Cardiology

Advances in Feline Cardiac Diagnostics

Advances in Feline Cardiac Diagnostics
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The diagnosis of cardiac disease in cats can be challenging and may require a combination of history, physical examination, laboratory evaluation, electrocardiography, diagnostic imaging, and systemic workup. This article presents 2 clinical cases, 1 with and 1 without clinical signs of heart disease, to highlight the use of tailored diagnostics to diagnose cardiac disease in cats.

CASES

Case 1: Tux

Tux is a 4-year-old male, castrated, domestic medium-haired cat presented for routine vaccination. His physical examination is unremarkable except for a new grade II/VI left parasternal systolic murmur. What recommendations should be made?

 

 

Case 2: Elvis

Elvis is an 8-year-old male, castrated, domestic long-haired cat presented for labored breathing, first noted by his owner this morning. A limited physical examination reveals regular tachycardia (heart rate, 220 beats/min), dyspnea, pale mucous membranes, and hypothermia (temperature, 99.0°F). Lung sounds are harsh dorsally and dull ventrally. A murmur is not auscultated. What recommendations should be made?

PHYSICAL EXAMINATION

Although exceedingly important, physical examination alone cannot be used to rule in or rule out heart disease in cats. A murmur is an important indicator of heart disease; however, cardiac auscultation alone can be misleading in the diagnosis of feline cardiac disease. Murmurs can be auscultated in cats with and without underlying heart disease, and up to half of all feline murmurs are found in cats without primary cardiac disease.1 Conversely, cats can exhibit heart disease, potentially severe, without a murmur.

Case notes: The presence of a new murmur in Tux does not equate to heart disease but does warrant further investigation. Likewise, the inability to auscultate a murmur in Elvis does not rule out heart disease.

Additional physical examination findings that may prompt cardiac diagnostic testing include a precordial thrill, muffled heart and lung sounds, gallop sound, arrhythmia, changes in pulse quality, pulse deficits, or jugular venous distention or pulsation. Diastolic heart sounds are abnormal in small animals, and S4 gallops, in particular, are often associated with advanced heart disease in cats. This extra sound in diastole indicates atrial contraction into a stiff ventricular cavity. Common arrhythmias in cats include sinus tachycardia, premature beats, and, in cases of severe heart disease and atrial enlargement, atrial fibrillation. Pulse deficits may accompany some of these arrhythmias. Jugular venous distention or pulsation indicates elevated right atrial pressures or arrhythmias demonstrating atrioventricular dissociation.

Case notes: Tux does not have physical examination abnormalities other than a murmur. Elvis, on the other hand, is tachycardic, tachypneic, and hypothermic and has dull ventral lung sounds, all of which could be consistent with congestive heart failure (CHF). He should be placed in an oxygen cage after a brief examination.

ECHOCARDIOGRAPHY

Echocardiography is used to definitively diagnose heart disease in cats and to determine disease severity. It provides information on cardiac size and function, as well as blood flow direction and speed. It is reasonable to recommend echocardiography as the first test in a cat with a murmur but without clinical signs of heart disease and then pursue further guided testing if the echocardiogram is abnormal. Detection of cardiac disease at this preclinical stage is considered important because medications can be initiated in an attempt to reduce thromboembolic risk, and the client can be educated regarding monitoring and further evaluations. If echocardiography is not pursued initially, then N-terminal pro B-type natriuretic peptide (NT-proBNP) would be a reasonable screening test (see Biomarkers).

Case notes: Echocardiography should be offered to Tux’s owner to determine whether heart disease is present, whether any medications are indicated, and when he should be rechecked.

The most common cardiac disease in cats is hypertrophic cardiomyopathy (HCM), which is characterized by primary left ventricular concentric hypertrophy detected by echocardiography (Figure 1). Secondary causes of hypertrophy (eg, systemic hypertension, hyperthyroidism) should be ruled out before HCM is diagnosed.

Figure 1. Two-dimensional short-axis ultrasonographic view of Tux showing concentric left ventricular hypertrophy and papillary muscle hypertrophy, consistent with hypertrophic cardiomyopathy. His left atrium was normal in size on other images. LV, left ventricle.

Other, less common cardiac diseases in cats are listed in Box 1. Although treatment of CHF is similar regardless of the underlying cause, more tailored treatment recommendations and prognostic information may be obtained by determining the underlying cardiac disease with echocardiography (eg, taurine analysis and supplementation for dilated cardiomyopathy).

BOX 1. Cardiac Diseases That Can Cause Congestive Heart Failure in Cats
  • Hypertrophic cardiomyopathy
  • Restrictive cardiomyopathy
  • Dilated cardiomyopathy
  • Unclassified cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy
  • Valvular disease
  • Congenital disease

In addition to facilitating a definitive diagnosis, echocardiography can also be used to determine disease severity, monitor progression, and guide treatment. For example, the severity of HCM can be assessed by the thickness of the left ventricle, the size of the atria, left atrial appendage velocity, and the presence or absence of spontaneous echo contrast. Estimating thromboembolic risk based on left atrial parameters is pertinent in light of a recent report showing that clopidogrel prolonged the time to recurrent thromboembolism in cats with cardiomyopathy.2 Other medications, such as atenolol, may be initiated in a cat with preclinical heart disease, especially if left ventricular outflow obstruction is detected echocardiographically. However, minimal evidence supports this recommendation.

For dyspneic cats, point-of-care cage-side thoracic ultrasonography is useful to aid in the clinical decision to treat for heart failure or respiratory disease. This is performed in the emergency department, often in the oxygen cage, with the cat in sternal recumbency to reduce stress. The goals of brief ultrasonography in this situation are to determine whether the left atrium is enlarged, screen for pericardial and pleural effusion, and determine whether hyperechoic lung artifacts (B-lines) are present, which could indicate interstitial fluid (Figures 2 and 3). A recent study showed high sensitivity and specificity of B-lines to detect CHF in cats (87% and 89%, respectively).3 Cage-side ultrasonography may also be useful to briefly assess left ventricle size and function; however, routine echocardiography is required to fully assess the underlying cardiac disease.

FIGURE 2. Two-dimensional cage-side thoracic ultrasonogram from Elvis showing pleural effusion and an enlarged left atrium (LA). LV, left ventricle; RA, right atrium.

 

FIGURE 3. Cage-side thoracic ultrasonogram from Elvis showing B-lines consistent with interstitial edema. Rib shadows are noted. Photo courtesy of Teresa DeFrancesco, DVM, DACVIM (Cardiology), DACVECC, North Carolina State University, College of Veterinary Medicine.

Case notes: Because of Elvis’s clinical instability, cage-side thoracic ultrasonography is indicated to assess left atrial size and screen for pleural effusion, which is clinically suspected on the basis of physical examination. Full echocardiography should be postponed until Elvis is stabilized; however, this initial assessment indicates the need for thoracocentesis and medical intervention for suspected CHF. The presence of B-lines suggests concurrent pulmonary edema, and the enlarged left atrium supports CHF as the diagnosis.

RADIOGRAPHY

Initial diagnostic imaging for cardiac disease may include thoracic radiography because it is relatively inexpensive and available to most veterinarians. Moderate to severe cardiac enlargement can be appreciated on thoracic radiography; however, this modality is insensitive for the detection of mild cardiac disease and cannot depict concentric hypertrophy of the ventricle.

Case notes: Thoracic radiography is not a good screening tool for cats like Tux.

Thoracic radiography is the test of choice for dyspneic cats to determine whether respiratory signs are caused by CHF. Cardiomegaly, pulmonary vascular distention, and pulmonary edema or pleural effusion support a diagnosis of CHF (Figure 4). Pulmonary infiltrates in cats with CHF often appear as an unstructured interstitial to alveolar pattern with no typical distribution (in contrast to the appearance in dogs). Thoracic radiography is useful to document response to diuresis and to monitor for recurrent CHF. In most situations, radiography is the initial test to determine the underlying cause of respiratory distress. However, when patient instability precludes radiography, point-of-care, cage-side thoracic ultrasonography can provide important information on the likelihood of CHF.

FIGURE 4. (A) Right lateral and (B) dorsoventral thoracic radiographs from Elvis after thoracocentesis was performed. A small amount of residual pleural effusion is present, obscuring the cardiac silhouette in the dorsoventral view. The cardiac silhouette is enlarged and the pulmonary vasculature is enlarged. A mild interstitial pattern is present in the caudal lung fields, consistent with pulmonary edema.

Case notes: Point-of-care ultrasonography is the best choice to initially evaluate Elvis; however, after thoracocentesis and improved clinical stability, thoracic radiography is indicated to continue diagnostic evaluation for CHF.

ELECTROCARDIOGRAPHY

Electrocardiography is the test of choice for the diagnosis of arrhythmias and conduction disturbances but is relatively insensitive as a screening tool for the detection of heart disease in cats. It is recommended when an arrhythmia is auscultated or suspected (eg, syncope).

BIOMARKERS

A biomarker is a parameter that can be accurately measured and is an indicator of a normal or pathologic process, or a pharmacologic response to therapeutics.4 The two most commonly used cardiac biomarkers in veterinary medicine are cardiac troponin I (cTnI) and NT-proBNP.

Cardiac troponin I is a regulatory protein that binds actin and myosin in cardiac myocytes. When these cells are damaged, cTnI is released into the bloodstream and can be measured. Because of its exclusivity to cardiac cells, an increase in blood cTnI concentration is relatively specific for cardiac cell damage; however, elevations do not indicate a specific disease process.5 Cardiac troponin I has been reported to be higher in cats with moderate to severe HCM than in healthy cats, but because of the substantial overlap between groups this test is not considered a good screening tool for feline cardiomyopathy.6,7 Similarly, cTnI is higher in cats with respiratory distress due to CHF than in cats with a noncardiac cause of respiratory distress; however, values overlap enough that clinical utility of cTnI for this purpose is limited.7,8 The detection of arrhythmias or abnormal echocardiographic wall motion may prompt evaluation of cTnI as an indicator of acute myocardial damage.

B-type natriuretic peptide (BNP) is a hormone released in response to cardiac stretch associated with heart disease. The natriuretic action of BNP helps to control fluid homeostasis in the body by renal sodium excretion and so counteracts the volume-retaining effects of the renin-angiotensin-aldosterone system. The breakdown product of BNP (NT-proBNP) can be measured as an indicator of myocardial stress.9

Several studies have demonstrated the ability of NT-proBNP to help distinguish between normal cats and cats with preclinical heart disease with good sensitivity and specificity (76% to 92% and 71% to 93%, respectively).10–12 Because these studies compared the performance of NT-proBNP to that of echocardiography as the gold standard, this test is not additive if echocardiography is performed. Rather, it can be used as a screening test for patients at risk for cardiac disease.

Although NT-proBNP is sensitive and specific for the detection of cardiac disease, it cannot be used to determine the type of disease. Additional diagnostics are often required if the value is elevated. The negative predictive value of NT-proBNP is very high (ie, heart disease is unlikely if the NT-proBNP level is normal); however, diseases such as hyperthyroidism, hypertension, or renal disease can elevate NT-proBNP concentrations in the absence of cardiac disease. Thus, results of biomarker testing should be interpreted in conjunction with other clinical information.

Case notes: Evaluation of NT-proBNP would be a reasonable first step if Tux’s owner were not able to pursue echocardiography. An NT-proBNP level <100 pmol/L would provide assurance that significant heart disease is not associated with Tux’s new heart murmur. An NT-proBNP value >100 pmol/L could be consistent with the presence of heart disease and should prompt echocardiography or close monitoring.

Assessment of NT-proBNP also provides valuable information for differentiating between cardiac and noncardiac causes of respiratory distress.13,14 An NT-proBNP level >265 pmol/L suggests CHF in a cat with respiratory distress.12,14 Values <265 pmol/L but >100 pmol/L could indicate a noncardiac cause of dyspnea and concurrent heart disease.

A feline SNAP BNP test (idexx.com) is available and can be helpful in an urgent care setting to determine whether a dyspneic cat is likely to have CHF. A negative SNAP result correlates to an NT-proBNP level <100 pmol/L, indicating that CHF is unlikely in a dyspneic cat. A positive SNAP result correlates to an NT-proBNP level >270 pmol/L, supporting CHF in a dyspneic patient; however, concurrent respiratory causes of dyspnea and preclinical heart disease could also be the cause of a positive SNAP result. The final SNAP result should always be interpreted in light of the clinical examination and other diagnostic tests. Analysis of BNP in pleural fluid also correlates well to blood concentrations and may prove useful in some clinical situations.15

Case notes: Biomarker testing is not indicated for Elvis because other diagnostic testing rapidly yields his diagnosis of CHF.

GENETICS

Genetic testing using blood or cheek swab samples is available for known mutations associated with HCM in 2 cat breeds. Both mutations are single nucleotide substitutions in the cardiac myosin-binding protein C gene. The A31P substitution is found in the Maine coon breed, and the R820W mutation is found in ragdoll cats.16,17 Genotype determination may help guide breeding programs and cardiac therapy, but it should not be used as a substitute for echocardiography because other, undiscovered mutations are associated with HCM in both of these breeds.18–20 In addition, because of the many factors that can influence disease expression, genotype does not always equate to phenotype in individual patients.

Case notes: Because Tux and Elvis are mixed-breed cats, genetic testing is not recommended.

SYSTEMIC DISEASE WORKUP

The hallmark echocardiographic finding of HCM is left ventricular hypertrophy. However, other disease processes can also induce wall thickening. The most common systemic causes of left ventricular hypertrophy include systemic hypertension and hyperthyroidism. Less common causes include acromegaly, infiltrative myocardial diseases (eg, lymphoma), and left ventricular outflow obstructions (eg, aortic stenosis or mitral valve dysplasia causing systolic anterior motion). The echocardiographic finding of left ventricular hypertrophy should therefore prompt an assessment of blood pressure and thyroid concentration in any middle-aged to older cat. Treatment of systemic hypertension or hyperthyroidism is expected to improve or resolve echocardiographic abnormalities, but coexisting primary HCM and systemic disease is possible.

Case notes: Blood pressure and thyroid status should be evaluated in Elvis. However, thyroid testing is not necessary in Tux given his young age. Although the test is low yield, he should be screened for systemic hypertension.

Brent Aona is a cardiology resident at North Carolina State University College of Veterinary Medicine. He completed his undergraduate and graduate studies at The Ohio State University, where he received his DVM. This was followed by a small animal rotating internship at Tufts University, after which he began his residency in cardiology at North Carolina State University. His clinical research is focused on echosonography of congenital cardiac defects, and his main clinical interest is interventional cardiology.

 

 

Darcy Adin is a clinical assistant professor of cardiology at North Carolina State University College of Veterinary Medicine. She received her DVM from Cornell University. She completed a rotating internship at VCA South Shore Animal Hospital and a cardiology residency at the University of California, Davis, with ACVIM board certification in cardiology in 2000. Dr. Adin has held positions in both academic and private specialty practice. Her clinical research focuses on the investigation of neurohormonal modulation of and new treatment options for congestive heart failure.

References

  1. Wagner T, Fuentes VL, Payne JR, et al. Comparison of auscultatory and echocardiographic findings in healthy adult cats. J Vet Cardiol 2010;12(3):171-182.
  2. Hogan DF, Fox PR, Jacob K, et al. Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). J Vet Cardiol 2015;17 Suppl 1:S306-S317.
  3. Ward JL, Lisciandro GR, Keene BW, et al. Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea. JAVMA 2017;250(6):666-675.
  4. Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS 2010;5(6):463-466.
  5. Liquori ME, Christenson RH, Collinson PO, Defilippi CR. Cardiac biomarkers in heart failure. Clin Biochem 2014;47(6):327-337.
  6. Connolly DJ, Cannata J, Boswood A, et al. Cardiac troponin I in cats with hypertrophic cardiomyopathy. J Feline Med Surg. 2003;5(4):209-216.
  7. Herndon WE, Kittleson MD, Sanderson K, et al. Cardiac troponin I in feline hypertrophic cardiomyopathy. J Vet Intern Med 2002;16(5):558-564.
  8. Connolly DJ, Brodbelt DC, Copeland H, et al. Assessment of the diagnostic accuracy of circulating cardiac troponin I concentration to distinguish between cats with cardiac and non-cardiac causes of respiratory distress. J Vet Cardiol 2009;11(2):71-78.
  9. van Kimmenade RRJ, Januzzi JL. The evolution of the natriuretic peptides – current applications in human and animal medicine. J Vet Cardiol 2009;11 Suppl 1:S9-S21.
  10. Connolly DJ, Soares Magalhaes RJ, Syme HM, et al. Circulating natriuretic peptides in cats with heart disease. J Vet Intern Med 2008;22:96-105.
  11. Fox PR, Rush JE, Reynolds CA, et al. Multicenter evaluation of plasma N-terminal probrain natriuretic peptide (NT-pro BNP) as a biochemical screening test for asymptomatic (occult) cardiomyopathy in cats. J Vet Intern Med 2011;25(5):1010-1016.
  12. Wess G, Daisenberger P, Mahling M, et al. Utility of measuring plasma N-terminal pro-brain natriuretic peptide in detecting hypertrophic cardiomyopathy and differentiating grades of severity in cats. Vet Clin Pathol 2011;40(2):237-244.
  13. Connolly DJ, Soares Magalhaes RJ, Fuentes VL, et al. Assessment of the diagnostic accuracy of circulating natriuretic peptide concentrations to distinguish between cats with cardiac and non-cardiac causes of respiratory distress. J Vet Cardiol. 2009;11 Suppl 1:S41-S50.
  14. Fox PR, Oyama MA, Reynolds C, et al. Utility of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats. J Vet Cardiol. 2009;11 Suppl 1:S51-S61.
  15. Janda S, Swiston J. Diagnostic accuracy of pleural fluid NT-pro-BNP for pleural effusions of cardiac origin: a systematic review and meta-analysis. BMC Pulm Med 2010;10(1):58.
  16. Meurs KM, Sanchez X, David RM, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet 2005;14(23):3587-3593.
  17. Meurs KM, Norgard MM, Ederer MM, et al. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics 2007;90(2):261-264.
  18. Li RHL, Stern JA, Ho V, et al. Platelet activation and clopidogrel effects on ADP-induced platelet activation in cats with or without the A31P mutation in MYBPC3. J Vet Intern Med 2016;30(5):1619-1629.
  19. Wess G, Schinner C, Weber K, et al. Association of A31P and A74T polymorphisms in the myosin binding protein C3 gene and hypertrophic cardiomyopathy in Maine coon and other breed cats. J Vet Intern Med 2010;24(3):527-532.
  20. Borgeat K, Stern J, Meurs KM, et al. The influence of clinical and genetic factors on left ventricular wall thickness in Ragdoll cats. J Vet Cardiol 2015;17 Suppl 1:S258-S267.

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Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' >Zimbabwe</option></select> <label for='input_6_10_6' id='input_6_10_6_label' 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