The Heart Whisperer: How Dr. Fred Apple Transformed Cardiac Diagnostics
Peace. This one word ends all his emails. He’s a product of the peace and love movement that encapsulated the 1960s and 1970s and cherishes the iconic song “Imagine” by John Lennon. It’s a life philosophy he’s carried with him throughout the decades.
Since 1982, Fred Apple, PhD, DABCC, has served in a number of roles at the Hennepin Healthcare System (HHS) and Hennepin Healthcare Research Institute (HHRI), including Medical Director of the Clinical Laboratories, Clinical Chemistry, Clinical and Forensic Toxicology Laboratory, and Point of Care Testing (POCT) at HHS and as the Principal Investigator (PI) of the Clinical Laboratory Improvement Amendments (CLIA)-certified Cardiac Biomarkers Trials Laboratory (CBTL) at HHRI. He is also a Professor of Laboratory Medicine and Pathology at the University of Minnesota.
An internationally recognized expert in the fields of clinical chemistry and toxicology, Dr. Apple’s research has focused on cardiac biomarkers involving acute coronary syndrome, heart failure, heart injury, and, most recently, COVID-19.
There’s never a dull moment for Dr. Apple. He has published extensively, amassing nearly 700 research papers, abstracts, letters to the editor, and article reviews over the span of his career. When he’s not writing or researching, he’s teaching and guiding the next generation of clinical researchers by mentoring undergraduate, graduate, post-doctoral students, residents, and fellows.
How it all started
One way he’s managed to stay peaceful? His love of exercise. Before joining HHRI, he used to run marathons. His early research as a PhD postdoctoral fellow focused on the heart and learning how to perform diagnostic and lab testing.
Dr. Apple recalls his early exploration into exercise biochemistry, “One of the first areas I was involved with was looking at the heart and studying what do we measure when someone has a heart attack? What do we measure in the blood when someone has heart failure? And how do we decide if it’s [an] injury, and how [can we] narrow it down to say what the mechanism is? Were you hit by a car or was it [a] heart attack?”
He explained how early biomarkers (measurable signals) released in the blood seemed to present as a heart attack, but they originated from skeletal muscle. It turns out that creatine kinase MB (CK-MB), a protein found in the heart, is also generated in skeletal muscle. Through his research, he was one of the first to discover that injury to skeletal muscle increases the production of CK-MB.
According to the Cleveland Clinic, “Creatine kinase (CK-MB) is an enzyme that’s found in your skeletal muscle, heart muscle, and brain. When any of these tissues are damaged, they leak creatine kinase (CK) into your bloodstream. Elevated CK levels may indicate muscle injury or disease.”
CK-MB became the standard biomarker used to determine whether a heart attack occurred.
What Dr. Apple and his early team realized, “CK-MB [is not] tissue specific. It was not just found in the heart. A lot of work that I was part of [early in my career] was to define another biomarker, which is a protein called troponin, to work the transition from a good [bio]marker, CK-MB, but not tissue-specific, to a better marker that was tissue-specific. If you see troponin circulating, it’s from one tissue, the heart.
Elevated levels of troponin (proteins found in your heart) in a person’s bloodstream are a sign that someone has recently had a myocardial injury and possibly a myocardial infarction, more commonly known as a heart attack. Using the current generation of cardiac troponin assays designated ‘high sensitivity’ troponin, the normal troponin upper reference limits are unique for males and females, 16 and 34 nanograms per liter (ng/L), respectively. Patients with values above these sex-specific cutoffs are indicative of myocardial injury that clinicians would use in differentiating a patient’s cause of injury to assist in patient management.
Medical Glossary
Cardiac biomarkers – enzymes released into the bloodstream when the heart is damaged or stressed.
Creatine kinase (CK-MB) – Creatine kinase (CK-MB) is an enzyme that’s found in your skeletal muscle, heart muscle, and brain.
Troponin – A protein mostly found in your heart’s muscle cells. Higher concentrations indicate signs of heart damage. Physicians will test a person’s troponin levels to determine heart conditions.
Principal Investigator (PI) – the lead researcher and decision-maker of a clinical trial or research project.
Co-Investigator (Co-I) – This person conducts the scientific research portion of a project.
Myocardial infarction – This is more commonly known as a heart attack. A heart attack occurs when blood flow to the heart is restricted or blocked due to fat, cholesterol, or clogged arteries.
Myocardial injury – This translates to an injury to the heart where a person’s troponin values are above the 99th percentile. It could signal a future heart attack.
Point-of-Care-Testing (POCT) – Medical testing that is performed outside of a laboratory, such as a hospital, emergency room, a person’s home, convenience clinics, or ambulances. This could be testing for things like COVID-19, the flu, pregnancy, strep throat, or blood glucose monitoring for people with diabetes.
It’s all heart
Dr. Apple’s lab, the Cardiac Biomarkers Trial Laboratory (CBTL), is currently composed of Clinical Research Laboratory Director, Principal Investigator (PI), and Co-Investigator (Co-I), Karen Schulz, DC, and PI/Co-I, Hannah Brown, PhD, along with a staff of medical technologists, research coordinators, and a nurse. The work of the CBTL is primarily funded through industry, bringing in approximately $1 million of grant funding every year for the past 25-30 years. Their research focuses on applied and clinical research, technology assessment, and ultimately, improving patient care and outcomes.
Since the CBTL’s inception, Dr. Apple and his team have conducted 450+ clinical studies, trials, and analytical evaluations. The lab has also functioned as a benchmark institution for forensic and clinical toxicology applied research studies.
“Our lab is 65-70% cardiac work, related to grants I’ve written on investigator-initiated studies, predominantly funded through industry. [For] the other 30% of the lab, we work with almost every manufacturer that makes immunoassay analyzers [and] want[s] to develop tests that will be brought to clinical practice. So, this is the first time they’ve developed this assay and they [want] us to test it, to [for example] detect a new protein [or] detect heart attacks. We help [industry] design studies, look at their design, and use it, put a budget and protocol together, get it through Institutional Review Board (IRB) approval, and initiate a human subjects trial in four to eight weeks,” explained Dr. Apple.
Dr. Karen Schulz, whom Dr. Apple describes as his dyadic work partner, shares how Dr. Apple’s career contributions and leadership have impacted her and the field of medicine.
“Before working in this field, I, like many others, didn’t fully appreciate the enormous infrastructure behind something as ‘routine’ as a blood test. When people are sick, they go to the doctor, have blood drawn, and receive a diagnosis, often without realizing that it’s the clinical laboratory that generates the data guiding that diagnosis. Dr. Apple has helped me see that our work in the lab isn’t behind the scenes; it’s at the heart of modern medicine. His career, particularly his role in shaping the Universal Definition of Myocardial Infarction and his leadership within the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), shows how deeply laboratory science influences global standards of care. Under his mentorship, I’ve come to view each clinical trial as a step toward improving patient outcomes.”
Dr. Apple has helped me see that our work in the lab isn’t behind the scenes; it’s at the heart of modern medicine. ~Karen Schulz, DC
Schulz’s fellow lab partner, Dr. Hannah Brown, shares how Dr. Apple’s discoveries have revolutionized the field of medicine.
“Fred was one of the first to recognize the value of the troponin assay for myocardial infarction. This early insight has had a tremendous impact on patient care and has contributed to saving millions of lives worldwide. Fred continues to push the field forward through his ongoing work in troponin fragment research, advancing our understanding and improving outcomes in cardiovascular medicine.”
With a little help from your friends
The impact of Dr. Apple and the CBTL’s work is recognized here and around the world.
Allan S. Jaffe, MD, a Cardiologist and Internist at the Mayo Clinic
Allan S. Jaffe, MD, a Cardiologist and Internist at the Mayo Clinic, states, “Fred is a stand-up, honest individual who is not afraid to say what he means and means what he says. In an ever-increasing political world, his forthrightness is a major contribution to science and collegiality.”
Dr. Yader Sandoval, MD, FACC, Interventional Cardiologist at Allina Health, discusses his professional experiences and personal relationship with Dr. Apple as both a colleague and friend.
Dr. Yader Sandoval, MD, FACC, Interventional Cardiologist at Allina Health
“Beyond his exceptional academic contributions, what sets Fred apart is the kind of person he is. He is a man of integrity, committed to the highest ethical standards, and a relentless pursuit of excellence. He has mentored countless PhDs, laboratorians, and clinicians, many of whom are now leaders in the field of cardiac biomarker research,” Dr. Sandoval said. “Fred is remarkably generous with his time, always willing to collaborate and advise colleagues around the world on designing the most rigorous and impactful studies. He is not only an outstanding scientist, but also an exceptional colleague, mentor, advisor, and friend.”
Leaving behind a legacy
Dr. Apple’s not retired yet, but he is inching closer to that finish line and wants to leave behind a legacy for the next generation of scholars. With this sentiment in mind, his lab has generously established a $1 million endowment entitled the Ann and Ira Apple Endowed Scholar in Laboratory Medicine and Pathology.
The purpose of the endowment is to promote excellence in the field of laboratory medicine at the Hennepin Healthcare System and appoint an endowed scholar within the Department of Laboratory Medicine and Pathology with input from Dr. Apple. The funding will enable the chosen scholar to advance their professional development, support research projects, and utilize departmental education funds in any area of applied sciences within the department. The name of the first Ann and Ira Apple Endowed Scholar in Laboratory Medicine and Pathology will be announced later this year.
Did you know?
5 fun facts you might not know about Dr. Apple
- He lives part of the year in Bretton Woods, New Hampshire.
- He does High Intensity Interval Training (HIIT) on the Peloton two times per week.
- He recently started as a Disc Jockey (DJ) at New Hampshire’s North Country Community Radio (NCCR) on Thursdays at 10 a.m.- noon ET, playing an eclectic blend of music all the way back to the 1930s.
- He has two daughters, 36 and 29, and 2 precious grandchildren.
- He has a passion for golf and hiking in the White Mountains.
Related Resources
- https://www.hhrinstitute.org/dr-fred-apple-to-lecture-conduct-research-in-spain/
- https://www.hhrinstitute.org/newsroom/hhri-research-heroes/research-heroes-profiles/
- https://ifcc.org/ifcc-education-division/emd-committees/committee-on-clinical-applications-of-cardiac-bio-markers-c-cb/podcasts/fred-apple/