Predicting the future: Progress in the diagnosis and management of hypertrophic cardiomyopathy

William McKenna, Professor of Cardiology at The Heart Hospital, University College London, UK, is a world-renowned expert in hypertrophic cardiomyopathy. At an educational meeting held recently by the UK Cardiomyopathy Association (June 2007), Professor McKenna spoke of his conviction that continued efforts to define the clinical features and underlying genetic causes of hypertrophic cardiomyopathy can change the perception that this is a highly unpredictable condition.

MedWire Reporter Caroline Price caught up with Professor McKenna at The Heart Hospital, to ask him about some of the key developments and remaining challenges in understanding and treating hypertrophic cardiomyopathy (HCM), and why he believes molecular genetic approaches are key to changing its unpredictable reputation.

Recognizing HCM

Awareness of HCM has increased markedly in recent years, according to McKenna, largely because “untreated or unrecognized, it is probably the commonest cause of sudden death in the young.”

As awareness of HCM has grown, so has research into the molecular genetic basis of the condition, which is inherited in an autosomal dominant pattern.

The clinical presentation of HCM is commonly unexplained left ventricular hypertrophy (LVH) in the absence of a recognized cardiac or systemic cause such as aortic stenosis or hypertension. But it is commonly perceived as an unpredictable condition because the clinical expression and severity of disease can be highly variable, even within families, and because it can cause sudden death in people with no symptoms or no clear family history.

“Untreated or unrecognized, [HCM] is probably the commonest cause of sudden death in the young.”

A major focus of the Cardiomyopathy Association meeting was the importance of pursuing the underlying genetic defect in suspected cardiomyopathy to enable prompt diagnosis of individuals at risk and the development of presymptomatic interventions.

At least 10 sarcomeric contractile protein gene abnormalities have been identified, McKenna explains, and there are likely to be others. These mutations account for around 60-70% of the disease, he notes, “which means there is another 30% where either we haven’t recognized the sarcomeric gene abnormality, or there are other gene abnormalities.”

Adopting a genotype-based approach to diagnosis also helps clinicians to differentiate between “pure” HCM and phenocopy conditions that have similar clinical features. These related conditions include the glycogen storage diseases and certain mitochondrial diseases, which usually have a different clinical profile and natural history to sarcomeric-disease HCM and require different treatments.

“I can remember at medical school that you had to memorize all these types of glycogen storage disease and it seemed largely to be an academic exercise, like memorizing a telephone directory, because you didn’t usually recognize them during life, patients died, there were no treatments, and there wasn’t much you could do about it,” McKenna recalls.

“That’s not true now, and the genetics are different, the treatments are different, the natural history’s different. So it is important to recognize them.”

Diagnosis

Making a diagnosis of HCM is generally straightforward, according to McKenna; where the challenge comes is where you have incomplete expression of the disease gene. This is when it is important to be aware that HCM is fairly common, he notes, at around 1:500 of the population, with the gene abnormality likely to be more common than that.

So an official diagnosis of HCM due to unexplained LVH on echocardiography (echo) may not always be possible, McKenna explains, “but when you’re trying to explain a symptom or an electrocardiogram (ECG) abnormality, that’s certainly part of the differential diagnosis - the incomplete expression of one of the HCM-disease causing genes.”

Variations in disease gene expression affect not only the severity of the phenotype but also the age of onset. Diagnosis can present different challenges depending on the patient’s age - children and adolescents present particular problems because the control population is more variable.

“What’s a normal 14-year-old?” asks McKenna. “A 14-year-old can be pre-pubertal and look like an 11-year-old or going on 18. Similarly if it’s a male it can be someone who is 6-feet tall or it can be someone who is 5-foot 2.

“Also often in the child, the ECG is the initial manifestation so you may have ECG changes without definite echo changes.”

“It’s not practical in our society, to screen huge numbers of normal people. So then you have to go to individuals who are at high risk.”

Making sure these abnormalities are picked up is a vital part of identifying individuals who are at high risk of sudden death.

“We can’t screen,” McKenna says. “It’s not practical in our society, to screen huge numbers of normal people. So then you have to go to individuals who are at high risk.”

The starting point in this process is often to perform an ECG, and preferably an ECG and echo, in a young person with cardiac symptoms - and if the ECG is abnormal but the echo is normal, the patient should still be followed-up, McKenna stresses.

“That should be the beginning of the story, that there is something funny,” he underlines. “We should be looking at the family, we should be getting the parents, siblings looked at by their local cardiologists because there may be some form of inherited abnormality.”

Risk stratification and primary prevention

Once a diagnosis of HCM is made, how it is managed depends largely on the patient’s risk of sudden death.

The American College of Cardiology and the European Society of Cardiology recommends non-invasive tests for risk stratification, including echo, exercise testing, and 24-hour ECG, as well as a high-quality history documenting syncope and a family history of sudden death.

“The bottom line is you can risk stratify and identify the high-risk subset and treat them with an ICD.”

“If you don’t have risk factors you can accurately reassure people, if you have two or more risk factors you’re into annual mortality rates of more than 3% so you need treatment. And if you have one risk factor, here the mortality rates are around 1% but the confidence limits are quite wide, they range from 0.2% to 2.0%,” McKenna summarizes.

The wide confidence limits make treatment decisions in the borderline-risk group difficult, McKenna notes, but he emphasizes that this risk stratification procedure is reliable.

“The bottom line is you can risk stratify and identify the high-risk subset and treat them with an implantable cardioverter defibrillator (ICD),” he says.

Again, there are some specific issues with treating younger patients when it comes to primary prevention. The complication rates with ICDs are high in HCM anyway, McKenna explains, and the complication rates in the young are higher still.

“In addition to the physical things, they also get a higher proportion who get inappropriate shocks because of difficulty in interpreting: ‘What is an arrhythmia?’ and ‘What is sinus tachycardia?’” he notes.

The psychological adaptation to such invasive treatment is also more challenging for a younger patient, McKenna adds.

“When you introduce that to a 16-year-old who’s thinking about passing his exams, his girlfriend, and whether he’s going to get his license to drive, it introduces a whole set of complexities that can be difficult to cope with.

“In general, its either denial or rejection at one extreme, or total acceptance and being petrified at the other. But getting that balanced response, which an adult will have, is harder.”

Treatment developments

McKenna explains that treatment for the majority of HCM patients who are not at immediate risk of sudden death aims to alleviate symptoms, increasing exercise capacity and reducing pain and breathlessness.

One feature that dictates a specific treatment approach is the presence of LV outflow tract obstruction, treatment for which is the subject of much research. Drug treatments for LV outflow tract obstruction are around 50% effective, McKenna explains, and when this fails, ventricular septal myectomy - surgery to reduce the thickening of the septum and so remove the obstruction - is an effective option in at least 80% of patients.

This may only provide a temporary resolution in younger patients, however, where maturation of the heart may lead to regrowth of the thickened septum and a gradient being re-established.

Septal myectomy is also generally limited to specialized centers, and McKenna notes that there has been much enthusiasm for the more recently developed catheter intervention alcohol septal ablation.

However, he explains, this treatment remains somewhat inexact, with a danger of uninvolved regions of the heart being damaged, resulting in a potential longer-term mortality risk. McKenna believes that specialists are still on a learning curve with the procedure, and views it as an alternative where surgery is unattractive, such as in older people who often have co-existent disease.

“We would consider alcohol ablation as a viable alternative in people in their late 50s, 60s or 70s,” he states. “We would not be enthusiastic about it in someone who is younger.”

Genetics in prognosis

At the Cardiomyopathy Association conference, McKenna highlighted that the “textbook” perception of HCM has cast doubts over the potential value of genotype-phenotype correlations in diagnosing and managing the condition, a view he believes is short-sighted.

As he tells MedWire, his experience and that of others suggests that already there are some clear correlations providing useful information.

For example, with ß-myosin heavy chain (ßMHC) disease there is a high degree of heterogeneity between families but not within an affected family, he explains.

This means there are some mutations where the phenotype is severe, with 100% disease expression, and within the family the prognosis is very poor among those carrying the defect. Meanwhile, there are other mutations in ßMHC where just 30% of carriers develop disease, and then they have only a mild phenotype and a low risk of sudden death.

Disease Gene	Characteristics
ß myosin heavy chain (ßMHC)	Allelic heterogeneity (between families) determines disease expression, prognosis
Myosin binding protein C	Late-onset, otherwise similar to ßMHC
cardiac troponin T	Mild expression, may die suddenly with mild/no LVH
cardiac troponin I	Heterogeneous expression (within families) but no sudden death without obvious risk markers
AMP kinase Danon’s	Associated cardiac phenotypes (Wolff-Parkinson-White syndrome, conduction disease)
Mitochondrial Disease Fabry’s	Associated noncardiac phenotypes

The current perception of genotype-phenotype correlations is largely due to a lack of data, McKenna explains. In some countries, notably the USA, the lack of a centralized health system limits access to the relatives of a patient, who may have different doctors and be under different health insurance schemes.

This problem is compounded by a lack of routine genetic testing.

“There will be a time when mutation analysis will be part of a routine armamentarium that we can apply to our patients… I think when we get there we’ll find these conditions are actually quite distinctive – [HCM] is heterogeneous but it’s not as unpredictable as it appears at present.”

“At present there is nobody routinely who can just see a patient with hypertrophy and order up a battery of 30 gene tests,” Mckenna says. “Most of the time we have to use the probabilities and send off for one or two tests, because of the expense.

“So I actually think we really haven’t begun to scratch the surface of the role of genotyping in the condition and that’s because we haven’t had it available to us on a routine clinical basis.”

McKenna calls for a more systematic approach to characterize the entire phenotype and the genotype of each patient.

“The technology has moved on enormously and there will be a time, whether it’s in a year or 5 years, I’m not sure, but there will be a time when mutation analysis will be part of a routine armamentarium that we can apply to our patients,” he asserts.

“And I think when we get there we’ll find these conditions are actually quite distinctive – [HCM] is heterogeneous but it’s not as unpredictable as it appears at present.”