Nancy Long Sieber Ph.D. August 31, 2015 Human Pathophysiology I: Diseases of the Cardiovascular, Respiratory and Renal Systems Nancy Long Sieber Ph.D. August 31, 2015

How are the cardiovascular, respiratory and renal systems linked? How does each system contribute to keeping the body in homeostatic balance? How does the failure of one system affect the function of the others?

All 3 systems are major players in chronic disease This course will be about things that kill a lot of people, but, importantly, it is about things that cause a great deal of disability and loss of healthy years of life. The infectious diseases of our great-grandparent’s days are largely under control, particularly in the US. What remains are the chronic diseases (often called “non-communicable diseases” or “NCDs”) – diabetes, heart disease, asthma, chronic bronchitis and emphysema, among others.

NCDs are the major cause of death worldwide.

Focusing on the US: Causes of death in 1900 and 2010 Focusing on the US: Causes of death in 1900 and 2010. Note shift from mostly infectious diseases to mostly NCDs. Note: in 1960, heart disease was responsible for 369 deaths per 100,000

What are the implications of this shift? People are generally living longer, but they spend more years of their lives being sick.

http://newsnumbers.wordpress.com/2011/06/

The rise in life expectancy has been uneven, with women in some counties experiencing a decline. Based on data from: http://vizhub.healthdata.org/us-health-map/

DALYs (disability adjusted life years) are a measure of the impact of disease on both the length and quality of life. One DALY = one year of healthy life lost. https://www.healthdata.org/sites/default/files/files/country_profiles/GBD/ihme_gbd_country_report_united_states.pdf

What are the implications of this shift? People are generally living longer, but they spend more years of their lives being sick. Health care costs are rising.

Social and behavioral factors are important predictors of NCDs. In the US, and increasingly in lower income countries, poverty is a major risk factor for NCDs. Global trends towards urbanization have led to changes in diet, exercise and tobacco consumption patterns. Environmental degradation, particularly air pollution in rapidly developing countries is also an important risk to both cardiovascular and respiratory health. While causes are complex, prevention is the best strategy.

Many of the risk factors for these diseases are modifiable by behavioral and societal changes https://www.healthdata.org/sites/default/files/files/country_profiles/GBD/ihme_gbd_country_report_united_states.pdf

To get started: A review of homeostasis and challenges of thermoregulation (which is actually a good preview of the cardiovascular system)

Internal vs. external environment As a single-celled organism, an amoeba has an external environment but no internal environment. How does this limit the kinds of places an amoeba can live? Amoeba

Multi-cellular organisms have homeostatic mechanisms to regulate the internal environment

Homeostasis is the maintenance of a stable internal environment in the face of physiologic or environmental challenges

These adaptations allow humans to maintain a consistent internal environment under extreme conditions. http://www.123rf.com/photo_2511947_first-person-view-of-a-camel-riding-experience--thar-desert-rajasthan-india.html http://runninghalf.wordpress.com/2010/10/07/the-worlds-most-exotic-marathons/

The Chilean Miners Lived for 18 days on: two spoonfuls of tuna a sip of milk a bite of cracker a morsel of peach every other day. --------------------------------------------------------------------------------------- Temperatures inside the mine were about 90°F (32°C), at 95% humidity. Oxygen and water were abundant - once food arrived, one miner ran several miles a day. The miners were rescued after 69 days underground. How did they survive?

Homeostasis This state is maintained by negative feedback control. Regulated variables are kept stable in the face of changing conditions. Adjustable variables change to keep the regulated variables relatively constant.

Negative Feedback Loop The effector changes the adjustable variables. The regulated variable is sensed by the sensor The response helps return the regulated variable to normal.

Sensor (or receptor): A system to detect the level of the variable being regulated Afferent pathway: Pathway that carries information from receptor to integrating center Set point: Target range for the regulated variable (i.e. what you want it to be) Intergrating center: A system that compares the set point with the information from the sensor. Efferent pathway: Pathway that carries information from the integrating center to the effector. Effector: Something that makes changes in controlled variables needed to bring the regulated variable back toward the set point. Response: Change that tends to bring the regulated variable back towards normal levels.

So, why are values of regulated variables sometimes outside the normal range? A change in set-point Circadian rhythm (normal variation) Fever Overwhelming challenge to regulated variables The body can usually adapt to a wide range of environments However, if the body is not able to respond with normal physiologic or behavioral changes, the system can be overwhelmed.

What happens when set point changes?

Circadian Rhythm in Body Temperature The set point for body temperature rises and falls over the course of the day. How would this affect your thermal “comfort zone”? http://www.circadian.org/vital.html

Fever Caused by an elevation in set point for body temperature. When set point rises, the body works to conserve and generate heat to elevate body temperature. An adaptive response to infection – higher temperatures, especially when accompanied by other changes, helps fight infection.

Challenges to Thermoregulation: The Boston Marathon, April, 2012 Boston.com On race day, temps were in the upper 80’s. More than 2000 runners sought treatment during the race, and 152 were treated at hospitals. One runner had a body temp of 108 °F. All recovered.

Challenges to regulated variables can be compounded by: Dysfunction of one or more components of the negative feedback loop – can keep the body from being able to respond to challenges. Conflicting regulatory systems – when maintaining one regulated variable interferes with another regulated variable

Dysfunction of Components of Feedback Loop Use of certain drugs as well as Injury to the hypothalamus interferes with temperature perception and/or activation of effectors. Anesthesia relaxes blood vessels and interferes with shivering Damage to sensors slows recognition of temp challenge

What happens when systems conflict? Example: regulating temperature and blood pressure during exercise in a hot environment. Particularly challenging situations: Marathons Military operations in the desert

Acclimatization helps people adjust to hot environments Acclimatization helps people adjust to hot environments. Among military recruits, the highest heat-related death rates are among people from northern states within the first few months of training. With acclimatization and physical training: Sweating occurs at a lower body temperature, and sweat production is increased. Blood volume is increased. Heart rate is less at any given work rate. Fat is lost and lean muscle mass is gained – body moves more efficiently.

What happens when you overheat? You sweat, losing fluid and salts. When the sweat evaporates, your body is cooled. You dilate the blood vessels in your skin – this allows you to dissipate heat. Net result: Body is cooled.

These responses tend to lower blood pressure. Sweating: The salt and water that you lose in your sweat comes from your blood. Excessive sweating reduces blood volume, lowering blood pressure. Vasodilation: When more of your blood goes to your skin, then there is less blood available to reach the muscles and brain. Blood pressure drops, reducing blood flow to these important organs.

How does the body resolve the conflict between maintaining body temperature and blood pressure? How do you feel when your body is heat stressed? What do you want to do when you feel this way? Are these responses helpful?

The dehydration that results from heat stress affects renal function The dehydration that results from heat stress affects renal function. Kidneys produce more concentrated urine. The volume and concentration of urine are adjustable variables. Urine concentration can range from as low as 30 mOsl/Lwith maximal water load, to about 1400 mOsl/L in dehydration. http://www.sarresponder.com/index.php?page=articles&art_id=5

If heat stress persists, it can lead to heat exhaustion or (worse) heat stroke Hot, dry skin Body temperature dangerously elevated > 107 °F Can quickly progress to coma, multi-organ failure, even death. Can have consequences years later. Heat Exhaustion: Sweating – moist, clammy skin. Body temperature close to normal. Extreme fatigue, fainting. Can progress to heat stroke

Three types of heat exhaustion: Salt depletion - from sweating without replacing lost salt (often water is replaced by drinking) Water depletion – leads to low blood pressure, relatively greater elevation in temp than just salt depletion. Dilutional hyponatremia – caused by drinking too much water, and not replacing lost sodium. We’ll talk about this in the renal system. These are generally treatable with cooling and fluids.

Two types of Heat Stroke Classic Heat Stroke Affects a vulnerable population - typically very young and elderly during heat waves and other exposures to high heat. Even with hospital treatment, mortality is high - 10 to 65%. Most patients still have functional impairments when they leave the hospital, and some may even worsen over the next 1-2 years. Exertional Heat Stroke More likely to affect young people during heavy exercise in warm to hot weather conditions. With hospital treatment, mortality is 3 – 5%,. Exertional heat stroke is characterized by more severe disruptions of homeostasis. Nonetheless, people with exertional heat stroke are more likely to make a complete recovery, probably because they were healthier to start with.

Leon, LR “Heat Stroke” in Comprehensive Physiology Vol 5, April 2015 Sign of muscle injury – damages kidneys Abnormal clotting Signs of liver failure Muscle/cardiac damage, renal failure Leon, LR “Heat Stroke” in Comprehensive Physiology Vol 5, April 2015

Proposed Mechanism of Heat Stroke (DIC) Summary of heat stroke pathophysiological changes that culminate in multi-organ system dysfunction and death. Heat stress and/or exercise cause an increase in core temperature, which stimulates multiple reflexive adjustments. Skin blood flow is increased to facilitate heat loss to the environment and is an important negative feedback pathway (dashed arrow) to limit hyperthermia. A decrease in gut blood flow facilitates the redistribution of blood to the skin surface. Prolonged reductions in gut blood flow stimulate oxidative/nitrosative stress and cause the gut epithelial barrier membrane to become ischemic. Gut ischemia causes the tight junctions of the gut to become leaky, allowing endotoxin to leak from the gut lumen into the systemic circulation. The innate and adaptive immune systems sense and respond to endotoxin (through toll-like receptors, such as TLR4) and stimulate the production of cytokines and other immune modulators. High body temperature causes thermal injury to the vascular endothelium and initiates the coagulation/fibrinolysis pathways that lead to occlusion of the arterioles and capillaries (microvascular thrombosis) or excessive bleeding (consumptive coagulation). The systemic inflammatory response syndrome (SIRS) and coagulation pathways interact to cause multi-organ system failure and death if not rapidly treated and resolved. Hyperthermia causes a reduction in cerebral blood flow that may be the initiating stimulus for increased blood-brain barrier permeability and brain injury. Hypothalamic damage has been thought to mediate hypothermia and/or recurrent hyperthermia during heat stroke recovery, although there are no clinical or experimental data to support this hypothesis. Gray shading indicates hypothetical mechanisms of injury, but clinical and experimental data are limited. Leon L R , Helwig B G J Appl Physiol 2010;109:1980-1988

Leakage of gut bacteria (which have LPS on their surface) causes release of cytokines IL-1 and TNF. Activating tissue factor in the extrinsic coagulation pathway Leon, LR Heat Stroke and Cytokines Progress in Brain ResearchVolume 162, 2007, Pages 481–524

Macario AJ, de Macario EC. N Engl J Med 2005;353:1489-1501. Heat shock proteins (HSP) protect against the effect of hyperthermia and other stressors Heat shock proteins are made in response to thermal stress, as well as many other kinds of stressors (infection, trauma, etc.). They act as “chaperones” helping To refold misfolded or unfolded proteins. They also help destroy irreparably damaged proteins. They trigger production anti-inflammatory cytokines, protecting tissues from damage. Figure 2. Chaperoning Teams. The chaperone machine is a team of three proteins: heat-shock protein (HSP) 70, HSP40, and nucleotide-exchange factor. HSP70 binds a client (unfolded or misfolded) polypeptide and, in collaboration with the other members of the team, assists the polypeptide to fold correctly and thus achieve its native conformation. Prefoldin consists of five distinct subunits arranged like a medusa. The mitochondrial chaperonin consists of two multimeric assemblages. The larger assemblage has 14 HSP60 subunits; the smaller one has 7 HSP10 subunits. The chaperonin-containing TCP-1 (tailless complex polypeptide 1) complex is similar in overall structure to the mitochondrial chaperonin, but eight distinct subunits (A through H) form each of its two rings. The small HSPs are chaperones, such as the α-crystallins, that are normally monomers. In response to cellular stress, they form multimers that participate in the protection of unfolded polypeptides. Macario AJ, de Macario EC. N Engl J Med 2005;353:1489-1501.

Treatment for Heat Stroke The patient needs to be cooled as quickly as possible. Patients need support for ventilation and circulation Other conditions that arise also need to be treated, such as rhabdomyolysis and fluid and electrolyte imbalances.

Long term consequence of heat stroke. In the weeks to months that follow a heat wave, many vulnerable patients die of multi-organ failure despite hospital treatment. This persistent risk is thought to be due to damage to the hypothalamus and continued inflammation. The damage may have life-long consequences – a study of military heat stroke victims showed a roughly 2-fold increase in death from cardiovascular, renal and liver failure within 30 years of their treatment for the condition, relative to patients hospitalized for non-heat related illnesses.