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High-output heart failure

Author Wilson S Colucci, MDAmir Haghighat, MD

Section Editor Stephen S Gottlieb, MD

Deputy Editor Susan B Yeon, MD, JD, FACC

Last literature review for version 16.1: January 31, 2008 | This topic last updated: May 18,

2006

INTRODUCTION — Most patients with heart failure (HF) have systolic dysfunction with a low cardiac

output and elevated systemic vascular resistance or diastolic dysfunction in which an increase in

ventricular stiffness impairs ventricular filling during diastole. In rare circumstances, the cardiac output is

elevated and calculated systemic vascular resistance is very low.

High-output HF is characterized by an elevated resting cardiac index beyond the normal range of 2.5 to

4.0 L/min per m2. Ineffective blood volume and pressure, chronic activation of the sympathetic nervous

system and renin-angiotensin-aldosterone axis, increased serum vasopressin (antidiuretic hormone)

concentrations, and chronic volume overload gradually cause ventricular enlargement, remodeling, and

HF.

As will be described in this topic review, a number of conditions lead to an obligatory increase in cardiac

output, which can be associated with HF in some patients. However, these conditions are rarely the sole

cause of HF; in most such patients, the high cardiac output provokes HF in the setting of reduced

ventricular reserve from some underlying cardiac problem. Thus, the presence of high-output HF should

prompt a search for another underlying cardiac problem.

PHYSICAL FINDINGS — Several characteristic findings are usually seen on physical examination in

patients with high-output HF. The heart rate is typically between 85 and 105 beats per minute, but it

may be higher with some causes, eg, thyrotoxicosis. Examination of the systemic veins may reveal a

cervical venous hum, heard best over the deep internal jugular veins, particularly on the right side. Less

often, a venous hum may be appreciated over the femoral veins.

Examination of the arteries may display signs related to increased left ventricular stroke volume. The

pulse is usually bounding with a quick upstroke, and the pulse pressure is typically wide. Pistol-shot

sounds may be auscultated over the femoral arteries, and a systolic bruit may be heard over the carotid

arteries. Although these findings may be seen in other cardiac conditions, such as aortic regurgitation or

patent ductus arteriosus, in the absence of these conditions, these signs are highly suggestive of elevated

left ventricular stroke volume due to a hyperdynamic state.

Cardiac examination may reveal an enlarged heart with a midsystolic murmur in the second and third left

intercostal spaces, and a third heart sound, which is due to the increased rate of ventricular filling.

Patients with chronic high output also may develop the signs and symptoms classically associated with

the more common "low-output" HF; specifically, they may develop pulmonary and/or systemic

congestion, while maintaining the above normal cardiac output.

PHYSIOLOGIC CAUSES FOR HIGH CARDIAC OUTPUT — There are a number of physiologic

circumstances that can substantially increase cardiac output:


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Excitement

Exercise (see "Exercise physiology")

Pregnancy

Fever

Pregnancy is associated with both systemic vasodilation and increased preload due to a rise in blood

volume [1] . (See "Renal and urinary tract physiology in pregnant women"). Fever increases metabolic

demand and produces vasodilation, especially in the skin. Resolution of the fever is accompanied by a

reduction in cardiac output to normal. A hot, and especially humid, environment also increases cardiac

output through mechanisms similar to fever [2] .

CAUSES OF HIGH-OUTPUT FAILURE — The disorders contributing to high-output heart failure include:

Systemic arteriovenous fistulas

Hyperthyroidism

Anemia, including the anemia of renal failure

Beriberi (vitamin B1 or thiamine deficiency)

Dermatologic disorders (eg, psoriasis)

Renal disease

Hepatic disease

Skeletal disorders (eg, Paget's disease, multiple myeloma)

Hyperkinetic heart syndrome

Other potential causes of high-output HF include obesity [3] , polycythemia vera [4] , and carcinoid

syndrome [5] . (See "Clinical features of the carcinoid syndrome").

Systemic arteriovenous fistulas — Arteriovenous fistulas may be congenital or acquired; acquired

cases may be iatrogenic or traumatic. As a result of such malformations, blood from a high-pressure

artery is shunted to a low-pressure vein, thereby decreasing systemic vascular resistance. A

compensatory increase in the heart rate and stroke volume ensues, and total plasma volume is increased.

The elevation in cardiac output associated with these fistulas depends upon the size of the

communication and the magnitude of the resultant reduction in systemic vascular resistance. The blood

flowing through the fistula bypasses the capillary circulation; thus, for capillary perfusion to be normal,

the total cardiac output has to be increased by the quantity of blood flowing through the fistula.

Physical findings in patients with high-output failure from arteriovenous fistulas depend to some extent

upon the underlying disease and the location and size of the shunt. Patients with sizable arteriovenous

shunts have a wide pulse pressure with brisk arterial pulsations; the heart rate is usually slightly

increased. There may be swelling, warmth, and redness, and a continuous "machinery murmur" with a

thrill over fistulas located near the surface. Transient maximal occlusion of the fistula usually decreases

heart rate, raises arterial pressure, and lowers venous pressure; this has been termed "Branham's sign"

[6] .

In the presence of an acquired fistula from trauma, the overlying skin is warmer and the increase in

blood flow to the affected limb may result in an increase in size compared to the opposite limb. The

chronically elevated venous pressure may lead to cellulitis, venostasis, edema, and a chronic dermatitis

with pigmentation.


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Congenital fistulas — Congenital arteriovenous fistulas result from arrest of the normal embryonic

development of the vascular system. In fact, these fistulas are structurally similar to embryonic capillary

networks. Congenital fistulas range from cutaneous hemangiomas to large channel communications that

can distort a limb [7] . Some patients have multiple fistulas and the clinical presentation can be varied

[8] .

One congenital abnormality, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease), is

characterized by hemorrhagic telangiectasias involving the mucous membranes, gastrointestinal tract,

and skin of the lips, nose, and finger tips. In about 15 percent of afflicted individuals, arteriovenous

malformations occur in the lung and may be associated with massive hemoptysis [ 9,10] . (See

"Pulmonary AVMs, including hereditary hemorrhagic telangiectasia: Etiology and clinical features" ).

Although the liver is less frequently involved than the lung, those patients with both lung and hepatic

involvement may develop clinically significant arteriovenous shunts and high-output failure [ 10-13] . In

some patients, high-output HF is the first manifestation of the disease [ 11] . Historical clues to the

diagnosis include epistaxis, recurrent gastrointestinal bleeding, unexplained hematuria, hemoptysis, or

family history of bleeding.

Treatment of congenital fistulas — The treatment of high output failure in patients with

hereditary hemorrhagic telangiectasia poses a clinical challenge and is of limited benefit. In

one study a patient with hepatic arteriovenous microfistulas and high output failure was

successfully treated by selective hepatic artery embolization, leading to prompt symptomatic

improvement, progressive decline in ascites and hepatomegaly, and normalization of cardiac

output [13] . Balloon embolization has been used to treat intestinal or pulmonary lesions [ 12]

.

Limited surgical excision is an option in symptomatic patients with pulmonary fistulae, but only minimal

tissue should be removed, since fistulas may continue to form and require further treatment [10] . If

there is diffuse disease involvement, surgery may not be an option [12] .

Giant cutaneous hemangiomas — Giant cutaneous hemangiomas can also promote the

development of high-output failure. Hemangiomas are the most common tumors of infancy, and seldom

cause more than a cosmetic problem [14,15] . Fifty percent of cutaneous lesions are present at birth; the

remainder usually surface by two months of age. In rare cases, high flow arteriovenous shunting in giant

cutaneous hemangiomas can lead to the development of high-output failure [ 8,16] . (See "Epidemiology;

pathogenesis; clinical features; and complications of infantile hemangiomas" ).

There are several therapeutic approaches to the patient with giant cutaneous hemangiomas and HF.

Arteriography with selective embolization has been shown to reverse the failure in select cases [ 14,15] .

Administration of corticosteroids has been shown to be effective in mild cases, but less effective in severe

cases [16,17] . Other options include surgical excision and radiation therapy to susceptible sites [ 14] .

(See "Management of infantile hemangiomas").

Hepatic hemangiomas — In rare cases, involuting hemangiomas involve the liver and produce

arteriovenous shunts and high-output failure in a condition called hepatic hemangiomatosis [ 18] . One

review of 27 patients with hepatic hemangiomatosis observed that 23 had concurrent cutaneous

hemangiomas and 25 had HF [18] . The diagnosis was suggested by the clinical triad of multiple

enlarging cutaneous hemangiomas, hepatomegaly, and HF. Almost every one of the infants studied died

of the disease or its complications. In one patient, hepatic artery ligation was performed after

arteriography, and effectively cured the patient. Nonetheless, this approach remains untested in adult

patients, since it may cause fatal hepatic necrosis.

Acquired fistulas — Acquired fistulas are usually posttraumatic or iatrogenic. Traumatic causes


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including bullet or knife wounds, especially in the thigh [ 19] . Iatrogenic fistulas are surgically

constructed arteriovenous fistulas used for access to the circulation in patients undergoing chronic

hemodialysis [20,21] . In one report of 15 patients, temporarily closing the fistula lowered the cardiac

output by 0.3 to 11 L/min [20] . Anemia (see below) and volume expansion due to salt and water

retention may contribute to the high-output state. (See "Nonthrombotic complications of chronic

hemodialysis arteriovenous vascular access").

Left ventricular hypertrophy due to hypertension and premature atherosclerosis are common in patients

with end-stage renal disease. This substrate can increase the susceptibility to the stress imposed by an

elevated cardiac output. (See "Myocardial dysfunction in end-stage renal disease" and see "Coronary

heart disease in end-stage renal disease (dialysis)" ).

Arteriovenous fistulas with high-output HF have also been described in patients with Wilms' tumor [ 22] ,

renal cell carcinoma [23] , and aortocaval fistula [24,25] .

Arterial puncture for cardiac catheterization is an increasingly common iatrogenic cause of arteriovenous

fistula. However, high-output failure is rare, with a reported incidence is 0.01 to 0.02 percent of all

catheterizations and a clinical presentation ranging from two days to several months postcatheterization

[26] . Most of the patients in whom this fistula develops have undergone separate ipsilateral arterial and

venous punctures. Surgical repair of the fistula is associated with resolution of the cardiac failure. ( See

"Arteriovenous fistulas of the lower extremity").

Other cases of iatrogenic arteriovenous fistulas associated with high-output failure include an ilioiliac

arteriovenous fistula after lumbar disk surgery [27] and a patient with high-output failure following

transjugular intrahepatic portal-systemic shunting [ 28] .

Treatment — Surgical therapy is an effective approach to close off or ablate arteriovenous fistulas

when this is desired and feasible. In the series of patients with high-output dialysis fistulas described

above, surgical correction of the fistula resulted in improvement in HF symptoms in 13 of 14 patients

[29] . Transcatheter embolization has been successfully used in some cases of multiple site congenital

malformations [30] .

Hyperthyroidism — Thyroid hormone is a potent regulator of whole body metabolism; an increased

circulating level of thyroxine produces an increase in metabolism accompanied by a reduction in systemic

vascular resistance and an obligatory increase in cardiac output [31-35] . (See "Cardiovascular effects of

hyperthyroidism"). Thyroid hormone also increases the intrinsic contractility of heart muscle and

myocardial oxygen demands and consumption [36] . The heart rate is increased and pulse pressure is

widened.

These changes can precipitate HF in patients with underlying heart disease which may be caused in part

by a hyperthyroid cardiomyopathy [37] . An additional cause of HF in patients with hyperthyroidism is

atrial fibrillation with an excessively rapid ventricular response. Atrial fibrillation, which is often

paroxysmal, occurs in about 10 percent of hyperthyroid patients. (See "Causes of atrial fibrillation").

Hyperthyroidism, even in the absence of high-output failure, is associated with palpitations, due to both

tachycardia and more forceful cardiac contraction, and exertional dyspnea, which is due more to

respiratory muscle weakness than cardiac failure. (See "Overview of the clinical manifestations of

hyperthyroidism in adults").

The physical findings in patients with hyperthyroidism are similar to those in other causes of high-output

HF including tachycardia, which is present at rest, during sleep, and during exercise; a hyperdynamic

precordium, indicative of the increase in cardiac contractility; systolic hypertension with a widened pulse

pressure; brisk carotid and peripheral arterial pulsations; a loud first heart sound; atrial fibrillation; and


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occasionally a "scratchy" midsystolic murmur (Means-Lerman scratch) heard along the left sternal border,

resulting from the rubbing together of the normal pleural and pericardial surfaces. ( See "Auscultation of

cardiac murmurs" and see "Auscultation of heart sounds").

Other findings on physical examination are associated with hyperthyroidism and include exophthalmos,

stare, fine tremor of the outstretched hands, and a firm thyroid gland with or without nodule formation.

The skin may be moist and warm as a result of cutaneous vasodilation; blood flow to the skin in

hyperthyroid patients can be increased three times or greater than that in euthyroid controls [ 33] . (See

"Overview of the clinical manifestations of hyperthyroidism in adults" ).

It is important to be aware of apathetic hyperthyroidism, a condition in the elderly population, in which

many of the usual manifestations of thyrotoxicosis may be absent [38] . Such patients may present with

unexplained HF or unexplained atrial fibrillation. Clues to thyrotoxicosis in the elderly include unusual

alacrity in the presence of a widened pulse pressure and either atrial fibrillation or unexplained sinus

tachycardia. Hyperthyroidism is more likely to lead to HF in elderly patients who often have underlying

cardiac disease [39] .

Mechanism — Enhanced sympathoadrenal activation may be one of the mechanisms by which

hyperthyroidism creates a hyperdynamic circulatory state [32,40] . In support of this is the

finding that the metabolic and circulatory changes in hyperthyroid individuals are similar to

those in normal volunteers during epinephrine infusion [ 31] . Furthermore, administration of

sympatholytic agents such as reserpine, guanethidine, or beta blockers to hyperthyroid

patients can decrease the heart rate, cardiac output, and pulse pressure toward normal [32] .

However, sympatholytic agents alone do not completely normalize cardiac parameters in hyperthyroid

patients. Thyroid hormone possesses strong, positive chronotropic and inotropic effects even in the

absence of autonomic innervation. Thus, there may be an independent role for direct thyroid hormone

activity. One study demonstrated the positive chronotropic effects of thyroid hormone on the sinoatrial

cells in isolated rabbit atria; the rate of diastolic depolarization was increased and the duration of action

potentials was decreased [41] . Other animal studies have demonstrated that thyroid hormone also has a

direct positive inotropic effect; the enhancement of myocardial contractility in hyperthyroidism may be

due to increased accumulation and release of calcium by the sarcoplasmic reticulum during

excitation-contraction coupling or by the stimulation of myosin with a higher ATPase activity [ 42] . (See

"Excitation-contraction coupling in myocardium" ).

Chronic volume overload, hypercontractility, and tachycardia enhance the development of cardiac

hypertrophy in hyperthyroid patients [32,39,43] . Direct activation of protein-synthesizing processes by

thyroid hormone may also contribute to myocardial hypertrophy. Studies using radionuclide

ventriculography have found that hyperthyroid patients have an abnormally low or absent increase in left

ventricular ejection fraction response to exercise [37,44] . It is possible that this decrease in cardiac

reserve could ultimately progress to impairment of ventricular function and the development of HF even

at rest.

Treatment — The appropriate treatment for HF due to hyperthyroidism is to return the patient

to a euthyroid state, usually with an antithyroid drug or radioactive iodine. The restoration of

euthyroidism typically leads to normalization of the heart rate, arterial pulse pressure, cardiac

output, and left ventricular ejection fraction, and a reduction in left ventricular diameter [ 43] .

(See "Treatment of Graves' hyperthyroidism").

Beta blockers may be beneficial by slowing the heart rate, but they should be administered cautiously

since there may be a further reduction in myocardial contractility. Beta blockers are particularly helpful in

patients with sinus tachycardia or atrial fibrillation due to hyperthyroidism.


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Anemia — Anemia, even when severe, rarely causes HF, and, when it does, it is likely that the

high-output failure is superimposed upon some cardiac abnormality such as valvular heart disease or

underlying left ventricular dysfunction. The loss of hemoglobin is partly compensated by the increase in

cardiac output and widening of the arteriovenous O2 difference [45] .

As an example, in a study of the hemodynamics in anemic patients, right heart catheterization was

performed and found that normal cardiac hemodynamics were maintained in patients with hemoglobin

values as low as 7 g/dL [46] . Furthermore, when the hemoglobin was less than 7 g/dL, cardiac output

increased and HF did not occur. Only in cases of severe anemia, ie, hemoglobin less than 5 g/dL, does HF

develop in the absence of underlying heart disease.

Chronic anemia may be an important contributor to the development of HG in patients with end-stage

renal disease. Although unproven, the correction or prevention of anemia in this setting may help prevent

myocardial dysfunction. (See "Myocardial dysfunction in end-stage renal disease").

Presentation — The presentation of patients with anemia depends upon the time course of its

development. Slow development of chronic anemia is well tolerated and frequently overlooked

for some time [29] . Iron deficiency and the anemia of chronic disease are the most common

causes, but a specific etiology must be identified and corrected where possible. (See "Causes

and diagnosis of anemia due to iron deficiency" and see "Anemia of chronic disease (anemia of

chronic inflammation)").

Mechanism — The mechanism of HF in anemia is not completely understood. Decreased left

ventricular afterload secondary to reduced serum viscosity may play a role [47] . Additionally,

severe anemia can result in left ventricular volume overload and increased stroke volume that

can alter left ventricular function [48] . As an example, one study obtained serial

echocardiograms in 124 patients with sickle cell anemia and found progressive chamber

enlargement and increased left ventricular mass [49] . Moreover, the left ventricular systolic

time interval and the left ventricular pre-ejection period were higher in the sickle cell group

compared with same-aged controls, suggesting a decline in left ventricular function with time.

Physical examination — On physical examination, the skin, mucous membranes, and

conjunctival membranes are pale. Arterial pulses are bounding and the pulse pressure is

widened. A mild systolic flow murmur is frequently present along the left sternal border and

heart sounds, particularly the pulmonic component of the second heart sound, may be

prominent. (See "Examination of the arterial pulse").

Treatment — The management of HF associated with anemia depends upon the type and

severity of the anemia. Diagnostic tests for determining the type of anemia should be carried

out immediately. (See "Approach to the adult patient with anemia").

The treatment for HF due to chronic anemia should be specific for the cause of the anemia, eg, iron,

folate, vitamin B12, or erythropoietin in patients with renal failure.

If the anemia is more acute or the patient is sicker, more rapid therapeutic measures may be required

while the work-up for the cause of the anemia is proceeding. Bedrest and oxygen by nasal cannula are

appropriate. Transfusion of packed red blood cells must be done cautiously and slowly to avoid further

volume overload and worsening HF. One-half unit should be given over three or four hours, and the

patient should be monitored for dyspnea and signs of pulmonary edema. Diuretic therapy, beginning with

an intravenous loop diuretic (eg, 20 to 40 mg furosemide) can be used to treat volume overload.

Vasodilator therapy has no role because of the marked reduction in systemic vascular resistance.

Chronic anemia and HF due to other causes — Chronic anemia may play a contributory role in the

development of HF. In patients with HF due to other common causes, there is evidence that chronic


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anemia is associated with the progression of HF, but anemia is also associated with a number of common

comorbidities. There is conflicting evidence regarding whether anemia is an independent cause of HF

progression and worse outcomes, or if it is simply associated with overall disease severity. (See "Impact

of anemia in patients with heart failure").

Beriberi — Beriberi heart disease is due to severe thiamine (vitamin B1) deficiency and is most common

in Asia where the diet consists of a high intake of polished rice which is deficient in thiamine. In the

United States, thiamine-enriched bread has virtually abolished the disease except in malnourished

individuals (eg, alcoholics) or those on fad diets. Beriberi can also develop in patients on prolonged

diuretic regimens [50] or in patients receiving enteral nutrition [51] . (See "Overview of water-soluble

vitamins").

Beriberi disease is classically divided into two types [ 52] :

A "dry" form, with neurologic manifestations, including peripheral neuropathies with both

sensory and motor components

A "wet" form, with cardiovascular involvement

Seven diagnostic criteria for classic beriberi heart disease have been proposed [53] :

Three or more months of thiamine-deficient diet

Enlarged heart with normal sinus rhythm

Dependent edema

Signs of neuritis, pellagra or both

Minor electrocardiographic changes such as non-specific ST-T changes

No other identifiable cause for heart disease

Response to thiamine therapy or autopsy evidence

Laboratory diagnosis of thiamine deficiency can be made on the basis of an increase in thiamine

pyrophosphate effect (TPPE) or a decrease in blood thiamine concentration, or a decrease in erythrocyte

transketolase activity.

Mechanism — The mechanism for high-output failure in beriberi is multi-factorial. Thiamine

deficiency initially presents as a high-output state secondary to vasodilation and an increase in

blood volume [54] ; this is followed by eventual depression of myocardial function and the

development of a low output state [55] . The high cardiac output is due to reduced systemic

vascular resistance and augmented venous return. It is not totally clear what causes the

marked reduction in systemic vascular resistance, but it may reflect direct vasomotor

depression [54] .

It is possible that the development of HF is due to the superimposition of impaired myocardial function.

Postmortem gross examination of the heart shows dilation without other changes. Histopathologic study

shows nonspecific changes, including interstitial myocardial edema, granulation of cell plasma, and

hydropic or fatty degeneration [56] .

A biochemical lesion due to thiamine deficiency may contribute to the cardiac failure in beriberi [ 54] .

Pyruvate and lactate are important substrates for oxidation and energy production in heart muscle, but

thiamine deficiency blocks their utilization; specifically, thiamine pyrophosphate is needed for the

decarboxylation of pyruvate and its subsequent oxidation in the citric acid cycle. As a result of thiamine

deficiency, pyruvate and its precursor lactate build up in the blood; increased blood lactate level has been


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used in the diagnosis of beriberi, but is nonspecific. Thiamine deficiency also inhibits the function of the

hexose monophosphate shunt, contributing to insufficient oxygenation of the tissues. ( See "Overview of

water-soluble vitamins").

Symptoms and physical examination — Patients in Asia generally present with fatigue,

malaise, and edema (wet beriberi) [54] . In the United States, severe malnutrition, peripheral

neuropathy, and evidence of a high cardiac output are more common (dry beriberi). Anemia

may be present, a result of iron and folate deficiency, and there may be hyperkeratinized skin

lesions and painful glossitis.

In addition to the characteristic clinical picture, laboratory studies show a reduced thiamine level [57]

and increased serum pyruvate and lactate together with a low red cell transketolase [58] .

Treatment — With appropriate treatment, eg, up to 100 mg of thiamine intravenously and 25

mg/day for two weeks, the cardiac index and heart rate are reduced and there is an increase in

systemic vascular resistance [59] . Treatment of concomitant nutritional anemia may also be

required.

In the United States, the association of thiamine deficiency with chronic alcoholism may result in the

concomitant presence of alcoholic cardiomyopathy and a depression in left ventricular systolic function.

Such patients do not respond well to digoxin, diuretics, or vasodilators; a diagnosis of thiamine deficiency

must therefore be considered so that specific therapy with thiamine can be given. The initial loading

doses of thiamine are in the range of 100 to 500 mg intravenously, followed by 25 to 100 mg per day

orally for at least two weeks. (See "Alcoholic cardiomyopathy").

Patients with furosemide-associated thiamine depletion maintain their ability to absorb thiamine and

respond to thiamine repletion with improved left ventricular function and effective diuresis [ 60] .

Magnesium may have to be coadministered with thiamine, particularly in magnesium-depleted patients

[52,61] . In animal models, magnesium depletion alone leads to a blunted response to thiamine

supplementation and loss of thiamine from tissues [62] . The mechanism for this relationship is unknown,

although it has been proposed that magnesium depletion may interfere with the activation of

transketolase [61] .

Dermatologic disorders — A large increase in cardiac output may be associated with some

dermatologic disorders such as active widespread psoriasis, exfoliative dermatitis, or Kaposi's sarcoma

[63] . (See "Epidemiology, clinical manifestations, and diagnosis of psoriasis" ). The elevated cardiac

output results from substantial cutaneous dilatation and an increase in blood flow to the skin since the

widespread lesions are warm and red. As in the other causes of high-output HF, the increase in cardiac

output itself rarely causes heart failure; it is more often a contributing factor to an already impaired

cardiac reserve resulting from some underlying heart disease.

Treatment — The treatment is that of the primary skin disorder. As the lesions heal and warmth

disappears, there is a concomitant reduction in the elevated cardiac output.

Renal disease — As noted above, high-output heart failure in patients with chronic renal failure most

often results from an arteriovenous dialysis fistula and anemia (which is now less common due to the

widespread use of erythropoietin) superimposed on underlying heart disease. (See "Erythropoietin for the

anemia of chronic kidney disease among predialysis and peritoneal dialysis patients" and see

"Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients" ).

Volume expansion due to sodium and water retention also may contribute to the high-output state. In

acute postinfectious glomerulonephritis, for example, edema (including pulmonary edema) and

hypertension can occur [64,65] . These changes are due primarily to volume expansion as the


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renin-angiotensin system is suppressed and the serum atrial natriuretic peptide concentration markedly

elevated [65] . These changes are reversed with fluid removal, eg, with diuretics.

Cirrhosis — Cirrhosis of increasing severity is progressively associated with systemic vasodilation

[66,67] , a high cardiac output [68] , a low blood pressure, and signs of reduced tissue perfusion (such

as low urinary sodium excretion and increased plasma levels of the "hypovolemic" hormones renin,

norepinephrine, and antidiuretic hormone) [62,68] . (See "Hyponatremia in cirrhosis", section on

Vasodilation and hyperdynamic circulation).

The increased cardiac output is primarily due to splanchnic vasodilation and the development of

intrahepatic or mesenteric arteriovenous shunts. Intrapulmonary arteriovenous shunting is also observed

in some patients [69] . The development of cardiac failure is insidious in these patients, but most die

from hepatic failure prior to symptomatic heart disease. Treatment of the liver disease, which is often

best achieved by hepatic transplantation, may normalize the cardiac output. In one study, the cardiac

index decreased by a mean of 35 percent after transplantation [70] .

Acromegaly — Heart failure is not uncommon in newly diagnosed acromegaly. (See "Clinical

manifestations of acromegaly"). In a review of 102 such patients, 10 had overt heart failure at the time

of diagnosis [71] . Compared to those without heart failure, these patients had an increase in left

ventricular mass index that was largely due to chamber dilation, a reduction in left ventricular ejection

fraction (42 versus 66 percent), and a significant elevation in cardiac index (4.3 versus 3.5 L/min per m2

versus 3.1 L/min per m2 in controls).

Skeletal disorders — A high cardiac output has been noted in patients with polyostotic fibrous dysplasia

(McCune-Albright syndrome), osteitis deformans (Paget's disease) [72] , and multiple myeloma [73-75] .

(See "Clinical manifestations and diagnosis of Paget's disease of bone" ). It is presumed that there are

multiple minute arteriovenous fistulas in the bony lesions [ 74] . Extensive bone involvement (more than

20 percent of the skeleton) is required to increase the cardiac output to the point at which it may

contribute to high-output problems [73,74] .

An additional factor for the increase in cardiac output in Paget's disease may be increased cutaneous

blood flow resulting from local heat production by the increased metabolic activity of affected bone. There

appears to be a linear relationship between the amount of skeletal involvement and cardiac index in

patients with this disease [76] . In one study, a statistically significant increase in cardiac index and

heart size was noted in patients with greater than 15 percent skeletal involvement [ 77] .

The high-output state is usually well tolerated for years. As with most causes of high-output HF, clinical

manifestations are not typically seen in the absence of underlying heart disease. In most patients,

treatment of the Paget's disease with a bisphosphonate or calcitonin leads to normalization of the cardiac

index within six months [76] .

Hyperkinetic heart syndrome — The hyperkinetic heart syndrome is a poorly defined entity. It has

been described in young patients and is associated with sinus tachycardia and elevated systemic blood

pressure in the absence of hyperthyroidism or pheochromocytoma [78,79] . The cardiac output is

considerably increased and is accompanied by systolic hypertension and a systolic flow murmur [ 78] .

This may be a prelude to sustained hypertension later in life [ 79,80] . Symptoms include palpitations,

mild hypertension, and chest discomfort; heart failure is not part of the syndrome.

The syndrome is probably mediated through excess catecholamines or increased receptor sensitivity to

beta agonists since it is responsive to beta blockers.

Pregnancy — Between 20 and 24 weeks of pregnancy, the resting cardiac output is increased to about 6

liters per minute. Increased blood volume, the presence of the placenta acting as an arteriovenous shunt,


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and increased metabolic demands may contribute to the elevated cardiac output in pregnancy. ( See

"Renal and urinary tract physiology in pregnant women"). Women with an underlying cause for a high

cardiac output, such as an arteriovenous fistula, hereditary telangiectasia, or anemia, are more likely to

develop high-output heart failure during pregnancy [81-86] . In addition, multiple pregnancies in a

patient with underlying fistulas may progressively exacerbate vascular malformations and lead to the

development of heart failure despite a history of previous uncomplicated pregnancies [ 82] .

The treatment of high-output failure in pregnancy depends on the severity of the failure and its etiology.

In mild cases, bed rest and a loop diuretic may be effective but often no specific therapy is necessary;

the cardiac output generally normalizes between 2 days to 2 weeks post-partum [86] . (See

"Management of heart failure in pregnancy").

In some cases of arteriovenous malformations, surgical resection of the fistula has been performed during

pregnancy with resolution of the failure symptoms [81] . In more severe cases, emergent termination of

the pregnancy has been required [85] .

Miscellaneous causes — Other causes of high-output heart failure include polycythemia vera, morbid

obesity, cor pulmonale, carcinoid syndrome, and anagrelide used for the treatment of chronic

myeloproliferative disorders [87] . Symptomatic therapy for the heart failure and treatment of the

underlying disease is indicated.

RECOMMENDATIONS — Although high-output states are uncommon as a sole cause of heart failure,

they may contribute to heart failure in patients with underlying cardiac disease and reduced ventricular

reserve. As a result, the clinician must carefully consider the possibility of an associated cause in patients

with physical findings that suggest an increase in cardiac output, including warm extremities, wide pulse

pressure, bounding pulses, a hyperkinetic heart to palpation, and a systolic flow murmur. These findings

may be less striking in patients with overt heart failure.

Appropriate laboratory and diagnostic tests help to define the particular cause of the high cardiac output.

Therapy is aimed at correcting the cause of the high-output and can sometimes dramatically reverse the

heart failure. This approach should be more useful than standard therapy employed in typical low output

heart failure (eg, angiotensin converting enzyme inhibitors, beta blockers, diuretics, and digoxin). (See

"Overview of the therapy of heart failure due to systolic dysfunction").

Vasodilators will be of little benefit in a patient who already has an extremely low systemic vascular

resistance, while digoxin is of little benefit if the ejection fraction is near normal and the patient is in

sinus rhythm; diuretics have a limited role in selected patients.

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