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Dual-Biomarker Strategy Helps Identify Nonresponders to Cardiac Resynchronization

Key findings

  • Uncompensated cardiorenal syndrome at the time of device insertion, as defined by levels of NT-proBNP and cystatin C, was associated with a >9-fold increased risk of nonresponse to cardiac resynchronization therapy (CRT)
  • The two-year risk of a major adverse cardiovascular event (MACE) was increased 8-fold in patients with baseline uncompensated cardiorenal syndrome
  • High cystatin C at one month after CRT was associated with a greater risk of nonresponse and greater risk of MACE
  • The findings suggest that cardiorenal disease may be responsible in part for decreased efficacy of CRT, and that measuring NT-proBNP and cystatin C levels may be useful for patient selection and early monitoring of response

The term cardiorenal syndrome refers to any disorder characterized by acute or chronic cardiac and renal dysfunction. It can be difficult to distinguish between the two main groups of affected patients:

  1. Those whose disorder is driven primarily by cardiac dysfunction and right heart congestion and who may respond to aggressive treatment of heart failure (HF), such as with cardiac resynchronization therapy (CRT)
  2. Those who have coexisting intrinsic renal disease, which is not easily reversed and tends to confer a worse prognosis

Addressing this diagnostic challenge, in Heart RhythmJagmeet P. Singh, MD, PhD, associate chief of the Cardiology Division at Massachusetts General Hospital, Neal Chatterjee, MD, research fellow in Medicine, James Louis Januzzi, MD, Hutter Family professor of Medicine and director of the Dennis and Marilyn Barry Fellowship in Cardiology Research, and colleagues propose a dual-biomarker approach to patient selection for CRT. They've demonstrated that in patients with HF, levels of N-terminal pro b-type natriuretic peptide (NT-proBNP), a marker of HF severity, and cystatin C, a marker of renal function, are associated with the risk of nonresponse to CRT and the risk of a major adverse cardiovascular event (MACE) afterward.

Analysis Within the BIOCRT Study

Dr. Singh's team examined data on 92 patients in the Biomarkers to Predict CRT Response in Patients with HF (BIOCRT) trial, a prospective observational study of patients undergoing CRT at a single tertiary care hospital. Patients eligible for this analysis had NT-proBNP and cystatin C level concentrations measured during device implantation and one month after treatment.

The researchers stratified preimplantation cardiorenal status into four categories, based on biomarker levels:

  • Uncompensated cardiorenal syndrome: high NT-proBNP (>1000 pg/mL) and high cystatin C (>1 mg/L) (37% of patients)
  • Compensated cardiorenal syndrome: low NT-proBNP and high cystatin C (7%)
  • Uncompensated HF: high NT-proBNP and low cystatin C (26%)
  • Compensated HF: low NT-proBNP and low cystatin C (30%)

Baseline Cardiorenal Status and Clinical Outcomes

At six months after device implantation, 38 patients (41%) had an unchanged or worsened Heart Failure Clinical Composite Score and were classified as CRT nonresponders. By two years after implantation, 25 patients (27%) had suffered a MACE (the composite of death, cardiac transplant, left ventricular assist device or HF-related hospitalization).

Using patients with compensated HF as the reference group, the researchers calculated the risk of CRT nonresponse according to preimplantation cardiorenal status. Patients with compensated cardiorenal syndrome had a >30-fold increase in the odds of CRT nonresponse, and those with uncompensated cardiorenal syndrome had a >9-fold increase, even after adjustment for age, left bundle branch block and ischemic cardiomyopathy.

The risk of CRT nonresponse was not significantly increased in patients with uncompensated HF.

Uncompensated cardiorenal syndrome at implantation was associated with a >8-fold increase in the cumulative two-year risk of MACE, relative to patients with compensated HF. The risk of MACE did not differ significantly among the other three groups.

Early Change in Cystatin C and Clinical Outcomes

The research team classified the cohort into four categories of cardiorenal disease, based on changes in cystatin C between baseline and one month:

  • Irreversible cardiorenal disease: high cystatin C at baseline persisted at one month (36% of patients)
  • Progressive cardiorenal disease: a transition from low to high cystatin C (16%)
  • Reversible cardiorenal disease: renal function normalized (8%)
  • Normal renal function: low cystatin C at baseline persisted at one month (48%)

Patients with reversible renal dysfunction had no MACE over the two-year follow-up. For that reason, the researchers combined them with the normal group and defined all patients in those two groups as having non-intrinsic renal disease.

The group with irreversible renal dysfunction were at greatest risk of CRT nonresponse, nearly a 14-fold increase compared with the reference group of patients who had non-intrinsic renal disease. Their risk of MACE was 5-fold greater than the reference group. Patients with progressive cardiorenal disease had similarly increased MACE risk.

Clinical Implications

Cardiorenal disease may be in part responsible when patients with HF exhibit decreased nonresponse to CRT, the authors conclude. They believe NT-proBNP and cystatin C may be useful for selecting candidates for CRT and monitoring the early treatment effect.

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