A step toward precision medicine: New drug targets for heart failure

A groundbreaking study in Nature Cardiovascular Research uncovers promising drug targets for heart failure (HF) and its subtypes, offering new hope for precision medicine in cardiology.

Study: Large-scale multi-omics identifies drug targets for heart failure with reduced and preserved ejection fraction. Image Credit: Owlie Productions / Shutterstock.com

A recent study published in Nature Cardiovascular Research identifies several promising drug targets for heart failure (HF) and its clinical subtypes. 

Treating HF and its subtypes

With each heartbeat, the heart pumps 50-70% of the blood volume present in the left ventricle to other organs throughout the body, which is otherwise known as left ventricular ejection volume (LVEF).

LVEF is used to classify the clinical subtypes of HF. Whereas HF with reduced ejection fraction (HFrEF) occurs when an individual’s LVEF is less than or equal to 40%, HF with preserved ejection fraction (HFpEF) occurs when LVEF is greater than or equal to 50%.

Current estimates indicate that about 64 million people throughout the world are diagnosed with HF. Despite the availability of several therapeutics for HF, some of which include aldosterone antagonists, beta blockers, and diuretics, most available treatments, except sodium glucose co-transport 2 (SGLT-2) inhibitors, are limited in their efficacy in the management of HFrEF.

About the study

In the current study, researchers use a combination of human genetics, proteomics, and transcriptomics data to identify potential drug targets for HF and its clinical subtypes. Mendelian randomization (MR) was used to identify proteins that are causally associated with the development of HFpEF and HFrEF.  

MR is a statistical method used to assess the causal effects of risk factors on human biology and disease. More specifically, this approach utilizes genetic variants of a certain risk factor to determine the causal impact of that risk factor on disease development. Since genetic variants are randomly inherited from parents to their children, they are not likely associated with confounding factors.

In the current study, a systematic MR was applied to data obtained from 27,799 HFrEF and 25,579 HFpEF patients across three major cohort studies including the Fenland, deCODE, and Atherosclerosis Risk in Communities (ARIC). A total of 4,988 unique human proteins from these samples were measured and correlated with genetic variants associated with the levels of these proteins.

For each gene that was significantly correlated with either HF clinical subtype, a therapeutic target profile was devised that also considered the therapeutic efficacy, on-target safety, novelty of the biological mechanism, druggability, and predicted mechanism of action of the gene. This profile was supported by data from knockout mice models, putative loss-of-function variants from the United Kingdom Biobank, and cardiac magnetic resonance imaging (MRI) parameters.

Study findings

The MR analysis led to the identification of 70 and 10 target genes for HFrEF and HFpEF, respectively, 49 and nine of which have never been previously reported. Some of the known cardiomyopathy genes that were identified included acitinin alpha 2 (ACTN2), filamin C (FLNC), Ras like without CAAX 1 (RIT1), and sarcoglycan delta (SGCD).

Several quality control steps were incorporated into the analysis to ensure that the MR findings were robust and not impacted by certain confounding factors like linkage disequilibrium or weak instrument bias. For example, 42 genes exhibited strong evidence of co-localization, thus suggesting any alterations in the expression of these genes likely contributes to HF risk.

We identified several several genes as plausible targets for HFrEF and HFpEF and found evidence from orthogonal sources to support their efficacy and inform on the mechanism of action needed for a therapeutic solution.”

MTSS1

MTSS1 encodes for the metastasis suppressor 1, a cytoskeletal protein that is involved in maintaining cell structure and migration. Numerous studies have reported the tumor suppressive action of MTSS1; however, more recent evidence indicates that this gene may also be implicated in certain cardiovascular diseases.

In the current study, increased messenger ribonucleic acid (mRNA) expression of the cis­-variant rs7461129/MTSS1 in the left ventricle increases the risk of HFrEF. Ten associations with left and right ventricular CMR findings were also identified, nine of which were directly related to HFrEF findings.

Taken together, these findings suggest that the inhibition of MTSS1 has the potential to be therapeutically effective against HF, particularly HFrEF, and warrants additional investigation.

ZBTB17  

Zinc finger and BTB domain-containing 17 (ZBTB17) encodes for the zinc finger and BTB/POZ family (ZBTB) transcription factor involved in gene regulation and cell differentiation. In the current study, ZBTB17 had a strong MR association with HFrEF and was significantly increased in the left ventricle, thus similarly indicating the potential role of a ZBTB17 inhibitor in future drug discovery studies.

NFATC2IP

Nuclear factor of activated T-cells, cytoplasmic 2 interacting protein (NFATC2IP) modulates the activity of nuclear factor of activated T-cells (NFAT) proteins, which are involved in the activation of T-cells, production of cytokines, and other immune signaling pathways.

In the current study, NFATC2IP was associated with an increased risk of HFpEF and larger left ventricle mass. Moreover, the association between NFATC2IP and an increased risk of HFpEF was correlated with several hallmark features of HF, some of which include high systolic blood pressure (BP), C-reactive protein (CRP) levels, and body mass index (BMI) values.

Conclusions

Other genes that emerged as potential drug targets for HFrEF include interleukin-6 receptor (IL6R), adrenomedullin (ADM), and endothelin receptor type A (EDNRA), whereas lipoprotein(a) (LPA) emerged as a target for both HFrEF and HFpEF. Some of the key strengths of the current study include the large number of HFrEF and HFpEF cases, as well as the utilization of multiple orthogonal approaches, to confirm causal relationships between HF risk and druggable protein targets.