Myeloperoxidase (MPO) is a tetrameric, heavily glycosylated inflammatory enzyme whose first recognized clinical role was in the contribution to the innate immune system [84]. MPO is released from polymorphonuclear neutrophils and macrophages and functions to form different reactive oxygen species. This enzyme is released into the extracellular fluid compartment during inflammatory conditions and can be found in ruptured atherosclerotic plaques [85,86]. Furthermore, higher concentrations of MPOproducing inflammatory cells can be found in the atherosclerotic lesions of patients with acute coronary syndrome (ACS) compared to those with stable disease [87,88]. Studies have demonstrated that MPO contributes to the progression of atherosclerosis by oxidizing lipids and inactivating the bioavailability of nitric oxide [89]. Circulating levels of MPO are able to cross artery walls and elicit structural changes of the endothelial walls from the subendothelial matrix. In atherosclerosis, MPO is believed to play a key role in the degradation of the collagen layer of atheromas, which then leads to the erosion and subsequent rupture of plaques [90]. A wide spectrum of MPO’s actions in human health, such as infection or other inflammatory processes, has been described. This enzyme has been shown to correlate significantly with other established markers of inflammation, including IL-6, CRP, TNF-α, and WBC [91]. The secretion of MPO does not require cellular necrosis or mechanical activation, suggesting that it may be detected earlier in the disease process [92]. This property of MPO makes it a promising sensitive maker of plaque instability and endothelial dysfunction. One of the most common assays to measure MPO concentration (rather than activity) is the MPO sandwich immunoassay for plasma MPO measurements [93]. This is a relatively novel assay made available for clinical use. Nevertheless, there is still a lack of standardization among the field. The cutoffs applied in current studies of MPO have been varied and could be one explanation for some of the disparate clinical findings. This raises the need for an independent, peer-reviewed evaluation of the analytical performance of MPO in clinical use. MPO concentrations remain relatively stable in heparin samples stored on ice, but can be lower when stored in EDTA or citrate tubes [94]. Furthermore, storage of MPO at room temperature for 2 h can lead to a fourfold increase in MPO concentrations. Therefore, it is also important to scrutinize the effect of MPO handling on the interpretation of results.

Chapter | 21 Cardiovascular Biomarker Assessment Across Glycemic Status 253

Patients with coronary artery disease (CAD) have raised MPO levels compared to patients without atherosclerosis seen on coronary angiography. In this first epidemiological study conducted to assess the association between MPO and CAD, Zhang et al. found that leukocyte and blood-MPO levels from patients with established CAD were independently associated with significant increased risk of CAD even after adjustment for traditional risk factors [90]. Further studies observing patients with stable CAD compared to those with ACS saw increasing levels of MPO, which reflects the spectrum of acuity of CAD. Ndrepepa et al. demonstrated that higher serum MPO was associated with progression from stable CAD to non-ST-segment elevation ACS and to acute MI with the lowest MPO levels in patients with stable CAD and highest in patients with acute MI [95]. Although prior data from smaller trials suggest that the diagnostic performance of MPO for acute MI was inferior to cardiac troponins (cTns) with 88% sensitivity and 32% specificity, another cohort of 604 patients presenting with symptoms suggestive of ACS demonstrated more positive results [96 98]. Brennan et al. demonstrated that even in the absence of positive troponin, baseline MPO levels in these patients are predictive of major adverse cardiovascular events (MACEs) at 30 days and 6 months after initial presentation with chest pain. The diagnostic value of MPO, though still lower than cTn for diagnosis of MI, was comparable for diagnosis of ACS and much better for unstable angina [96,97]. The establishment of MPO levels and the presence of CAD led investigators to further explore the role of MPO in patients presenting with ACS. Another finding from Brennan et al. showed that MPO levels could also identify patients at risk for cardiac events in the absence of abnormal troponin levels at presentation [99]. The CAPTURE study studied a larger cohort of 1090 patients and came to similar conclusions. Their study saw that in patients with low troponin-T levels, elevated MPO levels were identified to be a subgroup with significantly increased adverse risk [100]. In the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, those above an MPO cutoff of 350 μg/L had a hazard ratio of 2.25 for 6-month incidence of death and acute MI independent of other markers such as CRP and cTn). Additional studies from Morrow et al. and Mocatta et al. further demonstrated that the predictive ability of MPO is also independent from NT-proBNP [96,101]. Increased evidence for risk stratification in different population cohorts using MPO has also been demonstrated. Tang et al. concluded that plasma MPO provides independent prognostic value for the prediction of longterm MACE in stable CAD patients [102]. The individuals with increased CRP but concomitantly low MPO levels had lower risk of MACE compared to those with both markers observed to be high. In another study, Tang et al. compared the MPO levels of chronic systolic heart failure

patients with a control group through a cross-sectional study. The plasma MPO levels in patients with chronic systolic heart failure were significantly elevated compared to those of the healthy control group [103]. Furthermore, Tang et al. has also been able to correlate plasma MPO levels with echocardiographic indices of systolic and diastolic heart failure [104]. These studies provide clinical evidence that MPO-generated cytotoxic products could be linked to ventricular remodeling that had previously been described in animal models. Other studies of heart failure patients have tied plasma MPO magnitude with an increased likelihood of more advanced heart failure and overall increased specificity in screening for patients with systolic heart failure [105 107]. Finally, MPO has also demonstrated importance in the evaluation for CVD in apparently healthy subjects. One of the largest studies is the EPIC-Norfolk Prospective Population study. In their case control study, healthy patients who developed CAD in 8 years of follow-up were observed to have higher baseline MPO levels compared to control subjects who had not developed CAD [108]. These observations were independent of CAD risk factors, and further demonstrated on individuals whose CAD risk was intermediate based on Framingham risk score calculations by another group. MPO levels in healthy subjects were also found to be associated with developing heart failure. In 3733 healthy elderly patients who were followed for 7 years, Tang et al. demonstrated that those in the top quartile of MPO levels had an increased risk for developing heart failure [107]. Evidence has accumulated for the usefulness of MPO as both a diagnostic and prognostic marker in macrovascular disease. However, conflicting results also exist. Studies from different groups have observed no additional diagnostic significance of MPO when added to cTns or similar sensitivities but decreased specificity [109,110]. Other groups have found no significant relationship between MPO and MI or independent associations with MPO and mortality in long-term follow-up [111 113]. In order to better understand MPO’s role as a marker, it is important for more studies to examine the beneficial impact of MPO-guided therapeutics. A 2011 study from Ndrepepa et al. looked at the impact of beta blockers, angiotensin-converting enzyme inhibitors (ACEis), and statins on levels of MPO [114]. The group observed MPO-lowering effects by all three drugs but only in patients with ACS and not stable CAD. Many smaller studies have been performed on the effects of medications on MPO levels. However, larger clinical studies must be performed to assess the role of MPO as a measure of treatment efficacy or even as a potential therapeutic target. The role of MPO as an inflammatory mediator in diabetes has not been extensively studied (Table 21.3) [115 119]. Observational studies have seen significant increases of MPO in the serum of CAD patients with

254 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

TABLE 21.3 Summary of Selected Studies Investigating the Prognostic Abilities of MPO Study Population

Study

N

Follow-up (Days/ Weeks/Months/Years)

Prognostic Cutoff Value

Prediction of Adverse Outcome

Refs.

CAD

Baldus et al.

1090

6 months

350 μg/L

HR 2.11

[100]

Brennan et al.

604

30 days 6 months

198 pM

OR third quartile 4.2, fourth quartile 4.1

[99]

Cavusoglu et al.

193

24 months

20.34 ng/mL

88% MI-free survival below cutoff vs. 74%

[98]

Apple et al.

457

4 months

125.6 μg/L

No difference in mortality

[115]

Morrow et al.

1524

30 days 6 months

884 pM

30 days OR 2.1 but 6 months OR 1.15

[96]

Mocatta et al.

668

5 years

55 ng/mL patients 39 ng/mL control

OR 1.8

[101]

Nicholls et al.

490

6 months

640 pmol/L

OR 2.4 highest vs. lowest quartile

[116]

Scirica et al.

4352

1 year

670 pmol/L

No difference in predictive ability

[117]

Rudolph et al.

1818

30 days 6 months

562 1070 pM

30 days HR 1.325 but 6 months HR 1.009

[118]

Kaya et al.

119

2 years

68 ng/mL

OR 3.843

[119]

Stefanescu et al.

382

3.5 years

52.6 75.0 μg/L

OR 1.96 but HR 1.06 not an independent correlate of mortality

[110]

Tang et al.

1895

3 years

322 pmol/L

HR 1.71

[102]

Meuwese et al.

3375

8 years

728 pmol/L

OR 1.49 highest vs. lowest quartile

[108]

Healthy

CAD, coronary artery disease; OR, odd ratio; other abbreviations as in Tables 21.1 and 21.2.

T2DM compared to those without [120,121]. Other studies have ranged from seeing mild increases in serum MPO of diabetic smokers with mild stable angina to observations of increased MPO in diabetic patients with or without CAD compared to controls or even reduced levels of MPO in patients with T1DM compared to controls [122 124]. In a recent multimarker study of patients across glycemic status from Tang et al., though MPO levels were slightly higher in the diabetes subgroup, MPO remained an independent predictor of 3-year MACE even after adjusting for the presence of DM [125]. The knowledge of MPO’s role as a useful biomarker in the setting of diabetes still requires additional study. However, the diagnostic and prognostic potential of MPO demonstrated in patients with a variety of CVDs makes it an important focus for future studies in the cardiovascular risk stratification of diabetes patients.

CARDIAC TROPONINS Troponins are intracellular regulatory proteins that play an essential role in the calcium-mediated cross bridge cycling

of actin and myosin during excitation contraction processes. Of the three general troponin subunits, cardiac troponin I (cTnI) and T (cTnT) are unique to the heart [126]. cTnI is not found outside of the heart at any stage of development; cTnT, although expressed to a limited extent in skeletal muscle, cannot be detected in these muscles through current assays [127]. During cardiac injury, the cardiac myocyte membrane integrity is disrupted, which results in the loss of intracellular components, such as releasable/cytosolic pools of cTn, into the extracellular spaces [128]. Clinically, elevated levels of cTns can be detected in acute clinical disease states such as MI, where an ample amount of myocyte necrosis has occurred [129]. There can be troponin increases in other various settings of myocardial dysfunction, such as acute and chronic heart failure, myocarditis, or drug-induced cardiotoxicities. Furthermore, cTn increases are observed in nondisease states such as extreme exertion, which raises the possibility of injury as a reversible mechanism [130 132]. A vast majority of cTn elevation is the result of myocyte necrosis, but there can be other causes, such as

Chapter | 21 Cardiovascular Biomarker Assessment Across Glycemic Status 255

increased membrane permeability, diminished renal clearance, or increased myocardial turnover [133 135]. Better understanding of this array of mechanisms for myocardial damage will aid the prognostic potential of cTns. cTnI and cTnT are specific markers for myocardial necrosis, although the T and I subunits provide largely identical information. Furthermore, they can be detected by using immunoassays. Through the recent developments of higher sensitivity assays, multiple groups have worked to standardize the assay and prospective criteria for analytic characterization. In 2012, the joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Health Federation endorsed the use of troponin as a marker for the definition of acute MI [129]. Laboratories were recommended to utilize a cutoff of 99th percentile of a normal reference population to define the presence of cardiac injury. cTn concentrations typically begin to rise 2 3 h after the onset of acute MI and up to 80% of patients with acute MI will have troponin elevations by 2 3 h after presentation [136]. In a young healthy individual, there is expected to be low or no measurable troponin in the blood [137]. Levels of detection may vary between manufacturers, which is important when evaluating studies of cTns [138]. Ideally, a high sensitivity assay will quantitate troponin levels in 100% of the population. Currently, the International Federation of Clinical Chemistry (IFCC) task force suggests that a cTn assay labeled as highly sensitive should detect measurable cTn in more than 50% of healthy subjects and preferably in more than 95% [137].

cTns as a Prognostic Tool The use of cTns in diagnosis of acute cardiac injury is well established [129,139,140]. However, the prognostic role of cTn levels is less well understood and under investigation. The prognostic value of elevated cTn in patients in both ST elevation and non-ST elevation MI has been demonstrated. A pooled study of 21 large studies by Ottani et al. involving 18,982 patients with ACS found that increased serum cTn was associated with death or reinfarction at both 30 days (OR 5 3.44) and long-term outcome of between 5 months to 3 years (OR 5 3.11) [141]. Meta-analysis of non-ST elevation MI revealed similar results [142]. Analysis by Heidenreich et al. of 7 clinical trials and 19 cohort studies of patients with non-ST elevation myocardial infarction (NSTEMI) observed higher mortality rates for patients with either elevated cTnI (6% vs. 1.5% at 28 weeks follow-up) or cTnT (5.5% vs. 1.7% at 10 weeks follow-up) after short-term follow-up. Further analysis from Ottani et al. saw a persistence of detrimental effects of elevated cTns after a long follow-up of 5 months to 3 years with observed rates of cardiac mortality of 10.1%

versus 4.0% [141]. Additionally, in the case of chronic stable heart failure, another recent meta-analysis looking through 16 studies of cTn levels in patients with chronic systolic or diastolic heart failure showed that the troponin levels are predictors of both all-cause mortality (HR 5 2.85) as well as combined adverse cardiovascular outcomes (HR 5 2.38) [143]. As assay technology has improved to become 10 times more sensitive than the most so-called “sensitive assay,” levels of cTn much lower than 10 ng/L can now be detected in patients [138,144]. The ability to detect these subclinical levels of troponin in otherwise healthy individuals has led investigators to challenge the “normal” range of troponin. Studies have now shown that detectable cTn utilizing the high sensitivity assays is independently associated with more left ventricular hypertrophy, depressed left ventricular ejection fraction (LVEF) and greater coronary calcium score as well as an increase in risk of new-onset heart failure, cardiovascular mortality, and ischemic cardiovascular events even when controlling for risk factors such as renal function, NT-proBNP, and hsCRP [145 148]. However, as seen in studies such as Atherosclerosis Risk in Communities Study and the Framingham Offspring Study, both cTnT and cTnI did not associate with MI as strongly as heart failure after adjustment for conventional risk markers [147,149]. Interestingly, this suggests mechanisms beyond asymptomatic MI for the release of these troponins. cTn levels were also observed to be dynamic among elderly subjects followed for 2 3 years in the Cardiovascular Health Study, with the direction of their troponin profile trajectory associating with the risk of new-onset heart failure and cardiovascular death [148]. The use of cTns to guide therapy has been successfully demonstrated in ACS. It has been seen that patients with chest pain with elevated cTn levels on admission benefited from intensive medical therapy when compared to a more conservative strategy [150,151]. However, in these studies, patients with troponin levels in the normal range did not seem to benefit from the therapy intensification. Extending the results from the fact that cTns may add additional prognostic information, a recent study from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) cohort’s biomarker subgroup looked at if the effects of statin treatment can be guided by levels of cTns [152]. Unfortunately, this study did not observe any relative treatment effect on the clinical outcome across levels of cTn, though statin treatment was associated with a slight but statistically significant decrease in cTn at 1 year. Retrospective study from the PEACE study also failed to show interactions between cTn levels and the benefits of ACEi trandolapril in lowrisk, stable CAD patients [153]. Therefore, despite studies

256 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

contributing to the routine use of cTn assessment in patients presenting with suspected MI and the use of cTn levels to guide treatment decisions in ACS, clinical benefits of using cTns in low-risk patients remain unproven. Additional understanding of how cTn is linked to the pathophysiology targeted by different therapeutic strategies will need to be understood.

Diabetes and cTns With the recent developments of higher sensitivity troponin assays, diabetic patients, with their already increased incident of cardiac events, are a valuable group to study. Although the risk of elevated troponin is recognized, few studies so far have been conducted to look at the prognostic value of cTn in stable patients across glycemic status and how these patients can be further stratified in macrovascular risk. A recent study from Tang et al. saw a strong association between the magnitude of subclinical myocardial necrosis, assay detectable levels of troponin below the cutoff for MI diagnosis, and risk of 3-year MACE (HR 5 1.98) even after adjustment for traditional risk factors, hsCRP, and creatinine clearance [154]. This study involved 1275 subjects in which 22% had subclinical levels of cTn and these patients tended to be older with cardiovascular risk factors and history of heart failure. The observations from the Tang et al. study is in line with previous studies that identified troponin “normal” groups of diabetic patients as at risk for early death [155]. These general findings were again seen in a study from Hillis et al. that observed cTnT being able to improve the accuracy of cardiovascular risk prediction [156]. Interestingly, Tang et al. also observed a paradoxically increased cTn related cardiovascular risk in on-treatment patients with HbA1c levels below 6.5%. This trend has been previously observed in intensive glycemic control studies of ACCORD [14]. The utilization of troponins in this case could be a way to help assess risk imposed by glycemic control to reduce future MACE events. The evidence suggests that detectable cTns offer prognostic information for diabetic patients, as well. However, like troponin studies in the general population, it is important to understand the mechanistic triggers of subclinical troponin release in order to design better risk reduction strategies for this newly identified group of at-risk patients.

B-TYPE NATRIURETIC PEPTIDE The natriuretic peptides act on the salt, water, and pressure regulation systems in the body. The B-type natriuretic peptide (BNP) is a member of the natriuretic peptide family. It was first identified from pig brains in 1988 and subsequently found to be present in high concentrations in the ventricles [157,158]. The atrial-natriuretic peptide

(ANP) is similar to BNP, but mainly released from the atria. These hormones are sensitive to stretch in their respective compartments, and BNP, being released from the cardiac ventricle, suggests it may be a more sensitive and specific marker of ventricular disorders [159]. Subsequent trials have confirmed plasma BNP levels to be a more important predictor of morbidity and mortality than ANP in patients with CAD [160]. BNP is stored within the ventricles and, to a lesser extent, the atria as proBNP, a 108-amino acid prohormone. As a response to myocardial stretch under increased pressure, proBNP is released and cleaved to the biologically active 32-amino acid peptide BNP and 76-amino acid biologically inert N-terminal fragment, NT-proBNP [161]. The active peptide has physiologic actions to stimulate natriuretic, diuretic, and antihypertensive responses [162]. Although blood levels of BNPs rise to a high level in the setting of acute failure, it has been found that many BNP assays also recognize the higher molecular weight prohormone proBNP that contains BNP before cleavage [163,164]. This explains the paradoxical finding of BNP insufficiency despite the high circulating levels of these biomarkers. Many studies have now been performed on assessing the utility of BNP and NT-proBNP levels as markers for diagnosis of acute decompensated congestive heart failure or prognosis in chronic heart failure. AHA/ACCF 2013 guidelines recommend measurements of BNP/NT-proBNP to support uncertain clinical decisions for the diagnosis of heart failure and to establish the prognosis or severity in chronic heart failure [165]. In general, levels of BNP and NT-proBNP are reasonably correlated for clinical testing purposes. However, the normal levels of BNP depend on the clinical features being tested because of the ability to detect subclinical levels of BNP. Furthermore, the levels of BNP are age- and gender specific and can be dramatically altered in states of renal dysfunction [166,167]. Generally, 90% of young healthy adults will have BNP ,25 pg/mL and NT-proBNP ,75 pg/mL [168]. For acutely dyspneic patients, the cutoffs are less clear but there are suggested values of BNP ,100 pg/mL and NT-proBNP ,300 pg/mL to rule out heart failure [169]. Though study parameters and endpoints vary, many studies have found BNP and NT-proBNP levels to be predictive of cardiovascular outcomes in both acute and chronic settings [170 173]. In heart failure patients, meta-analysis from Januzzi et al. observed that every 100-pg/mL increase in BNP resulted in 35% increase in risk of death during a mean follow-up of 1.4 2 years [174]. Furthermore, a 2009 meta-analysis pooling data from 40 long-term prospective studies and 87,474 patients to investigate the benefits of measuring BNP in settings of left ventricular dysfunction revealed a strong association between circulating concentrations of BNP and NT-proBNP in a variety of

Chapter | 21 Cardiovascular Biomarker Assessment Across Glycemic Status 257

TABLE 21.4 Summary of Selected Studies Investigating the Prognostic Abilities of B-Type Natriuretic Peptide Study Population

Study

N

Follow-up (Days/Weeks/ Months/Years)

Marker Cutoff Value

Prediction of Adverse Outcome

Refs.

HF

Doust et al. meta-analysis

652

1.4 2 years

Every 100 pg/mL increase in BNP

35% increase in RR

[176]

HF Subset, REDHOT Study

317

90 days

,200 pg/mL BNP

9% event rate vs. 29%

[177]

ICON Study

1256

76 days

NT-proBNP . 5180 pg/mL

RR 5.2

[174]

COPERNICUS

1011

29 months

NT-proBNP 1767 pg/mL

RR 2.7

[173]

ADHERE Study

48,629

In-hospital

BNP fourth quartile .1730 pg/mL

OR 2.2

[178]

Heart and Soul Study

987

3.7 years

1 SD increase in logNTproBNP

Each increasing SD HR 1.7

[179]

AtheroGene Study

1085

2.5 years

BNP . 100 pg/mL

HR 4.4

[180]

de Lemos

2525

10 months

BNP . 80 pg/mL

Highest quartile vs. lowest quartile OR 5.8

[181]

A Z

4497

1 year

BNP . 80 pg/mL

HR 2.5 at study entry, HR 3.9 at 4 months, HR 4.7 at 12 months

[172]

Berger et al.

452

1.6 years

BNP . 130 pg/mL

SCD in 19% of patient above cutoff vs. to 1% below

[182]

Stable CAD

ACS

ADHERE, Acutely Decompensated Heart Failure National Registry; BNP, B-type natriuretic peptide; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; HF, heart failure; ICON, International Collaborative of NT-proBNP; REDHOT, Rapid Emergency Department Heart Failure Outpatient Trial; RR, relative risk; SD, standard deviation; other abbreviations as in Tables 21.1 21.3.

circumstances [175]. The individuals in the top third of BNP level had a combined risk ratio of 2.82 compared to those in the lower third after adjusting for conventional cardiovascular risk factors.

BNP in the Prevention of Subclinical CVD The use of BNPs in longitudinal management of patients with chronic heart failure is far less established and it is not known how well BNP can be used to stratify risk and develop adverse event prevention strategies. However, recent studies have begun to shed more light on the experimental benefits of tracking BNP levels in patients (Table 21.4) [176 182]. A meta-analysis in 2010 from Porapakkham et al. combined data from eight randomized trials to study the benefits of BNP-level-guided heart failure therapy [183]. With a mean follow-up period of 17 months, their analysis revealed significant decreases in all-cause mortality in the BNP-guided arm (RR 5 0.76, P 5 0.03) in individuals under the age of 75, as well as a significant difference in medical treatment among the two groups. In the studies where data

were available, the BNP arm was characterized by more frequent medication adjustments and a twofold increase of patients who reached target levels of renin angiotensin aldosterone system (RAAS) antagonists or beta blockers (21% vs. 11.7% for RAAS antagonist, 22% vs. 12.5%, respectively). Two further meta-analyses of similar study sizes since have also concluded that BNP-guided therapy is superior to symptom-guided therapy [184,185]. More recent trials have evaluated the use of BNP to identify high-risk individuals for the implementation of preventative cardiovascular interventions. The Screening to Prevent Heart Failure (STOP-HF) study randomized 1374 patients (of which 27% had diabetes) with at least one cardiovascular risk factor to a BNP-guided arm versus usual care [186]. Those in the BNP-guided arm received yearly BNP measurements and any levels above 50 pg/mL received cardiovascular consultation. After a mean 4.2 years of follow-up, 8.7% of the control group were observed to reach the primary endpoint of asymptomatic left ventricular heart failure or incident heart failure compared to a significantly decreased 5.3% in the BNP-guided arm (OR 0.55).

258 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

Furthermore, a similar study involving a patient population with T2DM came to a similar conclusion. The PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease (PONTIAC) study randomized 300 patients with T2DM with a BNP level above 125 pg/mL to either a BNP-guided arm or conventional care at a diabetes clinic [187]. Those in the BNP arm received intensive treatment at a cardiac outpatient clinic for the up-titration of (RAAS) antagonists and beta blockers. After a 2-year follow-up, the biomarkerassociated group was associated with a 65% reduction in primary endpoint of hospitalization or death due to cardiac causes (HR 5 0.351). Given this promising result, it is important to note that the mechanism by which the BNP arm attained the strikingly different outcome is less than clear. The control group received significantly less neurohormonal therapy despite guideline-based care for both groups. Furthermore, the measured BNP levels of both groups were not significantly different at the end of the study. Nevertheless, the PONTIAC study is the first of its kind in using BNP-guided therapy as an avenue for targeting the at-risk diabetic population and provides optimistic results moving forward.

ALBUMINURIA Albuminuria, previously termed microalbuminuria, is a condition where moderately raised albumin levels can be detected in the urine [188]. Traditionally, increased levels of urine albumin have been considered to be a precursor of diabetic nephropathy but studies now have also demonstrated that albuminuria is also linked to adverse cardiovascular outcomes and death [189]. A majority of proteins in urine is albumin that is filtered from the plasma, and a normal healthy individual will be expected to lose ,30 mg in a day [190]. However, the mechanism by which albuminuria is reflective of CVD is not well understood. Evidence to date associates any level of albuminuria to a loss of vascular endothelial function in many organs. Impaired endothelial synthesis of nitric oxide has been independently associated with albuminuria and diabetes [191 193]. This provides a common mechanism for both increased cardiovascular and renal risk in patients with elevated albuminuria. Additionally, low levels of heparan sulfate in the glomerular glycocalyx lining as a result of low chronic inflammation in atherosclerosis could lead to increased glomerular permeability and albumin secretion [194]. Furthermore, there is an association of moderately elevated albuminuria with adverse risk factors such as age, increased blood pressure, and increased inflammatory markers in patients with or without diabetes [195,196]. One of the benefits of albuminuria is that it is easily measured in the urine with 24-h urine albumin excretion being the gold standard. Although this method is more

cumbersome and time-consuming, it can be more reliable than the albumin creatinine ratio (ACR) across age, weight, and serum creatinine concentrations. The 24-h method quantifies moderate elevation of albumin as $ 30 mg/day and severe elevation as $ 300 mg/day [188]. Urine ACR can be used to eliminate confounding values of urine volume on albumin concentration. Some confounding factors to consider for ACR would be differing creatinine ratios with race, diet, and muscle mass. However, this test is time-saving, well correlated with the 24-h urine albumin excretion, and the preferred screening strategy for moderately increased albuminuria [197]. Normal or slightly increased ratios are defined as ,30 mg/g of creatinines. Moderately increased levels are $ 30 mg/g of creatinine and severely increased levels are considered to be $ 300 mg/g of creatinine [188]. It is important to note that the terms micro- and macroalbuminuria refer to albumin secretions of 30 299 mg/24 h and more than 300 mg/24 h, respectively [198]. However, the lack of pathologic basis to these thresholds has caused guidelines to change their recommendation of using these terms. Epidemiological evidence has established that diabetes is one of the most common causes for end-stage renal disease. NHANES III data has found that 28.2% of patients with T2DM have moderately elevated albuminuria [199]. Of these patients, approximately 20 40% will develop renal failure. However, this total may be higher if the patients did not die due to cardiovascular complications first. Convincing evidence in recent years has independently associated albuminuria with adverse cardiovascular outcomes. Population studies have observed moderately elevated albuminuria to be significantly correlated with cardiovascular risk. In one study of a Prevention of REnal and Vascular ENdstage Disease (PREVEND) population, 40,000 patients were observed for a median of 2.6 years [200,201]. A 1.35-fold increase of cardiovascular mortality was documented for each doubling of urine albumin excretion. Later, analysis of the trial also observed that the risk of MACE was reduced among the participants whose albuminuria decreased after 1-year follow-up [202]. Furthermore, higher levels of albumin excretion even in the “normal” range have also been shown to be associated with increased cardiovascular risk. In the Third Copenhagen Heart Study, healthy patients within the top quartile of albumin excretion with 6.9 mg/day had an RR 5 2 for CAD [203]. Similar findings from the Framingham Heart Study subgroup saw healthy participants with higher-than-median ACR developing a greater risk for first cardiovascular event after 6 years follow-up [204]. Finally, a meta-analysis involving over 1 million participants in the general population saw increased risk of MI, heart failure, stroke, or sudden cardiac death associated with rising levels of ACR [205]. Strong observations of albuminuria and association of heart disease exist, but several trials testing the treatment

Chapter | 21 Cardiovascular Biomarker Assessment Across Glycemic Status 259

of albuminuria have been conducted without parallel benefit demonstrated across these studies. The Losartan Intervention for Endpoint Reduction (LIFE) in hypertension trial suggested a decreased risk for cardiovascular events when utilizing the magnitude of albuminuria as a guide to angiotensin-converting enzyme receptor blocker (ARB) therapy [206,207]. The results from LIFE were more striking from the diabetes subgroup, in which losartan was associated with a reduction of 24% in the primary endpoint, and a significant reduction of 37% in CV and 39% in all-cause mortality. Meta-analysis of over 8000 patients by Maione et al. saw reduced risk of nonfatal cardiovascular outcomes with ACEi or ARB in patients with at least one cardiovascular risk factor and albuminuria [208]. However, Maione et al. did not observe any reduced rates of cardiovascular mortality. Furthermore, a meta-analysis for the USPSTF by Fink et al. looking at 18 trials of ACEi and 4 of ARB observed the same lack of association between therapeutics and cardiovascular death [209]. Finally, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) trial evaluated the combination of ACEi and ARB in patients with diabetes or pre-existing peripheral vascular disease [210]. They observed that increased baseline albuminuria was associated with worse cardiovascular outcomes but not beyond ACR baseline values of 10 mg/g of creatinine. In the absence of clear data for improved cardiovascular outcomes with albuminuria-guided therapy, it is difficult to make clear recommendations on cardiovascular management strategies utilizing this marker. The addition of ACEi or ARB appears to improve nonfatal cardiac endpoint. However, the other deleterious effects of these drugs such as hyperkalemia may affect the overall mortality of these patients. Despite these observations, monitoring levels of albuminuria is still important for the development of other pathologies. Because albuminuria has been also demonstrated to be independently associated with increased mortality independent of diabetes, many guidelines recommend annual screening for albuminuria in diabetes patients or patients already at high risk for albuminuria [8,211,212].

PERSPECTIVES ON BIOMARKERS FOR CARDIOVASCULAR RISK Multi-Biomarker Profiles for Prognostics As new cardiovascular biomarkers are developed, a clear trend that has emerged that many markers reflect different pathophysiological pathways. One promising approach in light of this increased clinical data is the utilization of multiple markers and a multimarker score based on the number of markers within the set that are elevated. This combination can be useful to improve diagnostic and

prognostic information by increasing the specificity and sensitivity of detection for specific clinical scenarios. An early Framingham Offspring Study from 2006 was one of the first significant attempts to assess the prognostic value of a large combination of biomarkers that consisted of CRP, BNP, NT-ProBNP, aldosterone, renin, fibrinogen, D-dimer, PAI-1, homocysteine, and urinary albumin:creatinine ratio in improving cardiovascular risk stratification [213]. Unfortunately, a multimarker score from this study resulted only in a small ability to actually stratify risk. This same group followed up with another study that looked at a different set of biomarker profiles consisting of sST2, GDF-15, hsTnI, BNP, and hsCRP in predicting cardiovascular risk [149]. They observed significant increases in risk reclassification for outcomes in heart failure and all-cause mortality. This example demonstrates how the selection of biomarkers can impact the utility of a multimarker approach, and furthermore provides evidence of its potential utility in the clinic. A larger number of markers is not the key in a multi-biomarker profile because some may be associated with the outcome only by random chance. In a recent novel study employing a multimarker strategy for risk prediction, Tang et al. evaluated the prognostic ability of a multimarker score for the risk stratification in stable patients undergoing elective diagnostic coronary angiography [125]. Furthermore, this cohort consisted of individuals with varied glycemic status of diabetes, pre-diabetes, and normal based on HbA1c values. They evaluated the extent which BNP, MPO, and hsCRP alone or together could provide addition prognostic information for MACE in a 3-year follow-up of these patients. By adding the number of positive cardiac biomarkers, Tang et al. was able to develop a cardiac biomarker score (CBS) that integrated the risk profile of the study cohort and provided incremental prognostic value by Kaplan Meier analysis. Furthermore, Tang et al. observed that their multimarker strategy was able to be an independent predictor of 3-year MACE even after adjustment for traditional risk factors (HR 5 6.11). More importantly, this assessment remained strong among the subgroups of normal (HR 5 4.24), pre-diabetes (HR 5 7.62), diabetes (HR 5 5.61), and even those without significant angiographic evidence of CAD (HR 5 10.82) (Figure 21.1). The striking positive results further support the idea that the composition of biomarkers in a multimarker panel is essential and has to be carefully selected. The study from Tang et al. utilized FDA-approved markers that have already been extensively studied and strongly suggested to be prognostic for adverse cardiovascular outcomes. Finally, this study further explores the impact of different levels of glycemic control on the prognostic value of cardiac biomarkers and helps quantify the risk of both the at-risk patients and, more important, the normally considered lowrisk patients. This is an example of how combining

260 Glucose Intake and Utilization in Pre-Diabetes and Diabetes

FIGURE 21.1 (A) Kaplan Meier analysis of CBS predicting future MACEs after 3-year follow-up. (B) Event rates for future MACEs after 3-year follow-up stratified by glycemic status. *Reprinted from Tang et al. [125]. Copyright 2013, with permission from Elsevier.

biomarkers can be an effective way of gathering information from diverse pathologic processes to improve the performance of screening tests.

CONCLUSION The process to validate the use of biomarkers is rigorous, especially in a preventative setting. The factors generally used to determine causality from observation studies were first outlined by Hill in 1965 [214]. These factors include consistency, temporality, dose response, coherence of data across studies, and experimental evidence. Considering the evidence from the presented studies, HbA1c meets the criteria of association, temporality, and dose response. However, be it due to study designs or other factors, it has not met the criteria for coherence of data across data types, nor has it demonstrated its biomarker value through experimental evidence. Unlike well-established markers such as LDL, the value of HbA1c in predicting macrovascular events is much diminished. In a 2009 scientific statement from the AHA, the group published a set of evaluations that should be met

for ideal risk markers [215]. They advocated a six-step evaluation that looked at proof of concept, prospective validation, providing incremental value, clinical utility, clinical outcomes, and cost-effectiveness. Some of the biomarkers presented in this chapter have clearly met a portion of the evaluations. Moreover, the potential of utilizing multiple, carefully chosen markers can further help accomplish this task. Biomarkers that reflect distinct pathophysiologic processes can synergistically be related to a single measure to provide a better sense of an individual’s overall risk profile. The ability of having a set of markers for prognostics can also help limit the personto-person, day-to-day, or inter-assay variability of any individual biomarker. As data continue to accumulate for these biomarkers, rigorous statistical validation will be critical in order to select the markers that add most to clinical care. Furthermore, our ever-growing understanding of molecular basis for disease, continued refinement of biomarker assays, and firm dedication toward providing better patient care will allow novel risk markers to play a vital role in the future of CVD management and medicine.

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