Small Heart as a Constitutive Factor Predisposing to Chronic Fatigue Syndrome

The chronic fatigue syndrome (CFS), which affects many young people in modern, stressful society, is an important health problem, characterized by persistent and relapsing, severe disabling fatigue, not resolved by rest, causing a marked reduction of working activity. 1-4 Despite the public health burden imposed by CFS, effective diagnostic, treatment and prevention strategies are not available because the etiology, risk factors and pathophysiology remain unclarified. Various factors have been implicated in the genesis of CFS, including abnormal immune activation, chronic viral infection, impairment of central nervous system, exaggerated oxidative stress and current emotional disorders.1-8 Diagnosis of CFS can be made only after alternative known medical and psychiatric causes of chronic fatiguing illness have been excluded.1,3


Introduction
][3][4] Despite the public health burden imposed by CFS, effective diagnostic, treatment and prevention strategies are not available because the etiology, risk factors and pathophysiology remain unclarified.2][3][4][5][6][7][8] Diagnosis of CFS can be made only after alternative known medical and psychiatric causes of chronic fatiguing illness have been excluded. 1,3

Chronic Fatigue Syndrome (CFS) and cardiac dysfunction or low cardiac output
Cardiovascular dysfunction such as chronic heart failure, can be a main cause of disabling chronic fatigue and many symptoms seen in CFS patients are common in patients with low cardiac output syndrome.0][11][12][13][14] The reported findings included autonomic dysfunction, 15,16 lower plasma volume and/or red cell mass, 17,18 and abnormalities in neurohumoral systems of circulatory control. 19,20In 2003 Peckerman et al. 10 provided a preliminary indication of reduced cardiac output in patients with severe CFS.

Small heart syndrome
The concept that a heart small in relation to the body is inadequate for work was first stated by Laennec 21 in 1826.Later Master 22 reported several, so-called "neurocirculatory asthenia" cases with weakness or fatigue even after ordinary exertion, tachycardia, palpitation and dyspnea, who had a small heart shadow on chest radiography.The most frequent complaints are fatigue or weakness, rapid heart, precordial or chest pain, shortness of breath, nervousness, trembling, sweating and fainting, many of them resembling those in CFS patients.Master hypothesized that these symptoms were caused by diminished venous return, diminished cardiac output, anoxemic heart muscle and decreased oxygen saturation of the blood due to congenital or constitutionally small heart.Similarly DaCosta 23 described "irritable heart" in 1871, a peculiar form of functional disorder of the heart seen in the military population during the American Civil War.The disorder frequently presented either after an episode of diarrhea and persisted after the digestive disturbances had diminished, or originated suddenly without previous digestive disorder.Fatigue was an almost universal complaint in DaCosta's syndrome, although symptoms includes palpitation, cardiac pain, headache, dimness of vision and giddiness. 23,24Diarrhea may lead to dehydration and reduce venous return or preload, resulting in further decreases in stroke volume and cardiac output in subjects with small heart.
The apparent heart size or cardiothoracic ratio (CTR) is influenced by the position of the heart in the thoracic cage.A small heart may be due to a standing or dropped heart resulting from a low diaphragm and a narrow chest in association with a thin physique and low fat content in epicardial and pericardial spaces.Consequently, the pathognomonic significance of small heart has not been established and is now being overlooked or even ignored. 25 order to clarify the pathophysiological significance of small heart syndrome as a cardiovascular disease, we studied 47 patients (16 men and 31 women, mean age: 29±6 years) with a small heart shadow (CTR ≤42% on a chest roentgenogram) and without significant systemic disease who consecutively visited our clinic with possible cardiovascular symptoms, as well as 24 controls (C).These patients with small heart syndrome were divided into 2 groups, 25 patients with severe symptoms (S) and 22 patients with mild ones (M), according to the presence or absence of cardiovascular symptoms including general malaise, easy fatigability, fainting, dizziness, weakness, chest pain, dyspnea and palpitations that were sufficiently severe to significantly disturb their occupational, educational, social or personal activities.Figures 1 and 2 show the chest X roentgenograms of typical cases of group S.
All individuals underwent standard M-mode and two-dimensional echocardiography.The left ventricular (LV) dimensions were measured according to the recommendations of the American Society of Echocardiography. 26LV v o l um e w a s c a l c u l a te d b y t he Teichholz' formura, 27 and an ejection feaction was obtained by the conventional method.
Results are summarized in Tables 1 and 2 and Figures 3-6.As shown in Table 1, the symptom of general malaise and/or easy fatigability was significantly more frequent in S than in M (88% vs. 50%, p<0.05).In addition, symptoms including orthostatic dizziness, shortness of breath, dyspnea on effort, palpitations, fainting and chest pain were more frequent in S than in M, although no significant difference was found.In addition, physical findings including narrow chest, foot coldness, pretibial pitting edema, bimanual right kidney palpability, epigastric splash sound, mid-systolic click, late systolic murmur and hypotension were more frequently noted in S than in M, although no significant difference was found.Fig. 1.Chest roentgenogram of a 38-year-old male patient with small heart syndrome (cardiothoracic ratio: 28%) in which vertebral scoliosis was also noted.From about 15 years ago, the patient suffered from severe general malaise, easy fatigability, dyspnea on effort, palpitations and chest pain.He also occasionally developed severe dyspnea with hyperventilation, trembling, sweating and sleep disturbance.He found that upon obtaining employment, he could not work as expected.Upon consulting a psychiatrist 10 years ago, he was diagnosed with anxiety neurosis and treated with medication.He subsequently developed alcoholism.He frequently visited emergency outclinics due to severe dyspnea and anxiety.

38M
Cardiothoracic ratio: 28% Fig. 2. Chest roentgenogram of a 24-year-old female patient with small heart syndrome (cardiothoracic ratio: 32%).For about 7 years, the patient suffered from severe general fatigue, fainting and orthostatic dizziness.She also frequently developed a headache, chest pain and a sore throat.She was frequently unable to work as a dietician due to increasingly impaired shortterm memory and concentration.As shown in Table 2, both the mean body weight and body mass index were significantly lower in both S and M than in C, although the mean body height was not significantly different among the study groups.The mean body surface area was also significantly (p<0.05)smaller in S than in C, although the difference was not significant between M and C. The mean CTR (%) values were in the order of S (38±4) < M (40±3) < C (45±2).CTR was significantly (p<0.001)lower in S and M than in C, although no significant difference was noted between S and M.
Both mean stroke volume and cardiac output values were in the order of S < M < C. Both values were significantly smaller in S and larger in C than in M. The mean stroke volume index (mL/m 2 ) was significantly (p<0.001)smaller in S (30±7) than in M (37±6) and C (40±6) (Figure 5).The mean cardiac index (L/min/m 2 ) was significantly (p<0.001)smaller in S (2.0±0.4)than in M (2.6±0.5) and in C (2.8±0.6)(Figure 6).No significant difference was noted in the mean value of stroke volume index or cardiac index between M and C. The prevalence of low cardiac index (<2 L/min/m 2 ) was significantly (p<0.01)higher in S (60%) than in M (9%) and C (4%).LV ejection fraction (%) was quite comparable among S (68±6), M (69±6) and C (69±4).Mitral valve prolapse was diagnosed in some of the subjects in S (16%) and M (14%).
Thus, we concluded that in patients with a small heart shadow on a chest roentgenogram, a small LV size was generally associated with low cardiac output, which was particularly Fig. 7. Characterization of the patients with small heart syndrome.
Small heart syndrome postulated by Master in 1944 1) Small heart shadow on chest roentgenogram 2) Hypotension and/or orthostatic dysregulation 3) General malaise, easy fatigability, dizziness, palpitation, dyspnea, chest pain, headedness and cold feet 4) No organic heart disease or systemic disease 5) Thin physiques, asthenia, visceroptosis and wandering kidney 6) Straight back and flat chest 7) Often complicated with mitral valve prolapse syndrome 8) Young female dominant 9) Naïve, delicate and serious character Fig. 8.A typical "straight back" observed in a lateral view chest roentgenogram obtained from a 18-year-old female patient with small heart syndrome.marked in the patients with severe symptoms and therefore, the pathognomonic significance of a small heart should be recognized as a constitutional factor that predisposes individuals to low output syndrome. 28atients with small heart syndrome are known to have slender structures with low body mass indexes, frequently visceral ptosis with wandering kidney, asthenia, nervousness as well as foot coldness, suggesting physical, autonomic nervous and psychological irritability or lack of relaxation (Figure 7). 11,22,28,291][32] Many of the small heart subjects appeared to be emotionally sensitive, often delicate and nervous.These conditions may be genetically determined, although several other factors may also be involved in the constitution. 22 order to work and perform other duties without excessive exhaustion patients with small heart syndrome need to have enough rest and both physical and emotional relaxation. 11,12arious triggers including loss of appetite, diarrhea and summer sweating can cause dehydration resulting in preload reduction.It is possible that further reductions in cardiac performance due to preload reduction play an important role in predisposing subjects with small hearts to symptoms including general malaise, fatigue, dizziness, orthostatic dysregulation, dyspnea on effort and palpitations.Autonomic nervous dysfunction with possible accentuated basal parasympathetic tone may be associated with these symptoms through the inhibition of sympathetic activation, which is required to preserve proper cardiac function. 13Habitual exercise, which can facilitate autonomic nervous adaptation and induce pulmonary and cardiovascular conditioning, may improve the functional work capacity and fatigue by increasing cardiac output.Diarrhea, sweating and loss of appetite as triggering factors for exacerbation should be avoided or treated properly.Constitutional change or conversion is not easy.They may need to take holidays occasionally.And people in their work place and society should understand their specific needs.

Small heart syndrome as an unrecognized cause of CFS
][13] Specifically, a small heart shadow was often observed on the chest roentgenogram in these patients.In 2008 we first reported that "small heart" with low cardiac output demonstrated by both roentgenographically and echocardiography is prevalent in CFS patients. 11In this report.small heart syndrome (CTR ≤42%) was significantly more prevalent in the CFS group (n=56) (61%) than in the control group (n=38) (24%) (Table 3).In CFS patients with a small heart (n=34), narrow chest (88%), orthostatic dizziness (44%), foot coldness (41%), pretibial pitting edema (32%), r-kidney palpability (47%), and mitral valve prorapse (29%) were all significantly more prevalent than in the control group, and also in the CFS patients without small heart syndrome (Table 4).Echocardiographic examination demonstrated significantly smaller values of both LV end-diastolic and end-systolic dimensions, and stroke volume and cardiac indexes in CFS with a small heart as compared with control subjects with a normal heart size (42%< CTR <50%) (Table 5).Thus, a considerable number of CFS patients have a small heart and cardiac performance is actually impaired with low cardiac output due to a small LV chamber size and poor cardiac function with low stroke volume and cardiac indexes in many of CFS patients. 11In addition, both the reduced cardiac size and performance during the exacerbation phase was improved during the remission phase in CFS patients with "small heart", suggesting that small heart syndrome with impaired cardiac function may play an important role in the genesis of CFS (Table 6). 12Also cardiothoracic ratios increased significantly during the remission phase as compared with exacerbation phase (Table 6). 12Reduced LV ejection fraction was not observed in any patients, suggesting no myocardial systolic dysfunction.Many CFS patients have low cardiac output and the resulting low flow circulatory state may make it difficult for patients to meet the demands of everyday activity, and it may also lead to fatigue and other conditions.Small heart syndrome may contribute to the development of CFS as a constitutional factor predisposing to fatigue, and may be included in the genesis of CFS.although all of these symptoms are not necessarily attributable to cardiovascular dysfunction. 13Frequently noted physical examination findings such as epigastric splash sound, right kidney palpability, cold feet and pretibial pitting edema, may be related to visceral ptosis with slender build, and peripheral circulatory impairment. 13Weakness, rapid heartbeat and orthostatic dizziness may be related to hypotension and orthostatic dysregulation.Auscultatory findings including a late systolic murmur and a mid-systolic click suggested typical mitral valve prolapse in some of the patients.In addition, electrocardiograms showed severe sinus arrhythmia and vertical or right axis deviation in a considerable number of the patients, suggesting parasympathetic predominance and vertical heart position. 13Following our reports Hurwitz et al. 14

Orthostatic Intolerance (OI)
6][37] The patients predictably develop symptoms of disabling fatigue, dizziness, diminished concentration, tremulousness, and nausea while standing (Table 7).Simple activities such as eating, showering, or low intensity exercise may profoundly exacerbate these symptoms.7][38][39][40][41] Assuming an upright posture causes translocation of approximately 800 ml of blood from the intrathoracic venous compartment to veins of the buttocks, pelvis and legs. 42The normal compensatory cardiovascular response to this orthostatic stress is a neurogenically mediated increase in heart rate and in systemic vascular resistance. 42Not all vascular beds contribute equally to the reflex increase in vascular resistance. 42Splanchnic vasoconstriction accounts for one third, and skin and muscle vasoconstriction, approximately 40% of the increased vascular resistance during normal levels orthostatic stress. 42Symptoms of orthostatic intolerance develop as these reflexes approach the limit of compensation.

Similarities and overlaps between CFS and OI
Many of the primary symptoms of orthostatic intolerance are often seen in patients with disabling CFS. 17,42,43Both CFS and orthostatic intolerance affects many young people, predominantly women.Many symptoms of OI appear to be related to reduced cerebral blood flow.Symptoms are associated with inadequate systemic venous return to the right heart or thoracic hypovolemia, 35,36 although precise mechanisms remain to be clarified.Also excessive lower body venous pooling with delayed orthostatic hypotension, by reducing cerebral perfusion, has been suggested to be involved in the orthostatic component of fatigue in CFS patients. 44

Pathopysiology of OI
38][39][40][41]47 Several disorders including delayed orthostatic hypotension, 17 neurally mediated hypotension 48 and postural orthostatic tachycardia syndrome [35][36][37][38] underlies or promotes orthostatic intolerance.Delayed orthostatic hypotension can be caused by excessive gravitational venous pooling. 17,44Impaired vasoconstrictor function with relative bradycardia is often seen in neurally mediated hypotension. 48In 1995 Rowe et al. 48described the cases with an overlap in the symptoms of CFS and neurally mediated hypotension, suggesting that neurally mediated hypotension should be considered as a treatable cause of CFS.Exaggerated tachycardia and vasoconstriction without hypotension of postural orthostatic tachycardia syndrome (POTS) during standing can cause orthostatic intolerance, [35][36][37][38] although pathophysiology of POTS remains unclear.In 1982 Rosen and Cryer were the first to describe a woman with a 7-year history of disabling postural tachycardia and palpitations in association with an idiopathic reduction in plasma volume. 35In 1993 Schondorf and Low 36 reviewed the patients who exhibited exaggerated tachycardia at rest or during head-up tilt and named "idiopathic postural orthostatic tachycardia syndrome" which may be a manifestation of a mild form of acute autonomic neuropathy.2][43][44] Clinical evaluation of CFS patients should include response to standing.POTS may be an underrecognized condition in CFS as Hoad et al. 49 recently suggested.

OI and small heart
Recently it has been reported that patients with postural orthostatic tachycardia, which is often noted in patients with chronic orthostatic intolerance, had a smaller heart coupled with reduced blood volume compared with healthy controls. 50By using a cardiac magnetic resonance imaging technique, Fu et al. 50assessed precisely the heart size and mass in POTS patients and found that cardiac size and mass and blood volume were much smaller in the patients compared with healthy sedentary controls.The marked orthostatic tachycardia in these patients seemed to be a physiologic compensatory response to a smaller stroke volume and exercise training improved this syndrome in most patients. 50Fu et al. 50offered POTS a new name based on its underlying pathophysiology, the "Grinch syndrome", because in this famous children's book by Dr Seuss, the main character had a heart that was "two sizes too small".In their assessment of both sympathetic baroreflex sensitivity and cardiovagal baroreflex sensitivity, the function of autonomic nervous system was intact in the patients, 50 although other researchers have postulated autonomic nervous dysfunction with exaggerated sympathetic nervous activation over compensatory levels during standing as a major mechanism for the symptoms. 35,36,40,41,47though some dysautonomia cause orthostatic instability accompanied with abnormal changes in heart rate and blood pressure, whether disorders of the autonomic nervous system is responsible for OI and also OI in CFS patients is controversial. 38,39,43,44,50Recently, Jones et al. 51 reported that orthostatic instability was similar in persons with CFS and nonfatigued control subjects recruited from the general Wichita population.Interestingly persons with higher serum osmolarity levels had significantly higher abnormal tilt rates than those with lower serum osmolarity levels, suggesting that delayed responses to headup tilt tests may reflect hydration status. 51Reappraisal of primary dysautomia as a factor in the pathogenesis of CFS and also OI may be needed.In the meanwhile Ewan et al. 52 reported that use of the sinus node blocker ivabradine led to dramatic improvements in subjective and objective symptomatology in line with a reduction in heart rate on standing in a 21 year-old female patient with POTS.Use of this medication appears to not only improve tachycardia but also symptomatology, including fatigue, suggesting that tachycardia is not only unnecessary for maintaining cerebral perfusion while standing as a compensatory mechanism but also triggers many symptoms possibly through disturbances in autonomic nervous system.

Pronounced small heart in CFS with OI
We aimed to test a hypothesis that small heart is associated with OI in patients with CFS.
Among  8).In conclusion, a small size of LV with low cardiac output was noted in OI and marked in CFSOI.A small heart appears to be related to the genesis of OI and CFS via both cerebral and systemic hypoperfusion.CFSOI seems to constitute a well-defined and predominant subgroup of CFS.
CFSOI: patients with chronic fatigue syndrome and orthostatic intolerance OI: patients with orthostatic intolerance but without chronic fatigue syndrome Controls: healthy control subjects Elucidation of the pathophysiology of CFS and OI may lead to better therapeutic strategies.Recently, xenon-computed tomography blood flow studies demonstrated that CFS patients have global cerebral hypoperfusion with reduced absolute cortical blood flow in broad areas, especially in bilateral middle cerebral artery territories, compared with healthy controls. 53Impaired cerebral oxygenation due to reduced cerebral hemodynamics in young CFS with OI during an active standing test was suggested from the findings of continuous measurement of cerebral oxygenated hemoglobin using near-infrared spectroscopy. 54In the present study, low systolic and diastolic blood pressures were noted in OI patients with and without CFS compared with those in control subjects.Newton et al. 55 have consolidated the evidence using 24-hour ambulatory blood pressure monitoring that lower blood pressure occurs in CFS patients and lower nighttime blood pressure seems to be a significant problem that may lead to the enhanced diurnal variation.The putative mechanism by which OI and CFS are triggered or caused in patients with a small heart is shown in Figure 12.Reasonable potentiation of cerebrovascular flow without exaggerated activation or perturbation of autonomic nervous system may be needed for effective treatment.However, administration of nonselective vasoconstrictive agents may cause a simple reduction of cerebral blood flow via elevation of cerebrovascular resistance, although intravenous infusion of phenylephrine, a sympathetic nerve α 1 stimulator, has been reported to improve OI, as a result of producing significant peripheral vasoconstriction and venoconstriction in some OI patients. 56Volume repletion by increasing sodium intake or by treatment with fludrocortisones may theoretically improve OI and also symptoms of CFS by replenishing intravascular volume. 17,35,38,42,46Military anti-shock trousers as well as elastic stockings which compress lower extremities may also be effective via potentiation of venous return, resulting in increased cardiac output. 448][59] Various triggers including loss of appetite, diarrhea and sweating can cause dehydration accompanied by preload reduction, leading to further decreases in stroke volume and cardiac output, thereby impairing both systemic and cerebral circulation and exacerbating symptoms, and therefore should be avoided or treated appropriately.

Conclusions
Cardiac dysfunction with low cardiac output due to a small LV chamber may contribute to the development of chronic fatigue as a constitutional factor in a considerable number of CFS patients and its degree appears to be more pronounced in CFS patients with OI. 60 CFS with OI seems to constitute a well-defined and predominant subgroup of CFS.Small heart with reduced cardiac performance due to decreased preload may be an important target for the treatment of CFS.

Fig. 3 .
Fig. 3. Comparison of the left ventricular end-diastolic dimension (LVEDD) among the study groups.The mean LVEDD was significantly smaller in S (patients with small heart syndrome and severe symptoms) than in M (patients with small heart syndrome and mild symptoms) and C (control subjects).It was also significantly smaller in M than in C.

Fig. 4 .
Fig. 4. Comparison of the left ventricular end-diastolic dimension/body surface area (LVEDD/BSA) among the study groups.The mean LVEDD/BSA was significantly lower in S (patients with small heart syndrome and severe symptoms) than in M (patients with small heart syndrome and mild symptoms) and C (control subjects).No significant difference was found between M and C.

Fig. 5 .
Fig. 5. Comparison of the stroke volume index among the study groups.The mean stroke volume index was significantly lower in S (patients with small heart syndrome and severe symptoms) than in M (patients with small heart syndrome and mild symptoms) and C (control subjects).No significant difference was found between M and C.

Fig. 6 .
Fig.6.Comparison of the cardiac index among the study groups.The mean cardiac index was significantly lower in S (patients with small heart syndrome and severe symptoms) than in M (patients with small heart syndrome and mild symptoms) and C (control subjects).No significant difference was found between M and C.

Fig. 12 .
Fig. 12.The putative mechanism by which orthostatic intolerance and chronic fatigue syndrome are triggered in patients with a small heart.

Table 1 .
Comparison of the prevalence of symptoms and physical findings between the study groups with mild or severe symptoms

Table 3 .
Comparison of chest roentgenographic and physical examination findings in study patients CFS: Chronic fatigue syndrome; CTR: cardiothoracic ratio; NS: not significant Indeed, CFS patients had a variety of possible cardiovascular complaints, including chest pain, palpitation, dyspnea or shortness of breath, coldness of feet, dizziness and fainting,

Table 5 .
Comparison of echocardiographic findings in control with a normal heart size and CFS with a small heart

Table 6 .
Comparison of echocardiographic findings of 10 CFS patients with a small heart between the exacerbation and remission phases

Table 7 .
Symptoms while standing in patients with orthostatic intolerance www.intechopen.comSmallHeart as a Constitutive Factor Predisposing to Chronic Fatigue Syndrome 95 the 46 study CFS patients, 26 (57%) were classified as CFSOI according to the presence of OI.In addition, 11 OI patients and 27 age-and sex-matched control subjects (Controls) were studied.Left ventricular (LV) dimensions and function were determined echocardiographically.As shown in Table 8 and Figures 9-11, the mean values of than in OI (27%) and Controls (11%).The mean values of both LV fractional shortening and ejection fraction were comparable among the groups (Table : p <0.01 vs. Controls †: p <0.05 vs. Controls Comparisons of values between the study groups were performed with ANOVA followed by Student's unpaired t-test.Proportional data were analyzed by the chi-square test, with Yates' correction. IVS: interventricular septum thickness; PW: left ventricular (LV) posterior wall thickness; LVEDD: LV end-diastolic dimension; LVESD: LV end-systolic dimension; LAD: left atrial dimension; AoD: aortic root diameter; RVD: right ventricular dimension *

Table 8 .
Comparative echocardiographic data among the study groups