American Heart Association

Precision medicine for cardiac resynchronization: Predicting quality of life benefits

Contributor: Nicholas Hawkes

Who benefits from cardiac resynchronization therapy (CRT)? Studies show that among select HF patients CRT improves longevity, ventricular remodeling, and quality of life (QoL). The precision medicine approach asks the question, “Are there individual factors that predict QoL improvements?” Spertus and colleagues demonstrated that age, baseline QoL, and QRS duration predict individual QoL after CRT.

Early right ventricular assist device utilization in patients undergoing continuous-flow left ventricular assist device implantation: Insight from INTERMACS

Contributor: Steven Stroud

Frustrated by limited, single small center risk scores for RV failure? Kiernan and colleagues analyzed the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to identify factors associated with RV failure following continuous flow left ventricular assist device (CF-LVAD) support.

Not necessary to adjust NT-proBNP thresholds for HFrEF patients with atrial fibrillation

Contributor: Chris Sobowale

Heart failure patients with HFrEF and atrial fibrillation (HFrEF-AF) have higher NT-proBNP than HFrEF patients without atrial fibrillation (AF). This is thought to be a consequence of AF and not necessarily correlated with deleterious clinical outcomes.

HF clinical trials have stipulated different inclusion NT-proBNP levels for patients with HFrEF-AF. It turns out, a defined higher NT-proBNP level for patients with HFpEF-AF may not be necessary.

Follistatin-like protein 1 (FSTL1): A cardiokine that alters metabolism and reverses remodelling in tachy-pacing canine HF

Contributor: Mat Bull

FSTL1 is a molecule with tremendous potential. While already considered an important clinical biomarker and cardioprotective cardiokine (a molecule secreted by cardiac muscle), Recchia et al demonstrate that FSTL1 also serves as a regulator of energy substrate metabolism. Using a canine tachy-pacing HF model, infusion of recombinant human FSTL1 exhibited efficacy in reversing pathological cardiac metabolism and remodelling.

Increasing ketone body metabolism reduces cardiac dysfunction in a murine model of pressure-overload-induced heart failure

Contributor: Chris Sobowale

In a mouse model of pressure overload-induced heart failure, D-beta-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the interconversion of two major ketone bodies produced during fatty acid catabolism (acetoacetate and beta-hydroxybutyrate) is upregulated and increases ketone-body oxidation rate, i.e ketone body metabolism (KBM). Uchihashi et al generated cardiac-specific Bdh1-overexpressing mice to determine the role of ketone-body metabolism in the myocardium. They demonstrate that overexpression of Bdh1 resulted in increased ketone body utilization, resistance to pathologic cardiac remodeling, and a reduction in reactive oxygen species generation.

Ketone bodies are generated from Acetyl-CoA stemming from fatty acid metabolism in the liver. Ketones are then oxidized back to Acetyl-CoA in various tissues to provide energy. Interestingly, Beta-hydroxybutyrate (a component of ketone bodies) decreases ischemic reperfusion injury in rat hearts and decreases oxidative stress by inhibiting histone deacetylases (HDACs) and upregulating antioxidant genes. The less HDACs, the more histone acetylation, and the less oxidative stress.

Bhd1-overexpressing transgenic (Bdh1 Tg) mice were made by injecting Bdh1 cDNA into mouse embryos. All Bdh1 Tg and wild type (WT) mice then underwent a left thoracotomy. Half of the mice had traverse aortic constriction (TAC) by ligation of the transverse thoracic aorta to cause pressure overload-induced heart failure. The other half (sham group) had no ligation. Bdh1 levels were measured using proteomics and DNA microarray, and were further confirmed by PCR and Western Blot. The ketone body oxidation rate (KBM) was evaluated by measuring 14CO2 isotope levels 8 weeks after TAC.

At baseline, Bdh1 Tg mice had a significant increase in Bhd1 protein levels (2.5 fold) and KBM (1.7 fold) when compared to WT mice (p<0.05). TAC caused a significant increase in Bhd1 expression (2.8 fold higher in Bdh1 Tg mice) (p<0.05). Overall, the TAC Bdh1 Tg mice had a significant increase in KBM compared to TAC WT mice (p<0.05) (Figure 2A).

TAC caused enlargement of the LVEDd and reduction in EF. TAC operated Bdh1 Tg mice had less LV dilation and significantly less cardiac dysfunction compared to WT mice (p<0.05). The area of fibrosis after TAC was significantly decreased in Bdh1 Tg mice. Immunostaining revealed that reactive oxygen species (ROS) were induced by TAC but significantly reduced in TAC Bhd1 Tg mice compared to TAC WT mice (p<0.05). Also, gene expression of superoxide dismutase, an antioxidant was upregulated in TAC Bdh1 Tg mice.

No study is perfect. There were no hemodynamic data provided and it is unclear how working heart models will correlate with the Langendorff heart model used in this study.

In a heartbeat… Failing hearts depend on ketone bodies as fuel and increasing ketone-body utilization has potential to decrease cardiac dysfunction and ameliorate oxidative stress.

Study Link: Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload–Induced Heart Failure