As scientists plan trials to deal with New Zealand's "silent killer", Donna Chisholm looks at why our blood-pressure problems are so vast and poorly controlled.
Bain, 74, the chair of children’s charity Koru Care, takes five different drugs daily to control the high blood pressure she’s had since she was in her forties but which worsened recently when she was diagnosed with a kidney condition. She says her specialist has told her there are no more tablets she can take. “It’s a silent killer; I know that. I’d like to know what else I can do, because nobody wants high blood pressure. I’d like to know why. I know I could drop dead tomorrow.”
Auckland-based researchers are hoping to answer those questions by investigating how a little-understood but highly influential contributor to hypertension might be identified and treated.
Ask most people about the causes of high blood pressure and top of their list is likely to be our sedentary, self-indulgent lifestyles – we eat too much bad food, drink too much booze and exercise too little. Last year, a study of a remote Amazon tribe revealed remarkably stable low blood pressure, with no trend towards an increase as they aged. But in primary care in the First World, it’s one of the commonest chronic health problems doctors will encounter, with estimates that a third of men and a quarter of women will have raised blood pressure, although the threshold at which it is described as such varies between 130/85 and 140/90, depending on which expert you ask.
About 750,000 people in New Zealand are estimated to have hypertension, but only about half are treated. And of the half who are treated, only about 50% are well controlled. About 5-10% or more of patients are like Bain, who has hypertension that is resistant to treatment despite good compliance and optimal medication. Over time, high blood pressure damages blood vessels, increasing the risk of heart attacks, strokes, heart failure and kidney disease.
Julian Paton, a professor of translational physiology at the University of Auckland medical school, says in 95% of cases, doctors don’t know the primary cause of hypertension. But he believes a significant contributor is the activity of our sympathetic nervous system – the one we can’t control that activates our fight-flight response. “We know that in patients with high blood pressure this sympathetic nerve activity going to the heart, and to the blood vessels to control their diameter, is extremely high – much higher than it should be.”
But what about that Amazon tribe? Wouldn’t their sympathetic nervous system operate the same as ours? No, says Paton. “This tribe is isolated from many of the drivers of hypertension and sympathetic activity, including continual stress, high salt, high fat, smoking, alcohol and artificial preservatives and sweeteners. Their crops are free of artificial chemicals such as pesticides, herbicides and fungicides. I’m not surprised their blood pressure is normal.”
Where’s my motivation?
Treatment of hypertension is poor, partly because existing drugs don’t target sympathetic activity, says Paton. Poor control is also the result of treatment resistance, as in Bain’s case, as well as drug intolerance and poor compliance because of the side effects of some medication. “It’s a disaster,” says Paton. “When you take a tablet for a condition that doesn’t hurt – it’s not like arthritis, where every morning you are reminded to take your pills because your knees hurt – and you get side effects, and you feel tired and lethargic, and it destroys your sex life, and you felt better before, what is the motivation? It’s a really big clinical issue.”
Paton’s new $5 million Health Research Council (HRC)-funded study targets two tiny but powerful organs strategically located at the base of the skull, known as the carotid bodies, which control the sympathetic nervous response. The size of a grain of rice, they are the guardians of the brain’s blood-oxygen status, acting as a kind of smoke alarm telling the brain to increase blood pressure to maintain oxygen supply. They also force you to inhale again after holding your breath for long periods.
In an earlier study he did when based at the University of Bristol, Paton’s research team removed one of the carotid bodies in 15 patients to find out if it would lower blood pressure. “The answer was, ‘Bloody hell, did it lower blood pressure!’ – by a whopping 30mm of mercury.” Systolic and diastolic blood-pressure readings – the top and bottom figures – are measured in millimetres of mercury, so a 30mm reduction is dramatic indeed. In a 16th patient in the Bristol study, blood pressure did not change. It was later discovered that the tissue removed from that patient was fat and did not contain the carotid body.
Paton isn’t recommending carotid-body surgery as a treatment, however. Studies show it makes patients more vulnerable to potentially life-threatening sleep apnoea, and that blood pressure over time resets to original levels as the body tries to compensate for the change. However, a novel drug, known as a purinergic receptor antagonist, which Paton believes will dial down the carotid bodies and sympathetic activity and lower blood pressure, will be used in animal studies as part of the HRC research. He hopes that work will lead to big-pharma collaboration in the first clinical trial in hypertensive people in New Zealand.
The drug has been developed for people with chronic coughs and has been found to be highly effective in clinical trials – but those trials excluded patients with hypertension. The drug, originally developed by Roche, is now owned by Merck. Paton says it has taken more than three years of negotiation with the company to get it to agree to a clinical trial of the drug in sleep apnoea, which has no drug treatments. If that trial shows anti-hypertensive activity, it might be sufficiently attractive to take to market. “Big pharma is all about finding drugs that can hit markets that don’t already have treatments, or have only a few drugs. And currently, anti-hypertensives are cheap – we haven’t had a new one in about 18 years.”
The Auckland study will recruit at least 30 hypertensive patients who’ll be tested to measure their sympathetic nervous system activity. Microneurographer James Fisher will insert very fine acupuncture needles into the peroneal nerve on the side of the knee – it’s close to the skin and contains many of the sympathetic system fibres the scientists are targeting – to measure the electrical impulses and their pattern of activity. Paton says although they already know hypertensive people have “massive” activity compared with those with normal blood pressure, the work will produce results for the ethnicities common in the New Zealand population, which often aren’t found in European studies.
Turning up the hose
Discovering why Māori and Pacific people have disproportionately high levels of cardiovascular disease will be one of the key aims of Manaaki Mānawa, the new Centre for Heart Research based at the University of Auckland’s medical school. It will be launched in February and will bring together the work of 110 clinical and discovery scientists in Auckland, and a further 90 from around the country. It’s the first step in a bid to establish a $50 million centre of excellence for heart research, but a decision on that won’t be made until 2021.
One of the Auckland investigators is Fiona McBryde, who worked with Paton in Bristol on the carotid body studies. She returned to New Zealand in 2013, after winning the $500,000 Sir Charles Hercus Research Fellowship, to study the role of the “selfish brain” in regulating blood pressure.
McBryde says researchers have known for many years that the walls of blood vessels that supply the brains of people who have hypertension show signs of thickening, but this was always assumed to be a protective response to high blood pressure. In fact, she says, impaired brain blood flow can occur early and may be a primary trigger for high blood pressure. In 2015, she was awarded a $1 million, three-year HRC project grant to investigate how and why the brain responds to the reduced blood flow and low brain oxygen that occur during a stroke. Her laboratory can both see and measure blood flow to the brain thanks to a $1 million piece of equipment donated by the AH Somerville Foundation. “We can look in real time in the brain as the stroke is happening and we can look at the effect of blood pressure on stroke size, which we think is critical to try to salvage as much brain tissue as we can.”
Although about half of stroke patients have a history of hypertension, some will have normal pressure, and others will be on treatment. But 85% of patients will have a big surge in blood pressure after their stroke – an increase of 30-40mm of mercury. “If you have a blood vessel completely occluded, you’ve got part of the brain downstream from that with very little or no blood flow, so ‘turning up the hose’ can make it easier for blood to get in there and rescue that stroke area – that’s what the body is trying to do.”
So, what are the ramifications for aggressive blood-pressure control in those first hours or days after a stroke, if the brain is actually protecting itself? And what should be done about blood pressure in patients who undergo emergency clot retrieval to remove the blockage? McBryde hopes to address those questions in future research for which she is seeking grant funding.
It is vital that researchers understand the condition of the blood vessels that are feeding the brain in the first place, says Paton. “What we have found in animals and humans with hypertension is that there is a narrowing of the cerebral arteries to start with so their capacity to get more blood into the brain is restricted and that could be a cause of their hypertension.” In some patients, the cerebral arteries are missing, tiny or twisted. Says McBryde: “It’s like the brain trying to drink through a curly straw.”
Paton, who chairs the steering group for Manaaki Mānawa, says the centre, and the hoped-for national centre of research excellence, will be game changers for cardiovascular research in New Zealand, with novel findings that can be readily translated into clinical use. “Of all the centres in the world, we have a unique opportunity here because of the pioneering history in heart research and treatment at Green Lane Hospital and the multidisciplinary team we have assembled,” says Paton. “Auckland is at the forefront of many research disciplines, but people here don’t realise it. Many researchers from around the world are looking at New Zealand, and they’re impressed.”
Hypertension specialist Dr Walter van der Merwe has a number of beefs about the way New Zealand deals with hypertension. He says the condition doesn’t get the attention it deserves, and we don’t have the right combinations of drugs to treat it.
“You don’t hear about blood pressure much these days. People talk about cardiovascular risk, cholesterol and statins, but high blood pressure doesn’t get very much profile. You don’t see public-health posters saying, ‘Have you had your blood pressure checked?’”
Control of the condition here is poor, says van der Merwe. The most commonly prescribed drug for hypertension is the angiotensin converting enzyme (ACE) inhibitor cilazapril combined with a diuretic, hydrochlorothiazide. Last year, nearly 67,000 people took the drug. ACE inhibitors relax and dilate the blood vessels, making it easier for blood to flow through. Imagine your blood circulation as a garden hose. We’ve all put our thumb over the end to create more resistance, increasing the pressure and pushing the water further – but the amount of water coming out is a lot less when we apply our thumb. Diuretics increase urination to get rid of extra water and salt so there’s less fluid volume and lower pressure in your blood vessels – like a tap that’s not fully turned on.
The problem in New Zealand, says van der Merwe, is that the cilazapril-hydrochlorothiazide combination has only 12.5mg of the diuretic, and that’s too little to be effective. Randomised controlled trials internationally have found that it is no better than cilazapril alone and the combination is not commonly used elsewhere. Overseas, hypertension poly-pills contain up to 25mg of the diuretic. “It dates back to whenever Pharmac was first negotiating a package to get an ACE inhibitor, and New Zealand just got stuck with this,” says van der Merwe.
When patients’ blood pressure is not well controlled with that combination, they often end up on two, three or four pills, when the best solution would be a combination pill with double the dose of the diuretic, which is not available here. Also not available here are amiloride tablets. Amiloride is a potassium-sparing diuretic, but Pharmac funds the tablets only in exceptional circumstances, forcing patients to take the only alternative, a fluid that comes in 25ml bottles. “If you’re prescribed 10ml a day, you end up with all these bottles in your fridge, and if you’re going overseas it’s a nightmare,” says van der Merwe. He has put in numerous exceptional-circumstances applications, which have all been declined. Pharmac has said it’s unable to find a reliable supplier of the tablets, “but that’s just nonsense”.
Phamac told the Listener its sole supplier discontinued the product last year and it was seeking alternative suppliers. It did not answer questions about the strength of the diuretic used in combination with cilazapril, but said the agency funded 40 different drugs for hypertension and “does not mandate which medicines are used for which patients under which clinical circumstances. This is a matter for prescribers, with due diligence and professionalism as health professionals.”
Van der Merwe takes issue with the recommended approach of total cardiovascular risk when doctors assess the need for a patient to start anti-hypertension treatment. For example, a 50-year-old woman with a blood pressure of 158/95 wouldn’t be treated under current guidelines if she had no other risk factors, such as being a diabetic, smoker or having high cholesterol. The recommended level at which treatment of hypertension should begin regardless of total cardiovascular risk is repeated measurements in the doctor’s office of 160/100. “Her five-year risk of a heart attack or stroke is just 1.7%, and if the risk is under 5%, the benefits of treatment are said to be outweighed by the possible risk.” But van der Merwe says a five-year risk is meaningless. “A 50-year-old woman now wants and expects to live to her eighties or nineties and to be fit and healthy for all that time. With that blood pressure, her lifetime risk is 50%, and that’s what we should be looking at.” He says the long-term effect of even moderately raised blood pressure can be severe.
The stakes are high
That’s something Auckland car-rental reservation agent and part-time actor and singer Hugh Boyd has discovered to his cost. Boyd, 67, had hypertension for about eight years before he finally agreed to start taking medication in 2015. “The doctor would talk to me about it and monitor it and say we should do something about it and I sometimes tried to ignore it. But it’s not until you realise it’s a silent killer that you do anything. I didn’t want to go on pills – you read about the side effects and I’d had an allergy reaction to other drugs before. But I don’t think I really understood at the start what [hypertension] can do to you.”
In January last year, Boyd was admitted to North Shore Hospital with unstable angina and ended up getting two stents in his coronary arteries. “Knowing what I know now, I wouldn’t have delayed.” He’s now on five drugs – a statin, aspirin, an ACE inhibitor, a calcium channel blocker and a diuretic – and has had to change two medications when they caused gout and breast swelling.
Van der Merwe believes high blood pressure is “unquestionably” the biggest cardiovascular risk. “It’s all about long-term vascular damage and vascular remodelling and I don’t like the idea that you might wait before starting treatment. The younger you are, the higher the stakes. A lot of people in New Zealand start treatment only once they’ve had a heart attack or stroke, which is putting the cart before the horse. These conditions are preventable if they’re treated in a timely way.”
Ann Bain tries not to let her blood pressure stress her out. Towards the end of our interview, she takes her reading again and it’s dropped to 161/98 – still too high.
Van der Merwe says to get accurate readings on home monitors it’s important for patients to be on their own in a quiet room, have their arm comfortably supported, with feet on the ground and legs uncrossed. There should be no distractions – not even a television, pets or children. “Just being with someone and talking will push your blood pressure up.”
Bain says although van der Merwe, her specialist, has told her to call him if her reading goes over 170, she doesn’t. “You can’t call him at 2am and say ‘Walter, my blood pressure is 200/100.’” She says a 24-hour ambulatory monitor found her blood pressure actually went up when she is asleep.“It should be 130, but it’s very rarely that. It’s all over the place. And I just don’t know why.”
*Volunteers interested in taking part in the Auckland study, which is expected to start recruiting later this year, can email James Fisher at firstname.lastname@example.org for more information. The investigators will be seeking participants with high blood pressure (patient group) or normal blood pressure (control group), and with no other known health problems.
'I lost almost 20kg'
Exercise and diet changes can help reduce the need for blood-pressure drugs.
He was first diagnosed with hypertension in his late thirties, and his untreated reading was 170/100. He says it didn’t help when his weight started to rise as well, reaching a peak of 93kg a couple of years ago. To maintain his blood pressure at 125/80, he was on the angiotensin converting enzyme (ACE) inhibitor cilazapril, the calcium channel blocker amlodipine, the beta blocker bisoprolol and an alpha blocker, doxazosin.He originally planned to lose just a few kilograms ahead of his wedding anniversary, but his new regime – walking, working out on a stationary bike for about 30 minutes at a time, minimising his sitting time and giving up sugar and carbs – has stuck, and he has now lost almost 20kg. His blood pressure has fallen to 110/70 and is being maintained on just three of the four drugs (amlodipine has been stopped), at reduced doses. Doctors say serious weight loss can cause meaningful reductions in blood pressure. “For every kilo you lose, your systolic (top) reading might come down by 1-2mm of mercury,” says Auckland City Hospital cardiologist Matt Dawes, who is liaising with medical-school researchers on the hypertension studies. “If you can lose 10kg, the systolic reading can come down by approximately 15mm of mercury, which is what you’d expect a drug to do. In an appropriate person, it is very good blood-pressure control.”
A significant proportion of treated hypertensives don’t get below the recommended 140/90, he says, despite being on two, three or even four different medications. “Once you start getting on that number of meds, you increase the chances of side effects. The patient thinks the tablets are only making them feel worse, and they’re clearly not making them feel better, because they didn’t feel bad in the first place. There needs to be a good doctor-patient relationship over time to maintain good adherence.”
Singh says he’s never felt better. “Before, if I did any physical work for 20 or 30 minutes, it would exhaust me. Now, it’s like the difference between a day with thunderstorms and a sunny spring day.”
This article was first published in the September 14, 2019 issue of the New Zealand Listener.