Cardiovascular and Renal Research

Cardiovascular Research Lab (Cardiology/Department of Internal Medicine)

The Cardiovascular Research Laboratories of the Division of Cardiology and the Henry Ford Heart and Vascular Institute (HVI) conducts research into the causes and treatments of heart failure. This disease has reached epidemic proportions, affecting more than 6 million patients in the United States and more than 25 million patients worldwide. The general theme is translational research, that is, basic research with a potential for use in humans. This group is also concerned with understanding the basic mechanisms leading to progression of heart failure and ventricular remodeling, including the assessment of novel drugs and devices that may reverse this deleterious process that, if left unchecked, will culminate in the death of the affected patient.

With regards to better understanding of the pathophysiology of heart failure, a major focus of the laboratory during the past few years has been on evaluation of mitochondrial function in heart failure. Mitochondria are components of nearly every cell in the body, including heart and skeletal muscle cells, responsible for the production of energy for the cells to use. Seminal research in these laboratories have shown that mitochondria in heart failure are structurally and functionally abnormal and are unable to generate sufficient energy or ATP to meet the demands of the beating heart. In addition to understanding the role of abnormal mitochondria in driving the heart failure syndrome, the laboratories are also engaged in the development and testing of novel drugs that can improve the function of mitochondria and, in doing so, improve overall heart function. New drugs under investigation include elamipretide, a mitochondria targeting peptide and noladenoson, a partial adenosine A1-recptor agonist. Both drugs are currently being evaluated in clinical trials in patients with heart failure.

Research has also targeted acute decompensated heart failure, a condition resulting from acute worsening of the chronic heart failure state and one which requires urgent hospitalization. Current investigations are focused on understanding the mechanisms involved in cardiac decompensation and on therapies that can improve symptoms and survival. Several novel drugs are being tested for this condition, including compounds that promote vasodilation along with improvement in contractile dysfunction and compounds. Some of these compounds including some known as nitroxyl donors are currently being evaluated in clinical trials in patients with heart failure.

Beyond molecular biology and traditional biochemistry, the Cardiovascular Research Laboratories are also focused on developing and testing novel devices for treating heart failure. These include percutaneous devices that electrically stimulate nerve endings in the upper thoracic aorta to improve function of the failing heart. The laboratories are also investigating devices that improve the function in heart failure through electrical stimulation of the carotid baroreflex, technology known as Baroreflex Activation Therapy (BAT). Other devices being considered for testing include percutaneously delivered miniature blood pumps that are deployed in the aorta and designed to reduce the workload on the failing heart. In doing so, these devices are expected, over time, to improve the overall ability of the failing heart to pump blood commensurate with the needs of other essential body organs. Lastly, the division is using materials made of seaweed called alginates, deemed by the US Food and Drug Administration as devices, that when injected directly into the heart muscle, help support the failing muscle by preventing progressive enlargement of the heart and reducing wall stress, which, in turn, reduces energy expenditure.

Contact information: Hani “Tony” Sabbah, Ph.D. (313) 916-7360

Cardiology/Internal Medicine

1. The Preventive Cardiology Unit conducts research across a wide range of exercise testing and exercise training-related topics that address the primary and secondary prevention of disease.

Using large hospital-wide (Henry Ford FIT and FIT-CPX Studies) and other national databases, current research includes further describing the association between reported physical activity, measured metabolic equivalents of tasks (METs), or cardiorespiratory fitness (peak oxygen uptake) and clinical outcomes (incidence of disease, survival). The Preventive Cardiology Unit also engages in investigator initiated, externally funded research that evaluates the effects of exercise training in a broad spectrum of patients with known disease. These trials include cancer survivors (e.g. breast, prostate, lymphoma and colon) at various stages of treatment, patients having undergone left ventricular assist device implant (we conducted the first randomized exercise training trial in the United States), cardiac transplant, and patients with other cardiovascular diseases (e.g. peripheral arterial disease, heart failure, myocardial infarction). This work focuses on the effects of regular exercise training on physiologic adaptations, the development of unique exercise training methods to improve cardiorespiratory function and fitness, and the relationship between regular exercise and clinical outcomes. Our research has also included industry-sponsored trials evaluating the effectiveness of biologics and devices.

In addition to the above, we actively focus on the secondary prevention of cardiovascular disease through the evaluation of novel methodologies to deliver cardiac rehabilitation and exercise training in a manner that targets improved operational efficiencies and patient compliance. Past and current NIH-funded clinical trials in our unit asses the effect of chelation therapy on the risk of morbidity and mortality in patients having survived a myocardial infarction.

Finally, the Preventive Cardiology Unit operates a Clinical Exercise Physiology Core Laboratory Service that supports national and international drug and device trials that include, as one of their main endpoints, an assessment of physical function or fitness (e.g., peak oxygen uptake via cardiopulmonary exercise testing). Since 2002, the Henry Ford Clinical Exercise Physiology Core Laboratory has supported more than 25 national/international level clinical trials.

Contact information: Steve Keteyian, Ph.D. (313) 972-1920

2. Structural Heart Disease (SHD) is a unique, intensive, multi-disciplinary collaboration between cardiac surgery, interventional cardiology, and advanced imaging. The section's research focuses on treating valvular heart disease, cardiac imaging, heart failure, shock, and thrombo-prophylaxis through new technology, devices and pharmacology. SHD has a strong interest in innovation and has been a leader in translational research in collaboration with National Institutes of Health (NIH), responsible for the clinical development of cutting edge technologies and techniques for advancing minimally invasive procedures (e.g. transcaval access, intentional right atrial exit, LAMPOON). Our advanced cardiac imaging investigators in partnership with the Henry Ford Innovations Institute has yielded seminal research in planning minimally invasive procedures and use of 3D printing to advance medicine. The SHD imaging center functions as a core lab facility for investigational studies, serving as a leader in the imaging field. Furthermore, we are a high volume center and actively recruit for sponsor initiated studies for multiple studies in valvular heart disease, heart failure and left atrial appendage occlusion (PARTNER III, COAPT, AMULET).

Contact information: William O’Neill, M.D., Medical Director, (313) 916-8708

Hypertension and Vascular Research Division/Department of Internal Medicine

High blood pressure (hypertension) is the most common form of cardiovascular disease. Hypertension afflicts more than one in four adults in this country. African Americans and the elderly have significantly greater rates of hypertension than the at-large population. By the age of 60 nearly 65 percent of all Americans will have hypertension. However the causes of hypertension remain poorly understood.

Hypertension is the top leading factor for loss of health worldwide. This is due to the fact that hypertension causes heart disease, which is the major cause of death in the United States, surpassing all forms of cancer combined. Hypertension is a major risk factor for stroke, heart attack, congestive heart failure, kidney failure, and vascular disease. Hypertension directly damages the heart, blood vessels and kidneys. In the heart, it causes enlargement (hypertrophy) and fibrosis (increased connective tissue) of the left ventricle and atrium leading to impaired function of the heart and irregular heartbeats (arrhythmias). Hypertension damages the kidney and when combined with diabetes causes very rapid progression to kidney failure, something that has reach epidemic proportion in the US. In the kidney, hypertension damages the units responsible for filtering the blood and the cells that regulate salt and water excretion. This results in loss of the ability of the kidney to excrete waste products and elevated loss of proteins that normally are found in the blood.

Research in the division focuses on understanding the genetic, molecular and physiological mechanisms that cause hypertension. We study how renal abnormalities increase the prevalence and probability of developing hypertension and also the consequences of elevated blood pressure in the heart, vessels and kidneys. Because hypertension is often associated to diabetes and obesity, we also study the mechanisms by which these diseases interact to damage the kidney and the heart. These topics are addressed by studying how 1) the genes and proteins responsible for the movement of salt and water into and out of the kidney work; 2) these genes and proteins are altered in models of hypertension, by a high salt diet or by a high sugar diet ; 3) inflammation contributes to hypertension-related damage of the heart, vessels and kidney; 4) oxidants and reactive oxygen species are generated in kidney cells, the heart or blood vessels and their role in causing hypertension and organ damage; and 5) diabetes and obesity enhance high blood pressure, damage the heart, and change renal function, leading to cardiovascular and renal disease. Such studies require use of innovative state-of-the-art methodologies, many of which were developed within the division. These include non-invasive echocardiography to measure heart function, real-time telemetric measurement of blood pressure in animals, imaging of cell function in working kidneys by multi-photon microscopy, multi-modality microscopy imaging of renal tubules and renal blood vessels that are 10 times smaller than a human hair, genomic and transcriptomic analysis of isolated cells form the heart and kidney, bioinformatics, in vivo gene transfer, molecular biology, and fluorescence microscopy to study the movement of single proteins in individual cells. Additionally, whole animal physiological and histological studies are performed. These techniques are used in models of human pathology (high blood pressure, obesity, diabetes, metabolic syndrome) that are created by genetically modifying animals or treating them with diets similar to those consumed by the population in the US (high salt, high fructose, high sugar, high fat).

The research in this division is supported by multiple grants from the National Institutes of Health, including one Program Project Grant. These grants are multi-investigator efforts that provide more than $2.5 million in support each year. Other funding sources include the American Heart Association, the Michigan Kidney Foundation and the pharmaceutical industry. In 2016, more than $4 million in total costs was awarded to the division (7 senior scientists and their support staff) to pursue their studies of the causes and consequences of high blood pressure.

Contact information: Pablo Ortiz, Ph.D., Division Head (313) 916-7164