W.H. Wilson Tang, MD; Gary S. Francis, MD

Disclosures

J Am Coll Cardiol. 2010;55(7):688-696. 

In This Article

Evaluation of HF

Natriuretic Peptide Testing

One of the most important advances this year focused on the possible expanded use of natriuretic peptide testing to help guide medical therapy in patients with HF. First, the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure) study randomized 499 subjects >60 years of age to NT-proBNP–guided versus symptom-guided therapy. Investigators found no significant differences in survival or all-cause hospitalizations between the 2 groups, but some benefits were seen in the 60- to 75-year-old age group.[28] Similarly, the PRIMA (Effect of NT-proBNP Guided Treatment of Chronic Heart Failure) study randomized 345 subjects (of 2,900 screened hospitalized patients with elevated NT-proBNP ≥1,700 pg/ml) to an algorithmic approach that triggered an immediate intensification of HF treatment any time a patient's NT-proBNP value exceeded an individualized target versus standard of care. The NT-proBNP–guided arm did not show a significant difference in days alive outside the hospital compared with that guided by symptoms.[29] These findings are concordant with preliminary results reported from several smaller single-center studies, and highlight the lack of data supporting the use of natriuretic peptide testing to direct specific therapy. Nevertheless, there is still great interest in this strategy, with more studies likely to be done.

The question of how to best interpret natriuretic peptide levels in patients with HF has been raised by some investigators. In terms of serial measurements, preliminary data from the PRIMA study identified that almost 80% of patients reached their individualized target goal within the follow-up period of 1 year after hospital discharge.[29] Furthermore, better outcomes were observed among the 58% who maintained NT-proBNP target ranges for >75% of outpatient visits compared with those who did not maintain target ranges.[29] Clearly, changes in natriuretic peptide levels can track with long-term prognosis, as illustrated in an elegant analysis from the Val-HeFT (Valsartan in Heart Failure Trial).[30] In clinical practice, there seems to be a diminishing incremental value as natriuretic peptide levels rise above a certain threshold, yet only large reductions (>80% decrease) seem to favorably alter the long-term prognosis in patients with advanced HF.[31]

Novel Biomarkers

Although many novel biomarkers continue to search for clinical utility, some circulating metabolic and nutritional biomarkers that are available in clinical practice have been associated with long-term prognosis in the syndrome of HF. These include low serum estradiol[32] and testosterone[33] levels, high serum cobalamin[34] levels, as well as vitamin D deficiency[35] and low high-density lipoprotein[36] levels, to name a few. Low levels of coenzyme Q have also been associated with a poor prognosis in HF.[37] In addition, the presence of albuminuria has been identified as another strong prognostic marker of poor outcome that may reflect underlying vascular pathobiology. In a CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) substudy, the urine albumin–creatinine ratio was measured at baseline and during follow-up of 2,310 patients with HF. Investigators found that 30% had microalbuminuria and 11% had macroalbuminuria, regardless of impaired or preserved left ventricular function. The presence of any albuminuria was independently predictive of adverse cardiac events.[38]

Although the prognostic role of many novel markers such as ST2 and galectin-3 continues to be explored in HF,[39–41] there is more focus on biomarker predictors of HF development. In an elderly cohort of the Framingham Heart Study, high serum leptin levels were associated with increased risk of developing HF, although these levels had limited prognostic potential beyond clinical variables.[42] In contrast, resistin levels have been predictive of development of HF in several cohorts.[43,44] Metabolic syndrome has also been implicated as a risk factor for HF.[45] An impaired fasting glucose level itself does not seem to be a strong risk factor for development of HF independent of its risk for appearance of subsequent diabetes mellitus.[46] Myeloperoxidase,[47] interleukin-6,[48] and uric acid[49] have emerged as predictors of HF development in large epidemiologic databases. These observations validate to some extent the important concept that enhanced oxidative stress and inflammation may contribute to the development of HF independent of coronary events.

Genetic Testing

We have witnessed broader availability of clinical genetic testing for specific cardiomyopathies in recent times, which coincides with the 50th anniversary of the first clinical description of hypertrophic cardiomyopathy.[50] With the availability of genetic data, we are beginning to recognize that different sarcomeric mutations may be associated with different phenotypic expression patterns. In particular, a more significant disruption of myofilament architecture results from a frame-shift mutation rather than a missense mutation, which may explain different patterns of diastolic abnormalities with different gene mutations.[51] These findings imply that knowledge of specific mutations may someday provide valuable phenotype prediction and possibly even targeted therapeutic considerations.

Practice guidelines regarding genetic evaluation of cardiomyopathies have been published this year.[52] In general, the guidelines have emphasized the strong evidence that exists for genetic determinants of hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia. In the setting of dilated cardiomyopathy, conduction diseases and arrhythmia may point to specific etiologies, such as lamin A/C mutations, that portend a poor prognosis.[53] Hence, considerations for earlier device therapy in such patients may be warranted.[52] It is important to recognize that although identification of a specific genetic mutation is helpful in determining subsequent risks of mutation carriers among family members, the absence of any detectable mutation in the genes tested does not imply a truly negative result because the causative mutation may be unknown. In other words, low test sensitivity remains a hurdle for some disease conditions. Regardless of phenotype, genetic and family counseling is strongly recommended and a comprehensive family history must be captured. Education regarding disease transmission and family risk should be provided.[52] The guidelines also have highlighted the need for clinical screening, which includes history and physical examination, echocardiogram, and electrocardiogram, as well as some specific testing for certain cardiomyopathies, at regular intervals.

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