Novel Urinary Inflammation Marker Sharpens Prognosis of Stable CAD

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Elevated levels of a urinary marker of inflammation are associated with worse long-term outcomes among patients with suspected stable coronary artery disease (CAD), according to a prospective study published online July 25, 2013, ahead of print in the European Heart Journal. Moreover, the marker appears to add prognostic value beyond conventional risk factors.

Investigators led by Gard Frodahl Tveitevåg Svingen, MD, of the University of Bergen (Bergen, Norway), analyzed blood and urine samples from 3,224 patients who underwent elective angiography for suspected CAD at a single institution between January 2000 and April 2004 and were enrolled in the Bergen Coronary Angiography Cohort. Levels of kynurenine and tryptophan were assessed, and the ratio of the 2 chemicals (K-T ratio) was correlated with clinical outcomes.

According to the authors, the cytokine interferon gamma, which is associated with atherosclerosis-related inflammation, stimulates the breakdown of tryptophan into kynurenine, thereby increasing the K-T ratio. Earlier research demonstrated that an elevated plasma K-T ratio is an index of heightened risk of adverse events in stable CAD (Pedersen ER, et al. Aterioscler Thromb Vas Biol. 2011;31:698-704).

Risk Rises with K-T Ratio

Over a median follow-up of 55 months, 8.4% of patients experienced a major coronary event (primary endpoint; MI, sudden cardiac death, and sudden death). Urine K-T ratios were strongly associated with the composite endpoint in a dose-response fashion across a range of baseline characteristics (P for interactions ≥ 0.07).

On multivariable analysis, the K-T ratio was linked to increased risk of the primary endpoint as well as acute MI and both cardiovascular and all-cause death, but showed only a trend toward predicting ischemic stroke and noncardiovascular death (table 1).

Table 1. Multivariable Risk of Outcomes by K-T Ratio

Per Standard Deviation Increment

Adjusted HR

95% CI

P Value

Major Coronary Events

1.31

1.15-1.49

< 0.001

Acute MI

1.32

1.15-1.51

< 0.001

Ischemic Stroke

1.21

0.97-1.52

0.09

All-Cause Mortality

1.23

1.07-1.42

0.005

CV Mortality

1.31

1.09-1.56

0.004

Non-CV Mortality

1.10

0.88-1.39

0.40


Analysis limited to patients with significant stenosis at angiography yielded similar estimates.

Conversely, no link was seen between major coronary events and eGFR, urine albumin-creatinine ratio, CRP, or plasma K-T ratio.

In addition, about half of study participants were included in WENBIT (Western Norway B Vitamin Intervention Trial) and randomized to treatment with folic acid, vitamin B6, or placebo, but the associations between urine K-T ratio and outcomes were unaffected by these interventions (P for interactions ≥ 0.34).

Addition of the urine K-T ratio increased the discriminatory power of a model containing a multitude of demographic, clinical, and angiographic factors for predicting risk of major coronary events, acute MI, and all-cause and cardiovascular mortality (table 2).

Table 2. Predictive Power of Model Without vs. With Urine K-T Ratio

ROC-AUCa

Model Without Urine K-T Ratio
(95% CI)

Model With Urine
K-T Ratio
(95% CI)

P Value

Major Coronary Events

0.775 (0.738-0.813)

0.786 (0.751-0.822)

0.03

Acute MI

0.762 (0.722-0.802)

0.774 (0.736-0.812)

0.03

All-Cause Mortality

0.795 (0.750-0.840)

0.813 (0.771-0.856)

0.02

CV Mortality

0.847 (0.800-0.894)

0.867 (0.825-0.910)

0.01

a Receiver operator characteristic-area under the curve.

A ‘Striking’ Relationship

The authors conclude that the K-T ratio’s “striking dose-response relationship and specificity to acute atherosclerotic events [should] prompt further investigations into the role of tryptophan catabolism and renal inflammation in atherogenesis and plaque rupture.”

With the exception of microalbumin and an unsuccessful look at the metabolites of thromboxane, few urinary markers for CAD have been explored, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), told TCTMD in a telephone interview. Such markers have the advantage of not involving blood draws and thus can be easily repeated if necessary, he noted.

The K-T ratio is pathologically important in that it indicates “how active the T-lymphocytes are and how much [the catalytic enzyme] is revved up,” he explained. “When these are activated, it means a lot of damage is occurring to the vascular tree. And the more inflammation there is, the more need for a balancing mechanism.”

As the authors note, kynurenine itself has immune-suppressive and vasodilator properties and thus may have counter-regulatory, protective effects on vessels.

Important for Research, Not Clinical Use

However, Dr. Brener was skeptical of the clinical usefulness of the K-T ratio as a marker. “When you look at the [predictive] model before and after the addition of the K-T ratio, the difference is minuscule. But it’s statistically significant, so it looks [good],” he said. The K-T ratio is interesting for research purposes, “but it’s not like physicians are going to be using this in practice anytime soon,” he added.

Also, taking issue with the authors’ claim that the increase in hazard is proportional to the rise in K-T ratio for all outcomes, Dr. Brener noted that this holds true only for CV mortality. For major coronary events and MI, incorporation of the K-T ratio adds little predictive power, he said.

Nonetheless, “it’s very important to understand this [inflammatory] pathway,” Dr. Brener observed. “If we had an activator of [the catalytic enzyme for tryptophan] that is not related to inflammatory cells, that would be great. You could create an independent vasodilator that could be given to anybody who has endothelial dysfunction due to hypercholesterolemia or hypertension, for example.”

Study Details

The mean age of patients was 61.9 years, and 69.2% were men. Altogether, 28.8% were diagnosed with triple-vessel disease and 42.6% with single- or double-vessel disease; 28.5% of patients did not have significant CAD.

Compared with patients in the first quartile of the urine K-T ratio, those in the fourth quartile were older, more likely to have extensive CAD or diabetes, less likely to smoke, and were more likely to use ACE inhibitors or loop diuretics.

 


Source:
Pedersen ER, Svingen GFT, Schartum-Hansen H, et al. Urinary excretion of kynurenine and tryptophan, cardiovascular events, and mortality after elective coronary angiography. Eur Heart J. 2013;Epub ahead of print.

 

 

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Novel Urinary Inflammation Marker Sharpens Prognosis of Stable CAD

Elevated levels of a urinary marker of inflammation are associated with worse long term outcomes among patients with suspected stable coronary artery disease (CAD), according to a prospective study published online July 25, 2013, ahead of print in the European
Disclosures
  • Drs. Svingen and Brener report no relevant conflicts of interest.

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