The Management of Hypertension (Clinical Evaluation)

September 12, 2015 Cardiology, Diabetes, Infectious Diseases, Pharmacotherapy, Therapeutics No comments , , , , , , , ,

Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation including a comprehensive medical history, physical examination, and laboratory and/or diagnostic test is recommended after diagnosis to identify secondary causes, identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and assess for the presence of absence of hypertension-associated target-organ damage.

For the patients who have been diagnosed with hypertension, we should ask a few questions that are necessary to make a clinical evaluation for these patients. Here is an example of a patient with hypertension.

D.C. is a 44-year-old black man who presents to his primary care provider concerned about high BP. At an employee health screening last month he was told he has stage 1 hypertension. His medical history is significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and hypertension and died of a stroke at age 68. D.C. smokes on pack per day of cigarettes and thinks his BP is high because of job-related stress. He does not engage in any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination show he is 175 cm tall, weighs 108 kg (BMI, 35.2 kg/m2), BP is 148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, heart rate is 80 beats/minute. Six months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary-care provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking, with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen, 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL (Fasting?)

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol, 141 mg/dL

High-density lipoprotein cholesterol, 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram is normal except for left ventricular hypertrophy.

PS: Normal values are marked in green and abnormal values are marked in orange.

Clinical Presentation

Question 1 What is the clinical presentation D.C.?

All the information above could be the part of D.C.’s clinical presentation. Besides, we could classify the stage of D.C.’s hypertension as shown below.

D.C. has uncontrolled stage 1 hypertension. He has had elevated BP values, measured in clinical environments, and meets the diagnostic criteria for hypertension because two or more of his BP measurements are elevated on separate days. SBP values are consistently stage 1, whereas DBP values are all in the prehypertension range. The higher of the two classifications is used to classify hypertension.

Question 2 Why does D.C. have hypertension?

D.C. has essential hypertension; therefore, the exact cause is not known. He has several characteristics (e.g., family history of hypertension, obesity) that may have increased his chance of developing hypertension. Race and sex also influence the prevalence of hypertension Across all age groups, black have a higher prevalence of hypertension than do whites and Hispanics. Similar to other form of CV disease, hypertension is more server, more like to include hypertension-associated complications, and occurs at an earlier age in black patients.

Patient Evaluation and Risk Assessment

The presence of absence of hypertension-associated complications as well as other major CV risk factors (Table 14-5) must be assessed in D.C. Also, secondary cause of hypertension (Table 14-3), if suggested by history and clinical examination findings, should be identified and managed accordingly. The presence of concomitant medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be evaluated so that they can be used to guide therapy.

  • Hypertension-associated complications
  • Secondary causes of hypertension
  • Concomitant medical conditions

Question 3 Dose D.C. has secondary cause of hypertension?

The most common secondary causes of hypertension are list in Table 3-1. Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorders.

Table 3-1 Secondary Causes of Hypertension.

  • Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension.
  • In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness.
  • Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscle weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism).
  • Patient with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses.
  • Patient with renal artery stenosis may have an abdominal systolic-diastolic bruit.

Also, routine laboratory tests may also help identify secondary hypertension. For example, Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma rennin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renoascular disease.

Certain drugs and other products can result in drug-induced hypertension. For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identify a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.

Question 4 Which hypertension-associated complications are present in D.C.?

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A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Question 5 What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate of decline is greatly accelerated by hypertension. Hypertension is associated with nephrosclerosis, which is caused by increased intraglomerular pressure. It is unknown whether a primary kidney lesion with ischemia causes systemic hypertension or whether systemic hypertension directly causes glomerular capillary damage by increasing intraglomerular pressure. Regardless, CKD, whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need for dialysis. Studies have demonstrated that controlling hypertension is the most important strategy to slow the rate of kidney function decline, but it may not be entirely effective in slowing the progression of renal impairment in all patients.

In hypertension, stage 3 CKD or worse is considered a hypertension-associated complication (GFR values of <60 mL/min/1.73 m2). An estimated GFR of less than 60 mL/min/1.73 m2 corresponds approximately to a serum concentration of greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average woman. This level of kidney compromise lowers an individual’s BP goal to less than 130/80 mm Hg according to multiple guidelines. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine collection or 200 mg albumin/g creatinine on a spot urine measurement) also indicates significant CKD, for which achieving the more aggressive BP goal is a strategy to minimize the rate of progression to kidney failure.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

Question 6 Which major CV risk factors are present in D.C.?

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

PS: Estimated GFR calculated from online calculator for D.C. is 105 mL/min/1.73 m(online calculator: http://www.davita.com/gfr-calculator/).

So according to D.C.’s clinical presentation, he has major CV risk factors that are marked in orange, that is, 5 factors in total, including the essential hypertension.

Question 7 What is D.C.’s BP goal and how can Framingham risk scoring influence BP goal determination?

D.C. is a primary prevention patient because he does not yet have any hypertension-associated compilations (or compelling indications). He has multiple CV risk factors, so controlling his BP is of paramount importance to reduce the risk of developing hypertension-associated complications. The JNC-8 guidelines recommend the initial BP goal for hypertension patients with age of <60 years should be 140/90 mm Hg, which has grade A evidence (strong recommendation) for patients from 30 through 59 years of age, and grade E (expert opinion) for those from 18 through 29 years of age. So D.C.’s initial BP goal should be below 140/90 mm Hg.

The framingham risk scoring system is available as an online calculator at NIH site of http://cvdrisk.nhlbi.nih.gov/calculator.asp. According to D.C.’s clinical presentation, he will has a CV risk of  14% in a next 10-year period of expectation before we intervention, which means in a population cohort such as D.C., 14 in 100 individuals will develop CV diseases after a period of 10-year, if we don’t treat these CV risk factors (if these risk factors worsen, the incidence of developing CV diseases would be higher). If we treat D.C.’s current hypertension target the BP goal, with other interventions that target D.C.’s rest risk factors like habit of smoking, etc., the incidence of developing CV diseases would be attenuated (In D.C.’s example, the incidence would decrease to 5%, that is 5 in 100 of individuals will develop CV diseases in a period of 10-year). Compare the results without/with interventions to D.C.

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The intervention above does not include the management of dyslipidemia. According to the latest AHA guideline, four types of patients need the intervention for dyslipidemia, including: 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. (References: http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/). So we need to calculate D.C.’s ASCVD risk from another tool developed by ACC/AHA (American College of Cardiology/American Heart Association), which is available as iOs apps. So the result of ASCVD risk of D.C. is 9.7% (>=7.5%) without any intervention, whereas ASCVD risk is 8.6% (still >=7.5%) with interventions of antihypertensive therapy and smoke cessation. Therefore, the dyslipidemia should be treated for D.C.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.


Pathophysiology of Selected Vascular Disorders

June 2, 2014 Cardiology, Physiology and Pathophysiology 1 comment , , , ,


A condition that afflicts the large and medium-sized arteries of almost every human, at least in societies in which cholesterol-rich foodstuffs are abundant and cheap, is atherosclerosis. This condition begins in childhood and, in the absence of acelerating factors, develops slowly until it is widespread in old age. However, it is accelerated by a wide variety of genetic and environmental factors.

Atherosclerosis is characterized by localized fibrous thickenings of the arterial wall associated with lipid-infiltrated plagques that may eventually calcify. Old plaques are also prone to ulceration and rupture, triggering the formation of thrombi that obstruct flow.

Risk Factors Accelerating Atherosclerosis

First let see the risk factors that accelerate the progression of atherosclerosis, since treating the accelerating conditions that are treatable and avoiding those that are avoidable should reduce the incidence of myocardial infarctions, strokes, and other complications of atherosclerosis.

Detail mechanisms of lipid metabolism can be found here http://forum.tomhsiung.com/physiology-and-pathophysiology/402-the-pathway-of-lipids.html


Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women than in men. In addition, epidemiologic evidence shows that estrogen replacement therapy protects the cardiovascular system in postmenopausal women. But, in several studies, estrogen treatment of postmenopausal women failed to prevent second heart attacks (note here, it was secondary prevention, not primary prevention).

Homocysteine and related molecules

The effect of increased plasma levels of homocysteine and related molecules such as homocystine and homocysteine thiolactone, a condition sometimes called hyperhomocystinemia, deserves emphasis. These increases are assoicated with accelerated atherosclerosis, and the magnitude of the plasma elevation is positively correlated with the severity of the atherosclerosis. Markedly elevated levels resulting from documented mutations of relevant genes are rare, but mild elevations occur in 7% of the general population.

The mechanism responsible for the accelerated vascular damage is unsettled, but homocysteine is a significant source of H2O2 and other reactive forms of oxygen, and this may accelerate the oxidation of LDL.

Cholesterol and triglyceride

Evidence is now overwhelming that lowering plasma cholesterol and triglyceride levels and increasing plasma HDL levels slows, and in some cases reverses, the atherosclerotic process. For the ways to lowering serum cholesterol and triglyceride (including how to elevate HDL) please refer the thread describing the management of dyslipidemia.


Men who smoke a pack of cigarettes a day have a 70% increase in death rate from ischemic heart disease compared with nonsomokers, and there is also an increase in women. The deleterious effects of smoking include endothelial damage caused by carbon monoxide-induced hypoxia. Other factors may also be involved. In general, these deleterious increase the risk of atherosclerosis.

Blood pressure

Because of the increased shear stress imposed on the endothelium by an elevated blood pressure, hypertension is another important modifiable risk factor for atherosclerosis.


In diabetes, there are microvascular complications and macrovascular complications. These complications are shown below:


The nephrotic syndrome and hypothyroidism also accelerate the progression of atherosclerosis.

Pathogenesis of Atherosclerosis

The initial event in atherosclerosis is infiltration of LDLs into the subendothelial region. The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood. This is most marked at points where the arteries brach, and this is where the lipids accumulate to the greatest degree.

The LDLs are oxidized or altered in other ways. Thus, altered LDLs activate various components of innate immune system including macrophages, natural antibodies, and innate effector proteins such as C-reactive protein and complement. Altered LDLs are recognized by a family of scavenger receptors expressed on macrophages. These scavenger receptors mediate uptake of the oxidized LDL into macrophages and the formation of foam cells. The foam cells form fatty streaks.

The streaks appear in the aorta in the first decade of life, in the coronary arteries in the second decade, and in the cerebral arteries in the third and fourth decades.

Oxidized LDLs have a number of deleterious effects, including stimulation of the release of cytokines and inhibition of NO production. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima, where they proliferate, lay down collagen and other matrix molecules, and contribute to the bulk of the lesion. Smooth muscle cells also take up oxidized LDL and become foam cells.

Lipids accumulate both intracellularly and extracellularly.Screen Shot 2015-10-18 at 1.31.03 PM

As the atherosclerotic lesions age, T cells of the immune system as well as macrophages are attracted to them. The intercellular “soup” in the plaques contains a variety of cell-damaging substances, including ozone. Overally, the lesions have been shown to have many of the characteristics of a low-grade infection.

Growth factors and cytokines involved in cell migration and proliferation are also produced by smooth muscle cells and endothelial cells, and there is evidence for shear stress response elements in the flanking DNA of relevant genes in the endothelial cells. Major investigations found bacteria in plaques – Chlamydophila pneumoniae, whereas other organisms have also been found.

As plaques mature, a fibrous cap forms over them. The plaques with defective or broken caps are most prone to rupture. The lesions alone may distort vessels to the point that they are occluded, but it is usually rupture or ulceration of plaques that triggers thrombosis, blocking blood flow.

A characteristic of atherosclerosis that is currently receiving considerable attention is its association with deficient release of NO and defective vasodilation. As noted, oxidized LDLs inhibit NO production. If acetylcholine is infused via catheter into normal coronary arteries, the vessels dialte; however, if it is infused when atherosclerosis is present, the vessels constrict. This indicates that endothelial secretion of NO is defective.

PS: Acetylcholine (ACh) can effect vasodilation by several mechanisms, including activation of endothelial nitric oxide (NO) synthase and prostaglandin (PG) production[1].


1.Kellogg DL Jr1, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol (1985). 2005 Feb;98(2):629-32. [PMID: 15649880]


Current guidelines of Joint Natinal Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure define normal blood pressure as systolic pressure of <120 mm Hg and diastolic pressure of <80 mm Hg. Hypertension is defined as an arterial pressure greater than 140/90 mm Hg in adults on at least three consecutive visits to the doctor’s office.

The most common cause of hypertension is increased peripheral vascular resistance. However, because blood pressure equals total peripheral resistance times cardiac output, prolonged increase in cardiac output can also cause hypertension. These are seen, for example, in hyperthyroidism and beriberi.

In addition, increased blood volume causes hypertension (see below), especially in individuals with mineralocorticoid excess or renal failure; and increased blood viscosity (blood resistance increases with viscosity), if it is marked, can increase arterial pressure.

PS: Cardiac output is a function of stroke volume, heart rate, and venous capacitance. Increased blood volume increase cardiac preload, which causes increase in stroke volume, and finally the cardiac output and arterial pressure.

Pathogenesis of Hypertension

Gout and the Antihypertensives

August 4, 2012 Adverse Drug Reactions, Cardiology, Therapeutics 1 comment , , , , , ,

The inflammatory arthritic condition of gout.

Gout, the inflammatory arthritic condition triggered by crystallization of uric acid within the joints, has risen in the United States. A research studied by Dr. Choi (Hyon K. Choi, MD, DrPH) and his colleagues shown that 74% of US gout patients also have hypertension. Dr. Choi’s group also has shown that hypertension is an important independent risk factor for gout. In patients with hypertension, the incidence of gout has been calculated as 3 times higher than in normotensive patients.

Simplistic speaking, much of this added risk is attributed to the use of diuretics, which are associated with increased serum uric acid levels. But hypertension itself is associated with increased risk of gout. Not only diuretics, but also other nondiuretic classes of antihypertensive drugs have been shown to affect serum uric acid levels.

Generally, with the use of diuretics, beta-blockers, ACEI, and non-losartan angiotensin II receptor blockers (ARBs), the risk of gout incresed.

However as antihypertensive drugs, calcium channel blockers (CCBs) and losartan (a kind of ARBs), are associated with reduced risk of gout.

In an editorial published alongside the study report, Luis M. Ruilope, MD, (Hospital 12 de Octubre and University Autonoma, Madrid, Spain) noted that a reduction in serum uric acid “as well as reducing incident gout, could also improve the cardiovascular and renal prognosis of patients with hypertension.” Thus, to control the serum uric level is important for hypertensive patients.

A number of variables affect serum uric acid levels and the risk of gout, including many life style factors such as adiposity, represented by BMI; dietary factors, particularly alcohol consumption, fructose-rich beverages such as sugary sodas, and a purine-rich diet, particularly animal sources of purine such as red meat or seafood. And in right here, finally, drugs can cause increased risk of gout.

The mechanism of increased risk of gout with hypertension is that as blood pressure elevates, serum uric acid concentration increases, which appears to be a dose-response relationship. Also urate excretion is lower in hypertensive patients than in normotensive individuals. Reduced renal blood flow with increased renal and systemic vascular resistance may also contribute to elevated serum uric acid levels. eventually leading to an increased risk of gout.

The mechanism of increased risk of gout with antihypertensive drugs are variable. Diuretics, the loop and thiazide-type diuretics, can increase serum uric acid levels and the risk of gout. The mechanism of the nondiuretic antihypertensive drugs include ACE inhibitors, non-losartan ARBs are unknown. But clinical trials has shown beta-blockers can increase serum uric acid levels slightly. the mechanism of beta-blockers is unknown neither.

Here I find some data. With beta-blockers, the risk of gout was 48% higher in people with hypertension. ACEIs also have the identical effect. But there is an exception – the diuretics.

Fortunately, specific antihypertensive drugs contribute to the reduce risk for gout. The unique ARB, losartan, lowered uric acid levels in one clinical trial. Bench studies have shown that losartan causes increased uric acid secretion (uricosuria) by inhibiting urate/anion transport in brush-border cells of the renal proximal tubules through inhibition of urate transporter 1 (URAT 1). That is losartan inhibits uric acid reabsorption, causing uricosuria, eventually driving down blood uric acid levels and the reduced risk of gout.

Also CCBs including dihydropyridines and nondihydropyridines have the ability to decrease the risk of gout. The mechanism is unkown. For people with hypertension, taking CCBs lowered their risk of gout by 13% compared with people with hypertension who were not taking a CCB.

To rudece the risk of gout in hypertensive patients, we couldn’t avoid these antihypertensive drugs such as ACEIs, ARBs, or diuretics. Because these patients benefits from these drugs. Thus when the antihypertensive regimen contains drugs increasing risk of gout, we may add another antihypertensive drug that decreases the risk of gout. With the use of the protective drugs, like CCB or losartan, the risk should become even lower.