Thanks to genetic analysis of a porcine model, researchers from the University of California, Los Angeles (UCLA) are one step closer to understanding the effect of myocardial infarction on the cardiac nervous system.
According to preliminary data, chronic myocardial infarction induces remote changes in both the peripheral and central nervous systems. The fact that these changes occur regionally and are limited to the thoracic neuraxis suggests that this response may be due to alterations in afferent signaling from cardiac injury, the researchers reported.
“These findings importantly show that cardiac dysfunction associated with chronic myocardial infarction is affected not only by cardiac remodeling but also by regional neural remodeling,” said Kimberly Howard-Quijano, MD, MS, of the Department of Anesthesiology and Perioperative Medicine at the David Geffen School of Medicine at UCLA. “Future studies should be aimed at modifying neural remodeling to improve cardiac excitability post-myocardial infarction.”
As Dr. Howard-Quijano reported at the 2016 annual meeting of the Society of Cardiovascular Anesthesiologists (abstract 2), chronic myocardial infarction induces cardiac remodeling and autonomic nervous system imbalance, leading to increased risk for arrhythmias and sudden cardiac death. The mechanistic basis of this pathologic response, however, is unknown.
“One could hypothesize that some of the autonomic imbalances that we’re seeing in the heart may be due to neural remodeling that’s happening at several points along this cardiac neuraxis,” said Dr. Howard-Quijano. “This neural remodeling can lead to changes in neuronal excitability and neurochemical morphology.
“Since neuronal viability and excitability are regulated at the molecular level through coordinated gene expression, we can use transcriptome characterization to identify molecular fingerprints of pathological remodeling through differential gene expression,” she explained.
Porcine Neural Tissue
Tissue samples were obtained from healthy Yorkshire pigs (n=2) as well as chronic infarct six weeks after myocardial infarction (n=2). Neural tissue was taken from several different sites on the cardiac neuraxis: 1) stellate ganglia, 2) thoracic T1-T4 and lumbar L1-L4 dorsal root ganglia, and 3) thoracic and lumbar dorsal horn tissue.
Researchers then analyzed the tissue using whole-transcriptome profiling with next-generation RNA sequencing. Ingenuity Pathway Analysis (IPA; QIAGEN) was used to help discover specific cellular processes significantly affected in post–myocardial-infarction neurons.
“IPA uses prior biological knowledge to help come up with potential causal networks, either upstream regulators or downstream effects of the myocardial gene expression,” said Dr. Howard-Quijano. “We then looked at RNA expression of selected genes using qRT-PCR [quantitative reverse transcription-polymerase chain reaction].”
When compared with healthy controls, principal components and clustering analysis of RNA transcriptome revealed distinct molecular signatures of differential gene expression in the chronic post–myocardial infarction stellate ganglion tissues.
With this difference in molecular signature established, the researchers then tried to determine which particular pathway was involved. In chronic infarct stellate ganglion tissue, IPA analysis showed multiple cellular functions that were significantly affected: apoptosis, cell growth signaling and neural function.
Finally, Dr. Howard-Quijano and her colleagues were able to show regionality regarding differential gene expression: Validation by qRT-PCR in thoracic versus remote lumbar samples demonstrated that transcriptome changes were limited to the thoracic neuraxis.
“When we looked at the thoracic versus remote lumbar tissues, we found that the pathways associated with apoptosis and abnormal cell growth in the thoracic region were elevated in the thoracic neural tissue, whereas no changes were seen in the lumbar,” said Dr. Howard-Quijano.
Neuropeptide Y, a sympathetic nervous system neurotransmitter, also was reduced in the thoracic samples.
“These results show that chronic myocardial infarction, through alterations in afferent signaling, induces remote changes in neuronal function at the level of the thoracic stellate and dorsal root ganglia,” Dr. Howard-Quijano concluded.
Moderator of the session, Mark Stafford-Smith, MD, CM, FASE, FRCPC, director of Adult Cardiac Anesthesia and Critical Care Fellowship at Duke University School of Medicine, in Durham, N.C., commended the study for addressing a fundamental biological question.
“We associate many of the adverse outcomes we see to injury of the heart muscle itself,” said Dr. Stafford-Smith, “but there are nerves in the heart associated with abnormal rhythms and coordination of cardiac function. An insult on the heart damages not only the heart muscle but these nerves themselves, and potentially changes the signals that are going back to the brain.”
As these nerves connect to the central nervous system and to the brain, assessment of their functioning after myocardial infraction may be an important step to understanding—and treating—cardiac injury, Dr. Stafford-Smith concluded.