Cardiomyopathy

Diagnosing cardiac failure

History

LVF – cough and nocturnal dyspnoea. Consider asthma and mitral stenosis.
RVF – ankle swelling and abdominal distension. Consider nephrotic syndrome, cirrhosis and pericardial disease.

Examination

• If the patient is deeply cyanosed, cor pulmonale is the most likely diagnosis (Confirm – raised JVP, RV lift, hyperinflated)
• Swollen but JVP not elevated – unless a recently diuresed cardiac, more likely to be cirrhotic (alcohol history, liver not particularly enlarged) or nephrotic (protein on dip sticks, usually – although probably worth screening for it with a protein/creatinine ratio).
• Raised JVP and clear lungs – consider pericardial disease (clear fields on CXR with big cardiac shadow if effusion, small cardiac shadow if constriction)
• Confirm that there is cardiac disease: displaced apex and S3 gallop and fine basal inspiratory crackles.
• Consider also the possibility of chronic (or acute!) renal failure. (Presence of swelling, elevated JVP and pulmonary congestion is variable)

Examination – delving deeper

Many of the classical feature of heart failure are quite rare¹ Although most patients in this echocardiographic study complained of dyspnoea, orthopnea was only noted in 22%, PND in 39% (spec 80%, LR+ 2.0, LR- 0.8), an elevated JVP in 17% (spec 98%, LR+ 8.5, LR- 0.8) and a gallop in only 24% (spec 99%, LR+ 24.0, LR- 0.8.) Crackles were also rare (29%) and not very specific (spec 77%, LR+ 1.3, LR- 0.9.) However a displaced apex was found in 66%, with a specificity of 96% (LR+ 16.5, LR; 0.4.) The combination of a displaced apex and one or more of an elevated JVP, an S3 gallop, or crackles was found in 44%, but was highly specific (99%) – LR+ 44.0, LR- 0.6. Many of the patients in this series were probably given diuretics by their referring clinicians prior to the Echo booking, so these low sensitivities may not apply to new patient encounters.

It is worth feeling carefully for the apex, and finding it to be displaced together with one of gallop, raised JVP or crackles is very suggestive of the diagnosis.

Another sign which may be of some value is the abdominojugular test² – positive if application of 30 mmHg of pressure to the abdomen for 15 seconds causes elevation of the JVP of more than 3 cm for longer than 15 seconds. To learn the appropriate pressure to apply, press on a partially inflated BP cuff the first few times. The LR+ for a pulmonary capillary wedge pressure of more than 15 mmHg is 6.7; sensitivity 81%, specificity 80%. LR+: 4.1, LR-: 0.2)

A more recent publication³ looked at the performance of phonocardiographically detected S3 and S4 sounds, and found sensitivity for detecting an S3 gallop of only 52% (spec 87%, LR+ 4.0, LR- 0.6.) This thus confirms that finding a gallop is helpful, but not finding one does little to the diagnostic probability.

Chest XRay

The findings are usually straightforward – increased cardiothoracic ratio (measure it, before saying it is not increased) with a left ventricular configuration, congestion and sometimes an effusion. Kerley B lines are quite difficult to spot and often missed, and often not there in the first place. Upper lobe diversion is very subjective, and often over-called. A previous XRay is invaluable if it show progression or new development of some features.

Investigating heart failure

Remember the reversible causes:

• Thyrotoxicosis
• Phaeochromocytoma
• Pregnancy
• Thiamine deficiency (pregnancy and alcohol abuse classically, but any cause of malnutrition)
• Iron overload. (serum ferritin)
• Valvular heart disease. (Examine properly!)
• Ischaemic heart disease (History, ECG)
• Protracted uncontrolled tachyarrhythmias.

Basic investigations appropriate for most patients:

• Creatinine, urea, electrolytes and glucose.
• TSH
• Full blood count
• HIV status
• ECG
• CXR
• Consider a serum ferritin if no other obvious cause

Perspective -prognosis in patients with various types of cardiomyopathy

The main factor determining prognosis is the severity of the cardiomyopathy. However, patients with some causes are reputed to do worse than others. The reasons for this are usually obvious – a patient with a CMO after an anthracycline for cancer has an underlying disease that largely dictates mortality. In the table below, the data was extrapolated from survival curves in a cohort of 1230 patients from a US cardiology department⁴

Type of cardiomyopathy	5 year survival (%)
Peripartum	91
Idiopathic	77
Ischaemic	69
Anthracycline induced	42
HIV	24

As an aside, all 1230 patients underwent endomyocardial biopsy, which provided a diagnosis in 15% at a cost of 2 deaths from the procedure.

Perspective – other (rare) causes of cardiomyopathy

Two other conditions worth considering because of their potential for reversal/cure are the apical ballooning syndrome and hypersensitivity myocarditis.⁵. is also known as takotsubo cardiomyopathy, stress cardiomyopathy, and broken heart syndrome, and is characterised by apical myocardial stunning without coronary artery disease. It is associated with many stressors which lead to a sympathetic response with catecholamine excess (stroke, SAH, fits, status asthmaticus, pneumothorax, DKA, GIT bleeding and phaeochromocytoma.) LV dysfunction can be profound, with diffuse T wave inversion and QT prolongation, but cardiac enzyme rises are usually mild. Management is firstly to recognise the condition, treat the cause if possible, and also treat for LV failure. In some instances there may be good recovery.

Hypersensitivity myocarditis is characterised by acute necrotising eosinophilic inflammation of cardiac muscle, due to a wide range of medications such as sulphonamides, tetracyclines, beta-lactams, aminoglycosides, isoniazid, diuretics, phenytoin, carbamazepine, tricyclic antidepressants, non-steroidal anti-inflammatories, suphonlyureas and methylxanthines⁶ Onset is often fulminant, with associated fever and rash. There may be ECG changes suggestive of ischaemia, with elevated cardiac enzymes and eosinophilia. There is an associated pericardial effusion in 75% of cases, and mortality approaches 50%. Management is supportive, with withdrawal of all potentially causative medications, and consideration given to the use of high dose corticosteroids.

Management of cardiomyopathy

For perspective on these treatments, click here: https://medeval.co.za/wp/perspectives-in-cardiac-failure-therapeutics/

Non-drug therapy.

• Advise about salt restriction. With adequate doses of furosemide, this is not a major issue unless heart failure is refractory, but suggest no added salt in cooking, no salt on the table, and avoid foods that taste noticeably salty.
• Water restriction. Again, advisable mainly if failure is proving refractory.
• Stop any non-steroidal anti-inflammatory drugs. This is a well recognised issue; in Type II diabetics, use of any NSAID increased the odds of hospitalisation for heart failure by 50%.⁷
• Advise patients to stop drinking alcohol.
• Bed rest in the initial phase of treatment probably has a modest effect although there is only scanty evidence of true clinical benefit⁸.

Medication

Furosemide

Start with 40 or 80 mg per day if renal function is relatively normal. Increase to twice daily, and then increase the dose every few days as many times as required in order to eventually initiate a diuresis– e.g. 40 mg 2x/d, then 80 mg 2x/d, then 160 mg 2x/d, then 240 mg 2x/d.

ACE inhibitors

Unless there is evidence of an obstructive lesion (e.g. AS or MS) add an ACE inhibitor – e.g. enalapril 2.5 mg daily. Increase the dose to 5 to 10mg 2x/d day if tolerated. Do not be shy about the dose – the trials demonstrating benefit used doses equivalent to enalapril 10 mg 2x/d.

The absolute level of BP is not critical – a systolic of 90-100 is perfectly acceptable if the patient is ‘perfusing’ – not dizzy on standing and has stable renal function (repeat creatinine after one or two weeks.) Although titrating to highish doses is seen as desirable, the evidence that lower doses are insufficient is not available. A very large dose minimsation trial demonstrating non-inferiority would be required to settle this satisfactorily. The NETWORK trial in 1998 compared twice daily enalapril 2.5 mg, 5mg and 10 mg in 1532 patients and found no difference in mortality or the primary composite outcome (death, worsening heart failure, or hospitalisation for heart failure) but was underpowered to resolve this issue definitively.⁹ The larger ATLAS lisinopril study (3164 patients) reported a year later also failed to demonstrated a survival advantage but clearly showed a 4% absolute reduction in the composite of death or hospitalisation.¹⁰. A 2019 systematic review attempted to resolve this issue¹¹ found no mortality advantage with higher doses, but reduced hospitalisation – for every 1000 patients 53 fewer (95% CI 27 to 71) required admission.

Spironolactone

Add spironolactone 25 mg per day if renal function is normal (creatinine less than 220 micromol/l, and even then careful monitoring of potassium (check it one week later, and stop the spironolactone if it rises above 5.5 mmol/l and there is no other immediately reversible cause for the hyperkalaemia¹². Spironolactone should not be seen as a substitute for conventional diuretics – in the pivotal RALES trial all patients were on a loop diuretic. Pushing up the dose of spironolactone has little extra benefit in terms of diuresis – see it as a neuroendocrine modulator rather than a diuretic.

Beta-blockers

Beta-blockers are able to offer a survival benefit (e.g. carvedilol, starting at a test dose of 3.125 mg, and monitor BP for an hour after this; if tolerated give 3.125 mg 12 hourly, and double the dose fortnightly, again if tolerated, to a target dose of about 25 mg 12 hourly¹³. However this titration process is labour intensive and only appropriate for patients who are no longer at all fluid overloaded, and are able to come regularly for follow-up.

Digoxin

Digoxin. Hospitalisation events may be reduced by digoxin, although it probably confers little if any survival advantage, and there are now reports of increased mortality. It may be worth considering its use in some patients but it should no longer be considered routine care. An empiric dose of 0.125 mg per day should be reduced even further patients with renal impairment and in the elderly. (Aim for trough level of < 1 nmol/l)

Other medications to consider

Hydralazine and nitrates.

The addition of hydralazine and isosorbide to ‘standard’ therapy may offer a further survival advantage, although the evidence is still preliminary. In a study of Americans who labelled themselves as black¹⁴., a combination tablet of hydralazine 37.5 mg and isosorbide dinitrate 20 mg given three times a day was added to ‘background’ therapy (diuretic in 90%, ACE inhibitor in 70%, beta-blocker in 70%, digoxin in 60% and spironolactone in 40%). The exact proportion of patients on all 5 medications was not provided. Most of the patients were NHYA Class III or IV, the average weight was 90 kg, and 40% were diabetics. They nearly all had dilated LVs (LVIDD 6.5 +/- 1.0) with a mean ejection fraction of 24%. The absolute reduction in mortality was 4% (NNT 26, 95% CI 15 to 85.)

Anticoagulation

In patients with atrial fibrillation or other firm indications for warfarin, it is reasonable to use this agent, although dosing may be challenging in the face of a fluctuating INR associated with varying degree of hepatic congestion and compliance. In patients with heart failure and sinus rhythm another option is to use aspirin. Earlier small trials (HELAS, WASH, WATCH) were underpowered to determine if warfarin or aspirin was better, and indeed if either was better than placebo.¹⁵ randomised 2305 patients to warfarin or aspirin and followed them for 6 years. There was no difference in the composite primary endpoint of all cause mortality, intracerebral haemorrhage or ischaemic stroke. However the trial only had 69% power to detect a difference. The patients were predominantly male and elderly, and just under half had already had a myocardial infarction, and after 4 years, there was a trend in favour of warfarin. Essentially, this study legitimises the use of aspirin where there are problems with using warfarin, but doesn’t answer the question of whether either agent is better than placebo.

Monitoring.

It is important to measure response in order to be able to tailor maintenance therapy. Discharging patients on too much diuretic can also be harmful.

• Keep a record of weight.
• Check lung bases.
• Check pulse rate and blood pressure.
• Ask the patient how he or she feels, and whether able to sleep through the night.
• Ask about effort tolerance – able to walk to the toilet without assistance?

Communication and medication concordance in heart failure patients.

Too often, management of cardiomyopathy is seen as a question of tweaking drug doses. It is essential to invest time in explaining the rationale of therapy to patients, as well as the likely need for life-long treatment. Checklist:

• Can the patient access a steady supply of medication?
• Does the patient know what is wrong?
• Does the patient understand the need to take treatment daily?
• Is the regimen as streamlined as possible? (No extraneous drugs like multivitamins or sleeping pills, regimen once daily if possible.)
• Have you discussed low sodium diet and fluid intake?
• Does your letter to the clinic explain how to escalate the dose of furosemide if the patient deteriorates on treatment?

Further therapies in cardiomyopathy

Hypertrophic obstructive cardiomyopathy ??(clinical LVH and an ejection systolic murmur which gets louder on standing from squatting, due to decreased preload) can be confirmed echocardiographically. There will be LVH with the septum thicker than posterior wall with a late peaking high velocity outflow tract jet with gradient increasing on Valsalva. Treat with atenolol 25 mg 12 hourly, increasing dose to achieve resting pulse less than 70 bpm. If activity-limiting symptoms of angina or dyspnoea persist of if the echo gradient is greater than 30 mmHg (50 with provocation), consider referring for surgical myomectomy¹⁶ or septal ablation with alcohol.

Diastolic dysfunction (HFpEF)

(Renal artery stenosis should be considered in any patient presenting with pulmonary oedema but normal systolic function and no valve disease on echocardiography – so-called ‘flash’ pulmonary oedema.)

In some studies up to one third of patients have clinical evidence of cardiac failure but no valvular disease or systolic failure. If the ventricle contracts well in systole (normal ejection fraction or factional shortening) but relaxes reluctantly, this is referred to as diastolic dysfunction.

Various definitions exist, but this is peculiarly a condition that requires special investigation for its formal diagnosis – the simplest definition of diastolic heart failure is that where the patient has clinical evidence of cardiac failure but a normal ejection fraction (>50%) on echocardiography. On echo, there is usually evidence of LV hypertrophy, with a normal end-diastolic volume. The E:A ratio (the ratio of early ventricular filling velocity to later atrial-boosted filling velocity) reverses with mild diastolic dysfunction, but then normalises again as the condition worsens and left atrial pressure rises. Differentials include restrictive cardiomyopathy and constrictive pericarditis.

Treatment options have been poorly evaluated in RCTs, but the usual furosemide to get the patient out of pulmonary oedema is appropriate. Hypertension can be controlled with amlodipine (2.5 mg – 10 mg/d) but ACE inhibitors are probably quite adequate alternatives. Rate control with beta-blockers or diltiazem (not both) is appropriate, and there is some theoretical value of cardioversion of atrial fibrillation, although the evidence of survival benefit in this situation is still lacking.

In summary, most agents used in normal systolic function can also be considered in this situation, with the addition of conventionally available beta-blockers as another option¹⁷. However, they should be used because they are needed for another reason (e.g. hypertension) – there is little evidence of mortality benefit of any agent in HRpEF

Perspective: flash pulmonary oedema.

Some causes of flash pulmonary oedema:

And all the other more obvious ones (near drowning, electrocution, transfusion related acute lung injury, over-enthusiastic drainage of a pleural effusion, etc)
Perspective – frequency of ACE inhibitor associated cough

• Sympathetic crashing acute pulmonary oedema (SCAPE) (hypertension, tachycardia, vasoconstriction, often actually volume depleted, respond better to nitrates and non-invasive ventilation than to diuretics.)
• Bilateral renal artery stenosis
• Myocardial infarction
• Acute mitral or aortic regurgitation
• Post-partum (iatrogenic fluid overload, peripartum CMO, tocolysis Ho M, Cheung W, Tsai K. Acute Postpartum Pulmonary Edema: A Case Report. J Emerg Crit Care Med.2010;158:157-160., thyrotoxicosis)
• Negative pressure pulmonary oedema (usually associated with post-extubation laryngospasm)
• Pulmonary embolism
• Takotsubo (stress) cardiomyopathy Templin C, Gadhri J, Napp L et al. Clinical features and outcomes of Takotsoubo (stress) cardiomyopathy. N Engl J Med 2015;373:929-38 .DOI: 10.1056/NEJMoa1406761 (and reverse Takotsubo). Some of the others mentioned above may have been unrecognised examples of this.
• Neurogenic pulmonary oedema

The frequency of cough in patients taking ACE inhibitors varies because of the variation in reporting of side-effects in ACE inhibitor studies, with one review suggesting that side-effects reports were only available for 43% of 51 studies¹⁸. Another study¹⁹ reported cough as a side effect in 12% of patients, which may be reasonably representative. The same study suggested the problem was more common in older persons and in women. Of some interest, a need to stop the drug because of the cough is less common – perhaps 2-3%²⁰.

Dealing with refractory cardiac failure.

Some patients are admitted in pulmonary oedema with severe peripheral oedema and settle a little initially but then seem to plateau or deteriorate. Consider the following:

Wrong diagnosis. Nephrotic/cirrhotic. (Urine protein, serum albumin.) Or constrictive pericarditis.
Unrecognised precipitating or exacerbating factors – thyrotoxicosis (TSH), anaemia, pregnancy, mitral stenosis (straight left heart border on CXR).
Reversible causes of salt retention – non-steroidal anti-inflammatories (NB), high oral salt intake, I.V. saline, I.V. penicillin.
‘Irreversible’ salt retention – chronic renal failure.
Drugs not being given.
Wrong drugs – e.g. thiazides in persons with renal impairment.
Incorrect assumption – actually is diuresing, but this wasn’t recognised (weigh, look for wrinkling of skin around ankles, measure actual height of JVP, measure intake/output…)

After all the issues above have been addressed, the majority of patients will diurese. In those who don’t:

Paradoxically, in the initial acute stage there may be a better response to lower doses of ACE inhibitors²¹ because of better renal haemodynamics.
Increase your dose of furosemide by 30-50% every 2nd or 3rd day until you start to see a response. Some patients may need 250-500 mg/day.
Dividing a subtherapeutic dose is illogical, but once you reach a dose that cause the patient to tell you he/she notices something is working, repeating the same dose in the afternoon may help. Beware of multiple dosing (3 or 4x/d) in the chronic stage, as this may intolerably impair quality of life.
If not already on low dose spironolactone (25-50 mg), add this, and check the potassium again in the next week.
Giving intravenous furosemide after the first day or so is often recommended, (‘impaired absorption’) although there is little evidence to back up this practice.
Some patients responded to the addition of hydrochlorothiazide 12.5 – 25 mg/day.
Don’t forget the value of bedrest²² and patience – not everyone has to be fixed overnight!

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18. Agusti A, Bonet S, Arnau JM, et al. Adverse effects of ACE inhibitors in patients with chronic heart failure and/or ventricular dysfunction : meta-analysis of randomised clinical trials. Drug Saf. 2003;26:895-908 ↩

19. Morimoto T, Gandhi TK, Fiskio JM, et al. Development and validation of a clinical prediction rule for angiotensin-converting enzyme inhibitor-induced cough. J Gen Intern Med. 2004 Jun;19:684-91 ↩

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22. Abildgaard U, Aldershvile J, Ring-Larsen H, et al. Bed rest and increased diuretic treatment in chronic congestive heart failure. Eur Heart J. 1985;6:1040-6 ↩

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