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Afterload and Its Components

October 21, 2015 Cardiology, Critical Care, Physiology and Pathophysiology, Respirology No comments , , , , , , , , , , ,

joe_mazzello_sledgeAfterload

Also see information about afteroad in Pharmacy Profession Forum at http://forum.tomhsiung.com/pharmacy-research-study-and-policy/physiology-and-pathophysiology/699-preload-and-afterload.html#post1130

Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:

σ = (P x r)/(2 x h) [Laplace Equation]

where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.

Components of Afterload

The forces that contribute to ventricular afterload can be identified by their relationship to the variables in the Laplace equation. The component forces of ventricular afterload include end-diastolic volume (EDV/preload), pleural pressure, vascular impedance, and peripheral vascular resistance.

Pleural Pressure

Since afterload is a transmural wall tension, it will be influenced by the pleural pressure surrounding the heart. Therefore, negative pressure surrouding the heart will impede ventricular emptying by opposing the inward movement of the ventricular wall during systole. This effect is responsible for the transient decrease in systolic blood pressure that occurs during the insiratory phase of spontaneous breathing. When the inspiratory drop in systolic pressure is greater than 15 mm Hg, the condition is called "pulsus paradoxus" (which is a misnomer, since the response is not paradoxical, but is an exaggeration of the normal response).

Conversely, positive pressures surrounding the heart will promote ventricular emptying by facilitating the inward movement of the ventricular wall during systole. When intrathoracic pressure rises during a positive-pressure breath, there is a transient rise in systolic blood pressure, reflecting an increase in the stroke output of the heart. The inspiratory rise in blood pressure during mechanical ventilation is known as "reverse pulsus paradoxus". The "unloading" effect of positive intrathoracic pressure is the basis for the use of positive-pressure breathing as a "ventricular assist" maneuver for patients with advanced heart failure.

Impedance

Vascular impedance is the force that opposes the rate of change in pressure and flow, and it is expressed primarily in the large, proximal arteries, where pulsatile flow is predominant. Impedance in the ascending aorta is considered the principal afterload force for the left ventricle, and impedance in the main pulmonary arteries is considered the principal afterload force for the right ventricle. Vascular impedance is a dynamic force that changes frequently during a single cardiac cycle, and it is not easily measured in the clinical setting.

Resistance

(Systemic) vascular resistance is the force that opposes non-pulsatile or steady flow, and is expressed primarily in small, terminal blood vessels, where non-pulsative flow is predominant. About 75% of the vascular resistance is in arterioles and capillaries. In the beginning of arterioles, although the blood pressure is still pulsatile, the vascular smooth muscles have autoregulation function so the blood flow is steady. Becasue the flow is steady, the mean arterial pressure had been created to equal the "average" arterial pressure during a cardac cycle, under which the amount of blood flow per time is the same. So the relationship between SVR, MAP, and CO is:

SVR = (MAP – RAP) / CO

Similarly, the relationship between PVR, PAP, and CO is:

PVR = (PAP – LAP) / CO

However, SVR and PVR are not considered to be accurate representations of the resistance to flow in the pulmonary and systemic circulations. Because vascular impedance is not easily measured, vascular resistance is often used as a clinical measure of ventricular afterload. But animal studies have shown a poor correlation between direct measures of ventricular wall tension (true afterload) and the calculated vascular resistance. This is consistent with the notion that vascular impedance is the principal afterload force for ventricular emptying. However, the contribution of vascular resistance to afterload cannot be determined with the SVR and PVR because these parameters do not represent the actual resistance to flow in the circulatory system.


Determinants of Myocardial Oxygen Consumption

References:

1.http://www.cvphysiology.com/CAD/CAD004.htm

Myocyte contraciton is the primary factor determining myocardial oxygen consumption (MVO2) above basal levels. Therefore, factors that enhance tension development by the caridac muscle cells, the rate of tension development, or the number of tension generating cycles per unit time will increase MVO2. For example, doubling heart rate approximately doubles MVO2 because ventricular myocytes are generating twice the number of tension cycles per minute. Increasing inotropy also increases MVO2 because the rate of tension development is increased as well as the magnitude of tension, both of which result in increased ATP hydrolysis and oxygen consumption. Increasing afterload, because it increases tension development, also increases MVO2. Increasing preload (e.g., ventricular end-diastolic volume) also increases MVO2; however, the increase is much less than what might be expected because of the LaPlace relationship.

The LaPlace relationship has been discussed above. If we substitute ventricular end-diastolic volume/EDV for ventricular radius, we get below new LaPlace equation:

Screen Shot 2016-07-18 at 1.16.30 PMThis relationship indicates that a 100% increase in venticular volume (V) incrases wall tension (T) by only 26%. In contrast, increasing intraventricular pressure (P) by 100% increases wall tension by 100%. For this reason, wall tension, and therefore MVO2, is far less sensitive to changes in ventricular volume than pressure.

The Management of Hypertension (Pathophysiologic Basises)

September 10, 2015 Cardiology, Pharmacology, Physiology and Pathophysiology No comments , , , , , , , , , , ,

Hypertension is a common diseases and is defined as persistently elevated arterial blood pressure of >= 140/90 mm Hg. Most of patients belong to essential hypertension and a small percentage belong to secondary hypertension for which the most common causes include renal dysfunction resulting from severe chronic kidney disease (CKD) or renovascular disease. Besides, certain drugs or other products (Table 3-1), either directly or indirectly, can cause hypertension or exacerbate hypertension by increase BP.

Table 3-1 Secondary Causes for Hypertesnion

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Classification of Hypertension

  • Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
  • Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
  • Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
  • Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater

Hypertension Crisis: These are clinical situations where BP values are very elevated, typically >180/120 mm Hg. They are categorized as either hypertensive emergency or hypertensive urgency. The former are extreme elevations in BP that are accompanied by acute or processing target-organ damage. The latter are high elevations in BP without acute or progressing target-organ injury. Prehypertension is not considered a disease category but identifies patients whose BP is likely to increase into the classification of hypertension in the future.

Cardiovascular Risk and Blood Pressure

Hypertension must be treated and the reason why is that hypertension is a major cardiovascular risk factor and there indeed is a causal relationship between hypertension and cardiovascular diseases. Also, epidemiologic data demonstrate a strong correlation between BP and CV morbidity and mortality. (Starting at a BP of 115/75 mm Hg, risk of CV disease doubles with every 20/10 mm Hg increase.) Even patients with prehypertension have an increased risk of CV disease. Because hypertension and CV morbidity/mortality has a casual relationship, treating patients with hypertension with antihypertensive drug therapy provides significant clinical benefits.


Pathophysiology

To further discuss the pathophysiology, we first need to know the mathematic formula to estimate arterial BP. According to the physic law, steady flow (Q) through a closed hydraulic circuit is directly related to the pressure gradient across the circuit (Pin – Pout), and inversely related to the resistance to flow (R) through the circuit. So Q=(Pin – Pout)/R. In the cardiovascular system, Q is cardiac output (CO), Pin is mean arterial pressure (MAP) and Pout is right atrial pressure (RAP), whereas resistance to flow (R) is total peripheral resistance (TPR). So CO=(MAP – RAP)/TPR. Because in normal conditions RAP approaches zero mm Hg, so CO=MAP/TPR and after we make a rearrange we finally get the formula of MAP=CO * TPR. Note that in some pathophysiology status RAP increases significantly and cannot be removed from the formula above.

After the discuss above, the two determinants for MAP is the cardiac output (CO) and the total peripheral resistance (TPR). If we distinguish MAP to systolic BP (SBP) and diastolic BP (DPB), CO is the major determinant of SBP, whereas TPR largely determines DBP. So factors that elevate CO or TPR can elevate BP. We category these factors into 1.humoral; 2.neuronal; 3.peripheral autoregulation; and 4.disturbances in sodium, calcium, and natriuretic hormone.

Humoral Mechanisms

RAAS

RAAS stands for the rennin-angiotensin-aldosterone system, which is a complex endogenous system that play a range of functions including the regulation of arterial pressure. The RAAS regulars sodium, potassium, blood volume, and most important the vascular tone. Because the total periphery resistance (TPR) is primarily generated by arterioles, so elevated TPR could be a result of activation of RAAS – the angiotensin II (angII). For the detail discussion of TPR please refer to the threads of http://www.tomhsiung.com/wordpress/2015/06/flow-resistance-of-vessels-in-series-and-vessels-in-parallel/ and http://www.tomhsiung.com/wordpress/2015/07/vascular-resistances-and-compliance-map-and-pulse-pressure/, respectively, by Tom Hsiung. First, angII increase the vascular tone, including arterioles. Second, angII induced increased aldosterone synthesis and secretion sodium and water retention, which increase the blood volume. Increased blood volume and TPR eventually result in elevation of BP.

Vasopressin

Vasopressin is a polypeptide hormone, also known as antidiuretic hormone/ADH, which plays an important role in extracellular fluid homeostasis (blood volume/plasma volume). Vasopressin acts on collecting ducts in the kidneys to decrease renal excretion of water. This is the most important and wide-known function of vasopressin. However, vasopressin is also a potent arteriolar vasoconstrictor.

Natriuretic Hormone

Natriuretic hormones inhibits sodium and potassium-ATPase and thus interferes with sodium transport across cell membranes. Natriuretic hormone theoretically could increase urinary exertion of sodium and water. However, this hormone might block the active transport of sodium out of arteriolar smooth muscle cells. The increased intracellular sodium concentration concentration ultimately would increase vascular tone and BP.

Insulin Resistance and Hyperinsulinemia

Hypothetically, increased insulin concentrations may lead to hypertension because of increased renal sodium retention and enhanced sympathetic nervous system activity. Moreover, insulin has growth hormone-like actions that can induce hypertrophy of vascular smooth muscle cells. Insulin also may elevated BP by increasing intracellular calcium, which lead to increased vascular resistance. The exact mechanism by which insulin resistance and hyperinsulinemia occur in hypertension is unknown. However, this association is strong because many of the criteria used to define this population (i.e., elevated BP, abdominal obesity, high, triglycerides, low high-density lipoprotein cholesterol, and elevated fasting glucose) are often present in patients with hypertension.

Circulating Catecholamines

It is easy to understand the causal relationship between elevated levels of circulating catecholamines and the hypertension, from the perspective of MAP = CO * TPR.

Neuronal Regulation

Synaptic receptors, baroreceptor reflex system, and CNS are involved in the regulation of vascular resistances, cardiac outputs.

Central and autonomic nervous system are intricately involved in the regulation of arterial BP. Many receptors that either enhance or inhibit norepinephrine release are located on the presynaptic surface of sympathetic terminals. The alpha and beta presynaptic receptors play a role in negative and positive feedback to the norepinephrine-containing vesicles, respectively. Stimulation presynaptic alpha-receptors (α2) exerted a negative inhibition on norepinephrine release. Stimulation of presynaptic beta-receptors facilitates norepinephrine release.

Sympathetic neuronal fibers located on the surface of effector cells innervate the alpha- and beta-receptors. Stimulation of postsynaptic alpha-receptors (α1) on arterioles and venues results in vasoconstriction. There are two types of postsynaptic beta-receptors, β1 and β2. Both are present in all tissues innervated by the sympathetic nervous system. However, in some tissues β1-receptors predominate (e.g., heart), and in other tissues β2-receptors predominate (e.g., bronchioles). Stimulation of β1-receptors in the heart results in an increase in heart rate, and the force of contraction (so cardiac output is increased), whereas stimulation of β2-receptors in the arterioles and venues causes vasodilation.

So after the discussion of the two paragraph above, we know that the disturbance of the function of presynaptic and/or postsynaptic receptors would result the imbalance of autonomic nervous system.

Same with the autonomic nervous system but from a different aspect (above is output of autonomic nervous system and now it’s the input of nervous system),  the baroreceptor reflex system is the major negative feedback mechanism the controls sympathetic activity. Baroreceptors are nerve endings lying in the walls of large arteries, especially in the carotid arteries and aortic arch. Changes in arterial BP rapid activate baroreceptors that then transmit impulses to the brain stem through the ninth cranial nerve and vagus nerve. In this reflex system, a decrease in arterial BP stimulates baroreceptors, causing reflex vasoconstriction and increased heart rate and force of cardiac contraction. Also the periphery vascular tone increase too (TPR).

Stimulation of certain areas within the central nervous system can either increase or decrease BP. I think this mechanism must be rather complex, which involves with neurology. If we have time in future, I will take a look at the neurology.

OK. The purpose of the neuronal mechanisms is to regulate BP and maintain homeostasis. Pathologic disturbances in neuronal systems could chronically elevate BP. These systems are physiologically interrelated. A defect in one component may alter normal function in another. Therefore, cumulative abnormalities may explain the development of essential hypertension.

Peripheral/Local Mechanisms (including autoregulatory, etc.) 

Abnormalities in renal or tissue autoregulatory systems, which is just one of several local vascular regulatory mechanisms of human, could cause hypertension. Recall the formula that MAP = CO * TPR. Similarly, the disorders of local vascular regulatory .For detail information of local vascular regulatory mechanisms please refer to the thread of http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/ by Tom Hsiung.

Electrolytes

Epidemiologic and clinical data have associated excess sodium intake with hypertension. Population-based studies indicate that high-sodium diets are associated with a high prevalence of stroke and hypertension. Conversely, low-sodium diets are associated with a lower prevalence of hypertension. For the perspective of pathophysiology, more sodium, more water. We will discuss this phenomenon in threads that discuss the kidney.

Altered calcium homeostasis also may play an important role in the pathogenesis of hypertension. A lack of dietary calcium hypothetically can disturb the balance between intracellular and extracellular calcium, resulting in an increased intracellular calcium concentration. This imbalance can alter vascular smooth muscle function by increasing PVR (peripheral vascular resistance). Some studies have shown that dietary calcium supplementation results in a modest BP reduction for patients with hypertension.

The role of potassium fluctuations is also inadequately understood. Potassium depletion may increase PVR, but the clinical significance of small serum potassium concentration changes is unclear. Furthermore, data demonstrating reduced CV risk with dietary potassium supplementation are very limited.

Vascular Resistances and Compliance, MAP and Pulse Pressure

July 9, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , ,

Resistances In A Single Organ

In an organ, the consecutive vascular segments are arranged in series within an organ. Therefore, the overall vascular resistance of the organ must equal the sum of the resistances of its consecutive vascular segments,

Screen Shot 2015-07-08 at 9.51.16 PM

Because arterioles have a large vascular resistance in comparison to the other vascular segments (see above), the overall vascular resistance of any organ is determined to a very large extent by the resistance of its arterioles. And according to its histologic characteristics, we can change the diameter of arterioles either spontaneously or with will (i.e., arterioles inside the penis). Thus, the blood flow through an organ is primarily regulated by adjustments in the internal diameter of arterioles caused by contraction or relaxation of their muscular arteriolar walls.

When the arterioles of an organ change diameter, not only does the flow (in general flow is decreased) to the organ change but also the manner in which the pressures drop within the organ is also modified. Arteriolar constriction causes a greater pressure drop  across the arterioles, and this tends to increase the arterial pressure while it decreases the pressure in capillaries and veins. Conversely, increased organ blood flow caused by arteriolar dilation is accompanied by decreased arterial pressure and increased capillary pressure. Because of the changes in capillary hydrostatic pressure, arteriolar constriction tends to cause transcapillary fluid reabsorption, whereas arteriolar dilation tends to promote transcapillary fluid filtration (see thread Transcapillary Transport at http://www.tomhsiung.com/wordpress/2015/07/transcapillary-transport/).
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Resistances In A Whole Body

The overall resistance to flow through the entire systemic circulation is called the total peripheral resistance. Because the systemic organs are generally arranged in parallel, the vascular resistance of each organ contributes to the total peripheral resistance according to the following  parallel resistance equation:

Screen Shot 2015-07-08 at 10.51.03 PMAccording to the parallel vascular model, the TPR must always be less than that of any of the elements in the network (organ1, organ2, …, organn).


Compliance of Vassels

As indicated earlier, arteries and veins contribute only a small portion to the overall resistance to flow through a vascular bed. Therefore, changes in their diameters have no significant effect on the blood flow through systemic organs. The elastic behavior of arteries and veins is however every important to overall cardiovascular function because they can act as reservoirs and substantial amounts of blood can be stored in them.

Arteries or veins behave more like balloons with one pressure throughout rather than as resistive pipes with a flow-related pressure difference from end to end. Thus, we often think of an “arterial compartment” and a “venous compartment,” each with an internal pressure that is related to the volume of blood within it at any instant and how elastic its walls are.

The elastic nature of a vascular region is characterized by a parameter called compliance that describes how much its volume changes (ΔV) in response to a given change in distending pressure (ΔP): C = ΔV/ΔP. Distending pressure is the difference between the internal and external pressures on the vascular walls. The volume-pressure curves for the systemic arterial and venous compartments are shown in Figure 6-8. It is immediately apparent from the disparate slopes of the curve in this figure that the elastic properties of arteries and veins are very different. For the arterial compartment, the ΔV/ΔP measured near a normal operating pressure of 100 mm Hg indicates a compliance of approximately 2 mL/mm Hg. By contrast, the venous pool has a compliance of more than 100 mL/mm Hg near its normal operating pressure of 5 to 10 mm Hg.

Besides, arterial compliance also decreases with increasing MAP. Otherwise, arterial compliance is a relatively stable parameter.
Screen Shot 2015-07-09 at 8.35.11 PM

Because veins are so compliant, even small changes in peripheral venous pressure can cause a significant amount of the circulation blood volume to shift into or out of the peripheral venous pool. Standing upright, for example, increases venous pressure in the lower extremities, distends the compliant veins, and promotes blood accumulation (pooling) in these vessels, as might be represented by as shift from point A to point B in Figure 6-8. Fortunately, this process can be counteracted by active venous constriction. The dashed line in Figure 6-8 shows the venous volume-pressure relationship that exists when veins are constricted by activation of venous smooth muscle. In constricted veins, volume may be normal (point C) or even below normal (point D) despite higher-than-normal venous pressure. Peripheral venous constriction tends to increase peripheral venous pressure and shift blood out of the peripheral venous compartment.


Mean Arterial Pressure

Mean arterial pressure is a critically important cardiovascular variable because it is the average effective pressure that drives blood through the systemic organs. One of the most fundamental equations of cardiovascular physiology is that which indicates how mean arterial pressure is related to cardiac output and total peripheral resistance:

Screen Shot 2015-07-09 at 9.17.06 PM

This equation is simply a rearrangement of the basic flow equation (Q = ΔP/R) applied to the entire systemic circulation with the single assumption that central venous pressure is approximately zero so that ΔP = MAP. Of note is that all changes in MAP result from changes in either cardiac output or total peripheral resistance.


Arterial Pulse Pressure

The arterial pulse pressure (PP) is defined simply as systolic pressure minus diastolic pressure,

Screen Shot 2015-07-09 at 8.46.59 PM

To be able to use pulse pressure to deduce something about how the cardiovascular system is operating, one must do more than just define it. It is important to understand what determines pulse pressure; that is, what causes it to be what it is and what can cause it to change. As a consequence of the compliance of the arterial vessels, arterial pressure increases as arterial blood volume is expanded during cardiac ejection. The magnitude of the pressure increase (ΔP) caused by an increase in arterial volume depends on how large the volume change (ΔV) is and on how compliant (CA) the arterial compartment is: ΔP = ΔV/CA. If, for the moment, the fact that some blood leaves the arterial compartment during cardiac eject is neglected, then the increase in arterial volume during each heartbeat is equal to the stroke volume (SV). Thus, pulse pressure is, to a first approximation, equal to stoke volume divided by arterial compliance:

Screen Shot 2015-07-09 at 8.58.07 PM

If the stoke volume of a normal resting young man is approximately 80 mL and the arterial compliance is approximately 2 mL/mm Hg, arterial pulse should be approximately 40 mm Hg, according to the equation above. Because the compliance of arteries decrease as age grows, the arterial pulse pressure increases as age grows. Of note, arterial blood volume and mean arterial pressure tend to increase with age. The increase in mean arterial pressure is not caused by the decreased arterial compliance because compliance changes do not directly influence either cardiac output or total peripheral resistance, which are the sole determinants of MAP. And, the decrease in arterial compliance is sufficient to cause increased pulse pressure even through stroke volume tends to decrease with age.

In addition, MAP tends to increase with age because of an age-dependent increase in total peripheral resistance, which is controlled primarily by arterioles, not arteries.

The preceding equation for pulse pressure is a much-simplified description of some very complex hemodynamic processes. It correctly identifies stroke volume and arterial compliance as the major determinants of arterial pulse pressure but is based on the assumption that no blood leaves the aorta during systolic ejection. Obviously, this is not strictly correct. It is therefore not surprising that several factors other than arterial compliance and stroke volume have minor influences on pulse pressure. For example, because the arteries have viscous properties as well as elastic characteristics, faster cardiac ejection caused by increased myocardial contractility tends to increase pulse pressure somewhat even if stroke volume remains constant. Changes in peripheral resistance, however, have little or no effect on pulse pressure, because a change in total peripheral resistance causes parallel change in both systolic and diastolic pressures.