Faculty Spotlight: Zian H. Tseng, MD

Death and Life: Where the Twain Shall Meet

One of the ultimate divides in medical research stretches between death and life. Many clinicians spend their entire careers trying to prevent premature death, but rarely learn the details of how patients die unless they pass away in the hospital. Medical examiners piece together the circumstances of death, but almost never speak to the patient's doctors.

Cardiac electrophysiologist Dr. Zian H. Tseng is building a bridge between those two worlds, discovering clues about everything from how cardiac devices fail to how to develop better treatments for HIV.

As an electrophysiologist – a specialist in heart arrhythmias – Dr. Tseng wanted to learn how to better predict which patients were at risk for sudden cardiac death (SCD), also known as cardiac arrest. Unlike a heart attack, which happens when a blockage in an artery starves the heart of oxygen and nutrients, SCD usually is caused by a very rapid electrical rhythm – ventricular tachycardia or ventricular fibrillation – in the lower chambers of the heart.

A Novel Partnership

In 2005, Dr. Tseng started a study of blood samples from survivors of sudden cardiac arrest, trying to identify genetic predictors of potentially fatal arrhythmias. He was perplexed to find that his results contradicted the findings of a much larger study that was published by researchers at the University of Washington, Seattle in 2006.

He realized that the vast majority of previous studies all relied on retrospective review of paramedic records to determine the cause of death. About 95% of sudden deaths occur outside the hospital, because patients collapse and die before they reach an emergency department. "It dawned on me that although the cause of death could be classified as ‘sudden cardiac death,' that death could actually have been caused by non-cardiac causes such as hemorrhage, stroke or pulmonary embolism instead," said Dr. Tseng.

Unless patients die in the hospital, their autopsies fall under the jurisdiction of the coroner and medical examiner. "Medical examiners are busy investigating homicides, suicides and trauma deaths, so the more likely the cause of death is natural, the less likely they are to investigate it," said Dr. Tseng. For example, in a prior comprehensive surveillance SCD study in Portland, OR, the autopsy rate was only 11%. "That means that only 11% of sudden deaths were proven to be cardiac; the rest were just assumed to be cardiac," he said. "Yet we can't study the risk factors, underlying pathology or treatments for SCD until we correctly identify which patients actually died of that condition."

SCD is perennially thought to be the leading cause of death in the US, killing about 450,000 people each year by retrospective death certificate criteria. However, Dr. Tseng and his colleagues now believe that figure may be up to a two-fold overestimate, given the variable definitions and inconsistent methodologies used to define SCD and what they are discovering about inaccuracies in assumed causes of sudden death

Because autopsy is considered the gold standard for determining cause of death, Dr. Tseng launched an ambitious endeavor: partnering with the City and County of San Francisco's Office of the Chief Medical Examiner to prospectively identify in real time and autopsy every single sudden death occurring within county lines. Dr. Tseng found an enthusiastic partner in Dr. Ellen Moffatt, a forensic pathologist who conducts autopsies as assistant medical examiner for the City and County of San Francisco. She agreed to do a three-month pilot, which led to a grant from the National Institutes of Health (NIH) to conduct an ongoing investigation called the San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study. In addition to supporting data collection and analysis, the grant covers the additional staff time needed to conduct autopsies of all sudden death cases.

Dr. Tseng and Dr. Moffatt meet each Tuesday with Dr. Philip Ursell, a cardiovascular pathologist who directs the UCSF Autopsy Service, and Dr. Jeffrey Olgin, chief of the Division of Cardiology, to review every sudden death – on average, five to seven a week. The group reports on heart measurements, DNA and tissue samples, and toxicology reports. Because the medical examiner can also compel release of medical records, the team also has complete access to echocardiograms, EKGs and other studies the deceased person had during their lifetime.

To date, the group has studied more than 750 sudden deaths. Some of their findings include:

• Nearly half of "sudden cardiac deaths" were not cardiac: This profound finding has broad implications, from refining SCD incidence estimates to revising cost-benefit calculations for expensive therapies to treat fatal arrhythmias – such as implantable cardioverter-defibrillators – to defining previously unrecognized causes of sudden death.
  
  For example, a significant portion of non-cardiac causes of sudden death were neurologic, including strokes, bleeding in the brain, or Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Tseng is partnering with UCSF neurologist Dr. Anthony Kim to study this newly identified phenomenon that they have dubbed "sudden neurological death."
  
  "Dr. Kim and his group are very interested, because all the previous information they had on strokes and bleeds was from people who survived to make it to the hospital," said Dr. Tseng. "They actually missed the most severe presentations of those conditions, which are patients who died suddenly." Dr. Tseng has also developed a research partnership with Dr. Orrin Devinsky at New York University, a world expert on SUDEP.
   
• HIV and sudden death: In collaboration with Dr. Priscilla Hsue, an HIV cardiologist based at San Francisco General Hospital (SFGH), Dr. Tseng found that sudden death rates among HIV+ patients were about four times higher than in the general population and accounted for 13% of all deaths among HIV+ patients. Dr. Tseng recently received a $2.1 million NIH grant to identify risk factors in this population, which could include arrhythmia-inducing side effects of HIV drugs and the effect of the viral load on the heart's risk for fatal arrhythmias. Dr. Tseng and Dr. Hsue also hope to develop better prevention guidelines for HIV+ patients, such as if and when to implant a cardiac defibrillator.
   
• Detecting HIV reservoirs: Dr. Tseng is working with UCSF HIV researchers Dr. Joseph (Mike) McCune and Dr. Joseph Wong. "One of the obstacles to curing HIV is that even in people whose virus is well-controlled, it's still somewhere in the body," said Dr. Tseng. Unfortunately, previous studies of these hidden HIV reservoirs have relied on autopsies of patients who died of AIDS, where the virus had already spread throughout the body.
  
  "In my study, we are capturing people who are well one minute and die suddenly the next from a ventricular arrhythmia," said Dr. Tseng. "We're doing the autopsies anyway. In deceased patients who had well-controlled HIV, we can now sample tissues from many organs to see where the virus might be sequestering, in the hopes that we could identify a target for eventually curing HIV."
   
• Cardiac device malfunctions: About 5% of sudden deaths occur in patients who have a defibrillator or pacemaker. "If a person died suddenly despite an implanted device that is intended to prevent that, wouldn't you think – ‘Hmm, let's make sure there's not a problem with the device?'" asked Dr. Tseng. "That's never dawned on anybody before, including the FDA [US Food and Drug Administration]. In our study, we found some kind of problem with the device about half the time." These included malfunctions with the battery or the wires that sense electrical activity in the heart and deliver shocks, programming problems in the device's mini-computer, as well as physician-related issues such as inappropriate device selection.
  
  The FDA relies on a voluntary reporting system for device problems, which generally only captures issues from devices in living patients. "In the regulatory process we've been missing the most severe problems, because when someone dies, no one looks at the device," said Dr. Tseng. He recently made a presentation to the FDA about cardiac device malfunction in sudden death, and is applying for a research grant to expand this research.
   
• Pediatric sudden death: With support from the Centers for Disease Control and Prevention, Dr. Tseng recently broadened the POST SCD study of adults to include sudden deaths of anyone age 80 and below. He hopes to shed light on a poorly understood phenomenon called Sudden Death in the Young. "There are aspects of pediatric sudden death that aren't operative in adults, such as crib deaths, neglect and child abuse," he said. Because children often lack extensive medical records, Dr. Tseng and the medical examiner work with police officers, social workers and pediatricians, collect information from the family, and consider scene findings, such as the body position in which the deceased child was found.
   
• Family Sudden Death Initiative: Some cases of SCD are caused by rare genetic mutations that predispose people to develop life-threatening cardiac arrhythmias. "What if a young dad with three kids dies suddenly at work, and we discover he has a genetic heart condition?" asked Dr. Tseng. "Our findings were part of a research study, which isn't generally supposed to influence clinical care. Yet this is a critical risk factor for his children, who may have inherited a condition that can lead to sudden death." Dr. Tseng and Dr. Olgin have developed the Family Sudden Death Initiative, which reaches out to at-risk family members of people who died of SCD in San Francisco.
  
  "My original goal was to prevent sudden deaths, and the biggest bang for your buck would be to identify and risk-stratify people with a strong family history of SCD," said Dr. Tseng, who is also collaborating with Dr. Bernard Lo, the director emeritus of the UCSF Program in Medical Ethics, on the ethics of conducting research on the deceased.

Dr. Tseng's broad portfolio of investigations has flourished in part by tapping into UCSF's outstanding range of expertise, from experts in the Departments of Epidemiology and Biostatistics, Neurology, and Pathology to world experts in HIV/AIDS, as well as forging collaborations with government agencies and policymakers.

"Until I embarked on this partnership with the medical examiner, I was worried if one of my patients died suddenly, but it didn't dawn on me to ask the people who investigate sudden deaths about what they found, and how I could feed that back to my practice," said Dr. Tseng. "We as clinicians take care of living patients, they investigate deaths, and we never talked.

"A basic researcher is in complete control of their lab – but my lab now is the entire city limits of San Francisco," said Dr. Tseng. "To make this work, I have to understand governmental laws and regulations and all the players to achieve my ultimate research objective, which is high-quality investigation of every sudden death."

Deep Roots at UCSF

Dr. Tseng is a Bay Area "lifer:" he was born in San Francisco but considers Fremont his hometown, where he and his younger brother were raised by his mother, an accountant, and his father, an earthquake engineer. He majored in biochemistry at UC Berkeley and entered UCSF as an MD-PhD candidate. After a year of graduate studies working on neuronal calcium channels in a mouse model, he realized that benchtop basic research was too far removed from the bedside and clinical application. He earned his medical degree at UCSF, where he also completed his internal medicine residency and cardiology and cardiac electrophysiology fellowships and earned a master's degree in clinical research. Dr. Tseng joined the UCSF faculty in 2004. In addition to his research, Dr. Tseng sees patients in clinic, performs ablation procedures, implants pacemakers and defibrillators, and leads the UCSF Adult Congenital Heart Disease Arrhythmia Service.

Dr. Tseng is married with two young children. Together the family enjoys discovering new restaurants, exploring the outdoors – fishing, camping, hiking – and cheering for Cal sports.

For more information about the POST SCD study, visit their website at ziantsenglab.ucsf.edu.

– Elizabeth Chur