Heart Disease Detection Goes High Tech

Introduction

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When former President Bill Clinton was diagnosed with heart disease and underwent a quadruple bypass operation to clear his blocked heart arteries in 2004, some Americans panicked and opted to undergo all sorts of tests to find out if they, too, had heart disease. This hysteria — and call to arms — has been dubbed the “Bill Clinton Effect.” More than two years after he underwent surgery, cardiologists now have even better high-tech tests enabling them to diagnose heart disease earlier — with pinpoint precision. And more tests are being investigated.

“Ten to 15 years ago, industry and academia alike identified cardiovascular disease [CVD] as a disease to be tackled,” says Stanley l. Hazen, MD, PhD. Hazen is section head of preventive cardiology and cardiac rehabilitation at The Cleveland Clinic in Ohio. “The boon of this research has yet to be materialized, but there are an extensive number of compounds and screening methods in the pike that look promising and attractive.”

But studies have shown that almost half of the people who suffer coronary events have only two risk factors: being male and over 65. So it is very exciting when new tests come along that can help identify people before they have an event such as a heart attack.

In terms of blood markers, Hazen says that “the mainstay for assessing heart disease risk is low density lipoprotein [‘bad’] cholesterol testing”. But while we know that LDL plays a major role in determining heart disease, the relationship between severity and the timing of the disease is “incredibly poor. There is much room for improvement,” says Hazen.

Gazing into his crystal ball, Hazen tells WebMD that “there won’t be one single test in the future, but a blood-based array or panel to give the individual a snapshot of their long-term and near-term risks as well as which risks need to be worked on to help guide doctors in terms of where to focus risk-reduction efforts.”

“The CT scan provides remarkably sharp images,” Hazen says “The use of cardiac CT is going to explode. The images are spectacular.”

Hazen isn’t alone in his enthusiasm for this test. “The 64-slice CT scan is the most exciting new instrument we have,” says Edward B. Diethrich, the founder and medical director of the Arizona Heart Institute in Phoenix. “The results we have seen in patient assessment and care are really fantastic.” Hazen does add that the 64-slice CT is not for everyone, “Data from the CT is acquired between beats so it doesn’t provide as good of an image for people who are very large or who have an irregular heart rhythm or large calcifications in their arteries,” he says.

Although there is no doubt that the images with the improved CT scanners are very sophisticated, there is still controversy about the significance of calcium measurements in predicting heart disease. “The CT scan is good, but it is not as specific for heart disease because people sometimes have calcium in blood vessels and no heart disease or vice versa,” says cardiologist Gerald Fletcher, MD, of the Mayo Clinic in Jacksonville, Fla. Fletcher is a spokesman for the American Heart Association.

Because of this controversy regarding calcification scores, most insurance companies do not cover the heart CT scan as a screening test. But Flectcher says “the horse is out of the barn and people are paying out of pocket for it, and it has value as a screening technique when taken with precautions.” Richard D. White, MD, the clinical director of the Center for Integrated Non-Invasive Cardiovascular Imaging at the Cleveland Clinic, also urges caution with the use of cardiac CT scans. Cholesterol screens, stress tests, and other traditional risk stratification methods “are still the backbone of understanding the propensity of a patient to develop coronary artery disease,” White says. “It would be detrimental if we got so enamored with imaging that we put them completely on the back burner.”

White says the CT scan is best used when doctors have a significant concern about a risk for coronary artery disease in patients who are clearly not in need of a catheterization. “A swing vote from cardiac CT would help to decide whether to commit a patient to more testing or therapy” he says. Another test for which both White and Fletcher see a bigger role in the future is magnetic resonance imaging (MRI) of the heart. According to Fletcher, MRI is more accurate than CT scanning.

Although MRI is more difficult to perform and more expensive than CT scanning, he predicts that it will have an even bigger role in the future in detecting heart disease. Other tests available to doctors include intravascular ultrasound (IVUS), a catheter-based technique, which provides real-time, high-resolution images of the heart and its arteries. “The images are in four distinct colors to tell what kind of plaque is there,” Diethrich says. “We think that it is going to be very important because plaques differ a great deal. Some cause trouble and other plaques do not.”

Fletcher cautions that while the new tests hold tremendous promise, they should not replace the traditional screening tests. “We know that old-fashioned cholesterol and blood pressure are important and the American public is still not properly controlling these basic things to prevent CVD,” he says. “There is no easy way,” Fletcher says. “If you have high blood pressure and cholesterol and smoke or are overweight and sedentary, you need to address these risk factors before turning to new technologies,” he says. “Start with the basic things and then look for your calcium score or CRP.”

Applying precision technology to improve the detection of residual disease in cancer patients

“To mitigate the risk of recurrent disease, we often overtreat patients with stage II colorectal cancer based on pathological and clinical criteria, and physician choice. The clinical benefit for adjuvant therapy for these patients is modest,” said Joshua Cohen, co-founder and chief innovation officer at Haystack Oncology and a clinician researcher at Johns Hopkins University School of Medicine in Baltimore, Maryland.

“In stage III patients, the benefit of adjuvant treatment is undisputed, but we still need to know how aggressively these patients should be treated, as many receive a regimen that is not optimal.” Landmark MRD and beyond MRD testing can better stratify patients by risk of recurrence compared to the current standard of care because ctDNA provides higher-resolution detection of persistent disease in the post-surgical setting.

Patients for whom MRD is detected are likely to benefit from additional treatment, while patients for whom MRD is not detected are unlikely to recur, even without additional therapy. Ultimately, ensuring that patients who need therapy receive it, while also reducing overtreatment, greatly improves outcomes and quality of life and can reduce healthcare costs.

Beyond post-surgical evaluation, MRD testing can help inform other critical clinical decision points. For example, ctDNA testing allows clinicians to discern the effectiveness of treatment in real time so they can adapt therapy to match changes in disease burden. For patients who demonstrate no evidence of clinical disease, ctDNA can also be used to monitor molecular recurrence, which has been shown to precede recurrence detected by radiography, often with a significant lead time.

This early detection may present a window of opportunity where therapy can be applied when the greatest potential exists to eradicate cancer recurrence (Fig. 1). Chart showing how Haystack MRD offers superior information across all post-surgical clinical decision points Fig. 1 | Haystack MRD offers superior information across all post-surgical clinical decision points. “Every diagnostic is rooted in a biomarker. Many of the non-genetic biomarkers used in cancer aren’t sensitive or specific enough to accurately find all cases,” said Cohen.

“Because cancer is genetic at its core, detecting the mutations driving the disease can create a more potent diagnostic.” MRD can also be used to accelerate and streamline the clinical development of novel therapies. For instance, adjuvant trials can be enriched for subjects who are not successfully cured by surgery alone by enrolling only patients who are MRD-positive, rather than enrolling all-comers. This approach not only reduces the size of adjuvant trials but also allows easier visualization of therapeutic efficacy by excluding subjects for whom the disease is no longer present.

“Cancer clinical trials can take years. If we can select the patients who have residual disease, we may be able to conduct smaller trials and get faster results,” said Peter Gibbs, professor of medicine at The Walter and Eliza Hall Institute (WEHI) of Medical Research in Melbourne, Australia. Beyond systemic chemotherapy, MRD testing can help elucidate response to targeted agents such as kinase inhibitors and immuno-oncology therapies including checkpoint inhibitors and personalized cancer vaccines.

“As an example, in stage IV melanoma, the test would allow clinicians to gauge patient response to therapy with higher resolution than radiography, and to track the evolution of the tumor over time,” said Cohen. Seeing through the noise The primary challenge of ctDNA detection is the low level of tumor DNA in circulation compared to normal cell-free DNA from white blood cells. For every molecule of ctDNA, there may be a million or more normal DNA molecules that a test must search through to uncover the cancer-specific signal.

As difficult as ctDNA detection can be for late-stage disease, which is known to exhibit relatively high tumor DNA ‘shedding’ into circulation, one of the most challenging settings for reliable detection is in early-stage patients following curative-intent surgery. Non-metastatic patients are known to have less tumor-derived DNA present in their blood, a scarcity which is underscored after the primary tumor has been removed and there are few, if any, remaining tumor cells.

Therefore, a liquid biopsy–based test that is designed for MRD must employ a fundamentally different method than a test that is used for ctDNA detection in late-stage patients. Haystack’s Duo technology is the first next-generation sequencing method that was specifically designed for MRD for solid tumors. By offering significantly reduced technical noise compared to other next-generation sequencing (NGS) methods, even the lowest-level ctDNA signals stand out for reliable detection; in other words, exquisite specificity is what enables Haystack MRD’s unmatched sensitivity.

The test is personalized for each patient—tumor tissue is sent to Haystack for sequencing, and a bespoke Duo panel is built for each patient to assess up to 50 mutations that were identified in the tumor tissue. The test is then performed on patients’ blood samples to detect and measure ctDNA levels, which indicate the presence and quantity of residual, recurrent, or resistant disease.

“By taking a tumor sample and sequencing it, we know the ‘ground-truth’ mutations present for that individual patient’s cancer. This significantly increases our ability to find those known mutations in the blood, at the lowest levels,” said Cohen. Personalized MRD tests are designed to detect multiple tumor-informed mutations, with each mutation tracked representing another chance to detect ctDNA. However, each additional position sequenced can also introduce background noise that increasingly obscures accurate ctDNA detection.

This is why the primary purpose of Haystack Duo is to eliminate background noise—it ensures that the ctDNA signal increases faster than noise as additional mutations are tracked, resulting in improved sensitivity for MRD. In contrast, other tests that track 16 or even 1,800 mutations struggle to sift through elevated noise and must employ complex, proprietary methods to try to discern low-level ctDNA signals from background noise (Fig. 2).

High background noise limits the sensitivity of other MRD tests; as the false-negative rate increases, so does the risk that patients may not receive appropriate treatment. Graph showing the rate of noise increase versus mutations tracked Fig. 2 | Haystack Duo technology reduces background noise for better ctDNA detection in the MRD setting. The first prospective interventional trial for solid-tumor MRD The landmark DYNAMIC clinical trial for patients with stage II colon cancer was conducted at WEHI in Australia and Johns Hopkins Kimmel Cancer Center in the US; this represented the first prospective, randomized interventional MRD trial to generate practice-changing results.

“This was a paradigm-changing clinical trial. It showed that physicians could reduce adjuvant-chemotherapy use without compromising survival,” said Gibbs. Haystack’s Duo technology is based on the method developed by Cohen and others, led by Bert Vogelstein at Johns Hopkins University, and represents an evolution of the MRD detection method used in the DYNAMIC study. Regarding Haystack’s technology, Gibbs stated, “Duo is the culmination of decades of pioneering work in ctDNA and the only MRD [technology] to have been validated in randomized controlled trials.”

A new hope for early cancer detection — but is it reliable?

CORK GP Dr Nick Flynn didn’t think the lump in his right forearm looked nasty. This was four years ago and due to covid-related pressure on hospitals, he didn’t get the lump checked out until 12 months after he’d first spotted it.

“It turned out to be a sarcoma, which is normally severe. I was just very lucky mine wasn’t aggressive,” says Flynn.

On holiday abroad two years ago, he got a bout of food poisoning after which he spent a week in CUH. “During that week they incidentally found I had kidney cancer. I’d never have known but for the food poisoning.”

While a cancer diagnosis is never a happy thing, Flynn knows he has had a lot of luck and that, in a very personal way, he has experienced the importance of early cancer detection. He is now chief medical officer with Certior Health, a Blanchardstown-based company that has partnered with Indian cancer research company Datar Cancer Genetics, to provide a blood-based cancer-screening test called Trucheck.

“I’m the type of patient who will really benefit from this test, somebody asymptomatic with a silent cancer. With Trucheck you get an opportunity for early diagnosis where treatment’s most effective and less invasive,” says Flynn. Launched in Ireland in July 2023, the company claims the test can distinguish 70 types of cancers accounting for 81% of all cancer cases.

Daniella De PaulaDaniella De Paula Daniella De Paula, clinical scientist at Certior Health, explains that Trucheck evaluates blood samples to detect circulating tumour cells (CTCs) — cancer cells that escape from the tumour and enter the bloodstream. “It can detect solid tumours. It’s not intended to detect haematolymphoid cancers — tumours that affect the blood, bone marrow, lymph, and lymphatic system, such as leukaemia,” says De Paula. Flynn says screening programmes only cover 14% of cancers diagnosed in Ireland in any one year.

“Currently, 86% of cancers diagnosed aren’t subject to a screening test. The advantage of Trucheck is that it has the potential to detect 81% of cancers diagnosed in Ireland in any one year. It has a far broader scope than a screening test.” Trucheck is not the only new blood test promising early detection of cancer — several others are in various stages of development, chiefly in the US.

Examples are Guardant Health’s Shield blood test — according to the company’s website it is demonstrated to be accurate at detecting colorectal cancer — and Freenome’s blood-based test for early detection of lung cancer. Freenome is currently enrolling up to 20,000 individuals in a validation trial.

Grail’s Galleri test Some blood tests screen for multiple cancers (MCED — multi-cancer early detection) such as Exact Sciences’ Cancerguard, and Grail’s Galleri. Speaking to the Irish Examiner from Cleveland, Ohio, Dr Eric Klein, a scientist with healthcare company Grail which developed Galleri, says the MCED test is trying to fill a major unmet need: “In the US, we screen for five cancers: Breast, colorectal, cervical and prostate cancers, and lung cancer in smokers.

Explaining that the Galleri test is “designed to detect an array of cancers, including the 12 most aggressive that account for two-thirds of cancer deaths”, Klein says a study of the test in more than 6,000 “mostly asymptomatic” people found 1.5% of these participants had a cancer signal detected, and it found cancer in about 1% of participants including types for which there is no established screening method.

“The false positive rate for the test is 0.5% — meaning one in 200 people don’t actually have cancer, despite a cancer signal being detected,” says Klein. He compares it to a false positive rate for mammography, which he says is about 11%. Klein — who worked for 35 years in the field of urological cancers — says adding the Galleri MCED test to the cancer-detecting toolkit “doubled the numbers of cancers detected over standard-of-care screening”.

While different blood-based tests may each deploy different mechanisms for detecting cancer, the Galleri test works by looking for tiny fragments of cancer DNA in the bloodstream. The idea of using liquid biopsy for cancer detection — through blood, or potentially urine or saliva — has been around for decades, says Paul Mullan, professor of molecular oncology at Queen’s University Belfast (QUB):

“Advances in technology in the last five to 10 years mean we’re increasingly able to do it more sensitively and accurately, by being able to sequence low levels of tumour DNA circulating in blood. We’re able to detect mutations and methylation [a chemical modification of DNA] much quicker, and at much lower levels. Tests are much more sensitive, they may have many markers, or even measure different types of markers together, so we can get much more information back.”

Mullan says while tests like Galleri “look very promising”, there is a long way to go before they are accurate or sensitive enough to be rolled out in the general population: “Early detection of cancer, in particular, is a high bar to jump over. We cannot afford to make mistakes. And where you’re measuring methylation or mutation, the tumour may be so small and release such little signal that it’s going to be very difficult to detect.”

He also points to the complexity of the information coming back for analysis from some tests, which “may require specialist expertise that regular hospital labs may not have”. Not for general public Prof Lorraine O’Driscoll, research director at Trinity St James’s Cancer Institute, says while the emergence of MCED tests represents great hope, much more research is needed: “I think it’s very positive, but for the tests to be useful we’d want to be at the stage where regulators — FDA in the US, EMA in Europe and HPRA in Ireland — are saying: ‘Yes, we believe the evidence is strong enough now to take this on board’.”

Dr Antoinette Perry, associate professor in cell and molecular biology at UCD, also sees the tests as promising, but believes using them for early detection is very challenging: “If you look at the performance metrics for early stage detection for any kind of diagnostic test, you have ‘sensitivity’ — how good is it at catching people with the disease. And ‘specificity’ — how good is it at only catching people who have the disease and not giving false positives? “Looking at these tests, their sensitivity at picking up various cancers in the early stages is not very high.

On the other hand, their specificity tends to be quite high. Sensitivity is the issue, and the only way to address this is through different technological advancements that will get better at picking up really tiny tumour DNA or cells in the blood.” O’Driscoll would like the tests to be at the stage where health insurance companies are willing to reimburse the cost — these tests are expensive.

Galleri, for example, costs upwards of $900 and Trucheck, €1,450. Currently, says O’Driscoll, the tests are for “rich informed people but not the general public”. About 100 to 120 people here have taken the Trucheck test for cancer detection. “We’re looking to expand that through partnering with established medical organisations around Ireland,” says founder and director of Certior Health, Declan Malone. He confirms that 80% of those taking the test have a strong family history of cancer, while the remaining 20% “are proactive about preventive health”.

Work is being done on the development of such tests by scientists here, too. In 2022, the All-Ireland Cancer Liquid Biopsies Consortium (CLuB) — a collaboration between TCD, QUB and NUIG — was selected for funding under the North-South Research Programme of the Government’s Shared Island Fund. CLuB’s work is focused on identifying and developing minimally invasive, cost-effective blood tests to complement surgical biopsies for cancer diagnosis and treatment selection.

Mullan is the lead investigator on the QUB side of the collaboration: “We’re very interested in liquid biopsy — blood detection — of cancers, particularly the difficult-to-diagnose ones: Ovarian, pancreatic, lung, triple-negative breast cancer. The stage of detection for a lot of these cancers can be quite late when it has had more chance to spread and develop resistance to treatment.

Mullan says their work is most advanced in developing a blood test for ovarian cancer detection: “It’s a PCR-type test, a bit like some covid tests. It looks at a few different markers at the same time, focusing on changes in DNA methylation.” A spin-off company from QUB, Genome Diagnostics, is currently developing the test (called OvaME). “We’re hoping the finalised test will arrive towards the end of 2024. Then it has to be tested — validated in many independent samples — so it’s a long process.

As to when it will be released publicly, there’s no timeframe at present.” O’Driscoll leads the TCD side of the collaborative research CLuB group. While Mullan’s team in QUB is looking at DNA in blood samples donated by patients, O’Driscoll’s team is examining extracellular vesicles (EVs) in the same blood samples. “EVS are little packages of information that are released from cancer cells into the blood, like little mini-maps of the cancer,” she says.

A third element involves a research group studying circulating tumour cells (CTCs), breakaway cells from the tumour and in the bloodstream. O’Driscoll says studying three component parts from the same blood samples gives much more information than would be garnered by studying just one alone.

“We’re not going after one single thing, hoping that has all the answers. We’re studying everything being released into the blood by the tumour,” she says. A fourth group in Galway is “doing big data and number crunching” around the massive amounts of information generated, says O’Driscoll. It is also looking at “which component part gives the strongest signal for cancer.” Mullan says the combined approach could allow researchers to detect cancers earlier and more accurately, ultimately improving patient survival rates long-term.

“Blood is a richer source because the tumour cell is releasing a lot of information into it,” she says, adding that tissue biopsy is time-consuming, must be done in a hospital setting and isn’t easily repeated (unlike blood tests). The only drawback, says O’Driscoll, is that early cancer-detecting blood tests are not yet reliable enough: “More big-study research is needed to get to that point.”

She predicts a different timeline for different cancers: “For some in the next five years — but to complement tissue biopsy, not to replace it. For others, probably more than a decade.” O’Driscoll has a vision: “That the person at the tip of Kerry or Derry can have a blood test taken by a nurse locally and sent in [for analysis]. But we have to be comfortable that the tests are reliable, the best possible.

When that happens, I think it’ll be a game-changer.” Valerie Caro, ArizonaValerie Caro, Arizona A tumour was found but I had no symptoms Arizona-based Valerie Caro, aged 56, read about the Galleri test in 2022. Speaking to the Irish Examiner, she says: “I do conventional screening, but thought it [would be] great to have a baseline for other cancers with a simple blood test. “I received my results in about 10 days. I was called by two doctors who informed me a cancer signal [had been] detected in my gall bladder or pancreas.

The next step was to get an MRI. The MRI didn’t show cancer, but the radiologist said my gall bladder was ‘angry’ and needed to come out. “After the pathology report, it was confirmed I had a 4.5cm cancerous tumour in my gall bladder. I had no symptoms. I was surprised because cancer doesn’t run in my family. “I had a second surgery to confirm all cancer was removed around the gall bladder. Then I went through a six-month chemotherapy cycle as insurance that all cancer cells were gone. “I’m great now, my life is active. I meet with my care team twice a year to confirm I’m cancer-free.

Conclusion