American Heart Association

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

Old drug… new trick? Treatment with sildenafil may prevent device thrombosis and ischemic stroke in LVAD patients.

Contributor: Chris Sobowale

Bleeding and thrombosis account for almost half of adverse events in patients with CF-LVADs.

Saeed et al analyzed 144 HeartMate II (HMII) CF-LVAD patients in a single center, retrospective study. Patients in the sildenafil groups were on sildenafil for pulmonary hypertension or right ventricular dysfunction for at least 30 days after discharge from CF-LVAD implant. Patients were divided into four groups:

  1. Low level hemolysis not on sildenafil (n=31)
  2. Low level hemolysis on sildenafil (n= 16)
  3. No low level hemolysis not on sildenafil n= (76)
  4. No low level hemolysis on sildenafil (n=21)

Multiple inotrope use at lower doses led to excess 1A candidates in the post-geographic sharing era

Contributor: Steven Stroud

Status 1A heart transplant candidates are critically-ill patients requiring mechanical circulatory support (MCS) or high-dose / multiple inotrope therapy to maintain perfusion. Status 1A candidates are listed as highest priority, and are thus more likely to receive a heart transplant. In 2006, a significant change occurred in the Organ Procurement and Transplantation Network (OPTN) criteria with the intent of increase geographic sharing. Following the update, organs were shared within a 500-mile radius as opposed to offers first being made to all candidates (Status 1A, 1B and 2) within local organ procurement organization.

Parker and colleagues investigated whether this policy change affected clinical practice patterns in care of patients listed for heart transplant. The bottom line: following the policy change transplanted patients were more likely to be on low dose inotropes.

Using the Scientific Registry of Transplant Recipients (SRTR) a comparison was made between heart transplant candidates pre (7/2000-7/11/2006) and post (7/12/2006-7/2015) geographic sharing.Status 1A candidates had the following values analyzed: hemodynamic data, MCS type, inotrope type(s) and doses.Between 2000 and 2006, the number of 1A candidates declined from 656 (22% of total candidates) to 452 (18%). However, from 2006-2015, 965 (26%) candidates were Status 1A. The same trend is seen in 1B candidates as well. Not surprisingly, Status 2 candidates steadily declined from 2000-2015 (1,673, 55% to 1,038, 28%).

Among Status 1A candidates, the inotrope subgroup (candidates without MCS) decreased in the pre-sharing era (256, 11% to 174, 8%), but significantly increased in the post-sharing era (381, 18% in 2015, p<0.001). Specifically, multiple-inotrope therapy increased substantially, with 153 more multiple-inotrope 1A candidates in 2015 compared to 2005 (p<0.001). The mean dose of inotropes within the multiple-inotrope subgroup was lower in the post-sharing era compared to the pre-sharing era (dobutamine dose decreased 49%, dopamine dose decreased 55%, and milrinone dose decreased 29%, p<0.001). Interestingly, the cardiac index slightly increased (2.17 to 2.25 L/min/m2, p=0.044).

The single, high-dose inotrope 1A subgroup had relatively stable dosing of milrinone (p=0.063) and a decrease of dobutamine by 4%, p<0.005. Of note, milrinone was used more frequently in the post-sharing era, with a 10% increase in frequency, p<0.001.

The waitlist survival of 1A candidates also increased in the post-sharing era. In the pre-sharing era, 1A candidates had a 130% higher chance of dying, while in the post-sharing era 1A candidates had a 33% higher chance of dying in comparison to Status 2 candidates. This shift represents a 62% risk reduction in death (comparing the last three years of pre-sharing with 7/12/2006-12/31/2010).

No study is perfect. Not all advanced heart failure patients are included in the SRTR, and although hemodynamic data was provided, there may be other factors not listed contributing to the use of multiple inotropes. Improvements in heart failure medical therapy may also contribute to improved waitlist survival of 1A candidates.

Worth noting, there were 220 more CF-LVAD 1A candidates in 2015 compared to 2005 (p<0.001), which certainly contributed to the growing number of 1A candidates as well.

In a heartbeat… The use of multiple inotropes to shift patients to 1A status contributed to excess 1A transplant candidates in the post-geographic sharing era (7/12/2006-7/2015). Changes in policy that require clear hemodynamic rationale for candidate urgency may help stratify transplant candidates more appropriately.

Study Link: Trends in the Use of Inotropes to List Adult Heart Transplant Candidates at Status 1A

Bonus Points: December 2016 Proposal for six-status allocation system

MRI findings more prognostic than laboratory values in myocarditis

Contributor: Steven Stroud

A cardiac MRI (CMR) is worth a thousand labs. Or, that appears to be the case in myocarditis. Dr. Heidecker et al demonstrated that late gadolinium enhancement (LGE) on CMR is unrelated to cardiac enzymes and inflammatory markers, and more prognostic in myocarditis.

Twenty-four patients were prospectively enrolled (75% male, median age 32, 13% w/ concomitant CAD) at the University of Zurich after being diagnosed with myocarditis. Myocarditis diagnosis was based on clinical features, symptom onset < 10 days, ECG, and elevated high-sensitivity troponin T in the absence of acute obstructive coronary disease.

Decreased incidence yet increased prevalence of heart failure among Medicare beneficiaries

Contributor: Chris Sobowale

Over 6.5 million Americans have HF, costing over $31 billion annually. Those are big numbers, but what is the trend? Berry et al explored the epidemiology of heart failure by examining fee-for-service Medicare patients from 2002-2013. This was presented as a late-breaker at the AHA Scientific Sessions 2017 with simultaneous publication in Circulation: Heart Failure – the new editor teams’ first simultaneous publication – but hopefully not our last!