C-reactive protein predicts prognosis in mildly reduced-ejection-fraction heart failure

A Routine Inflammation Test May Reveal Hidden Long-Term Risk in Heart Failure

A standard blood test could help doctors identify heart-failure patients who face a substantially higher risk of dying over the following years—even when the test shows only a modest rise in inflammation. In a study of nearly 2,000 people hospitalized with heart failure and mildly reduced ejection fraction, researchers found that C-reactive protein, or CRP, was independently associated with all-cause mortality over a median follow-up of 30 months. The signal appeared at CRP concentrations as low as 5 milligrams per liter, a level that can easily be overlooked when clinicians are searching for evidence of severe infection or acute inflammation. Compared with patients whose CRP was below 5 mg/L, those with levels of 5 to less than 10 mg/L had a 72 percent higher adjusted risk of death. The risk rose further among patients with CRP levels of 10 to less than 50 mg/L and reached more than double the reference risk at 50 mg/L or above. The findings, published in Clinical Research in Cardiology, suggest that low-grade systemic inflammation may be an important marker of vulnerability in a form of heart failure that has received less attention than other major categories.

Heart failure is not a single disease. Clinicians commonly classify it according to the left ventricular ejection fraction, the proportion of blood pumped out of the heart’s main chamber with each contraction. In heart failure with mildly reduced ejection fraction, known as HFmrEF, the ejection fraction lies between 41 and 49 percent. This intermediate category accounts for roughly one-quarter of heart-failure patients, but people in it have historically been underrepresented in clinical trials and large registries. That has left physicians with less specific evidence to guide prognosis and treatment. The heart’s pumping ability in HFmrEF is impaired, but not to the extent seen in heart failure with reduced ejection fraction, while the biological processes affecting patients may overlap with both reduced and preserved ejection-fraction syndromes. Inflammation is one possible link. When the heart is strained, damaged or congested, immune and vascular systems can become activated, potentially amplifying tissue injury, impairing blood-vessel function and accelerating adverse remodeling of the heart. The new findings place an accessible inflammation marker at the center of risk assessment for this intermediate phenotype.

CRP is produced mainly by the liver after stimulation by inflammatory signaling molecules, particularly interleukin-6. It is part of the body’s acute-phase response and can rise sharply during bacterial infections, tissue injury and other inflammatory conditions. But CRP is not simply an on-off indicator of infection. Small, persistent elevations can reflect a broader state of immune activation associated with obesity, kidney disease, diabetes, vascular disease, chronic lung conditions and cardiovascular stress. In heart failure, inflammatory cytokines such as interleukin-6, tumor necrosis factor-alpha and interleukin-1 beta may contribute to a self-reinforcing cycle. They can influence vascular tone, reduce nitric-oxide availability, alter cardiac muscle function and promote structural changes in the myocardium. CRP may also participate in innate immune signaling, including activation of the classical complement pathway, although it remains uncertain whether CRP directly drives worsening heart failure or primarily serves as a highly useful indicator of underlying biological stress. The distinction matters: a prognostic marker can identify danger without necessarily being an effective drug target.

The researchers analyzed data from the HARMER registry, a retrospective, single-center registry of consecutive adults hospitalized with HFmrEF at University Medical Centre Mannheim in Germany between January 2016 and December 2022. To qualify, patients had to have symptoms or signs of heart failure and a left ventricular ejection fraction of 41 to 49 percent documented by standardized transthoracic echocardiography during the hospitalization. Of 2,228 patients initially identified, 44 were lost to follow-up, leaving 1,978 individuals for the primary analysis. Their median CRP concentration was 13.3 mg/L, with an interquartile range of 3.5 to 43.7 mg/L. The investigators divided patients into four predefined groups: below 5 mg/L, 5 to less than 10 mg/L, 10 to less than 50 mg/L, and 50 mg/L or higher. They then compared outcomes using Kaplan–Meier survival analyses and Cox proportional-hazards models, adjusting for factors including age, sex, body-mass index, coronary artery disease, chronic kidney disease, diabetes, acute decompensated heart failure, ischemic cardiomyopathy and anemia. CRP was also analyzed as a continuous variable after logarithmic transformation, a statistical approach that reduces the influence of its highly skewed distribution.

The raw outcome differences were striking. During the 30-month follow-up, death occurred in 17.0 percent of patients with CRP below 5 mg/L. The corresponding proportions were 30.1 percent among those with CRP between 5 and less than 10 mg/L, 36.4 percent among those with CRP from 10 to less than 50 mg/L, and 46.8 percent among those with CRP of at least 50 mg/L. Before adjustment, the highest CRP category was associated with a hazard ratio of 3.571 compared with the lowest category. After accounting for clinical characteristics, the association weakened but remained statistically robust: hazard ratios were 1.720 for 5 to less than 10 mg/L, 1.813 for 10 to less than 50 mg/L, and 2.275 for at least 50 mg/L. In the continuous analysis, each increase in the natural logarithm of CRP was associated with a hazard ratio of 1.250 for mortality. These results indicate a graded relationship rather than a single threshold at which risk suddenly appears. Even a mild elevation was informative.

Patients with higher CRP also tended to be older and more likely to have chronic kidney disease, diabetes, anemia, worse kidney-function measurements and more severe heart-failure symptoms. Their median NT-proBNP concentrations—a marker of cardiac wall stress—were higher, rising from 1,164 pg/mL in the lowest CRP group to 4,914 pg/mL in the highest. Moderate-to-severe mitral and tricuspid regurgitation were more common, and acute decompensated heart failure increased stepwise across the CRP categories. These patterns illustrate why the researchers used multivariable adjustment: high CRP can be a sign of several coexisting conditions rather than an isolated heart-failure mechanism. Even after these potential confounders were considered, the association with mortality persisted. The relationship was also broadly consistent across men and women, older and younger patients, and people with or without ischemic cardiomyopathy, although the strength of the association varied. In patients aged 70 or older, even the lowest elevated CRP category remained associated with increased risk, while among younger patients the clearest signal appeared at levels of 50 mg/L or above.

To test whether the results were being driven by obvious sources of inflammation, the investigators conducted a second analysis that excluded patients with infectious disease, acute myocardial infarction, stroke, malignancy, cardiogenic shock, cardiac arrest or rheumatic disease at admission. This produced a more narrowly defined cohort of 741 patients. The pattern survived the stricter test. Mortality occurred in 15.6 percent of patients with CRP below 5 mg/L, compared with 34.7 percent of those with CRP from 5 to less than 10 mg/L, 33.3 percent of those with CRP from 10 to less than 50 mg/L, and 38.9 percent of those with CRP at least 50 mg/L. In the adjusted model, the hazard ratios remained elevated at 2.370, 1.684 and 2.212, respectively. The persistence of the signal after removing major inflammatory conditions supports the idea that low-grade inflammation associated with heart failure or its comorbidities may carry prognostic information. However, it does not prove that inflammation causes the deaths. The study was observational and retrospective, so unmeasured differences between patients could still account for part of the association.

CRP did not perform in the same way for every outcome. Higher levels were associated with more heart-failure-related rehospitalizations in unadjusted analyses, but the relationship disappeared after multivariable adjustment. Instead, rehospitalization was independently linked to factors such as age, body-mass index, prior congestive heart failure, acute decompensation, anemia, aortic stenosis and mitral regurgitation. This contrast may be biologically meaningful. Mortality over several years can reflect a broad state of systemic vulnerability involving frailty, organ dysfunction, vascular disease and reduced physiological reserve, whereas hospitalization for worsening heart failure may depend more directly on congestion, valve disease, treatment decisions and access to care. The study also found higher rates of in-hospital death, 12-month mortality and major adverse cardiac and cerebrovascular events among patients with elevated CRP. Still, CRP was measured only once during the index hospitalization, and rehospitalizations were captured only at the researchers’ center, potentially missing events treated elsewhere.

The authors emphasize that CRP could become a practical addition to long-term risk stratification because it is inexpensive, widely available and already measured in routine clinical laboratories. The study does not justify using a CRP value alone to make treatment decisions, nor does it show that lowering CRP would improve survival. Two different assay platforms were used during the study period, and post-discharge treatment changes were not available. The single-center design also limits how confidently the findings can be generalized to other populations. Prospective, multicenter studies will need to determine whether repeated CRP measurements improve prediction beyond established markers such as NT-proBNP and whether combining inflammatory, cardiac and metabolic measurements offers a clearer picture of risk. Most importantly, clinical trials will be required to test whether inflammation is a modifiable driver in HFmrEF. Anti-inflammatory therapies, including interleukin-1 beta inhibitors and colchicine, have reduced cardiovascular events in selected settings, but evidence for direct benefit in heart failure remains limited and inconsistent. For now, the message is simpler—and potentially more useful: in HFmrEF, a CRP result that looks only mildly abnormal may be an early warning of much greater long-term danger.