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Tectonic Bets On GPCR Heart Failure Drug Following Reverse Merger With Avrobio
Tectonic Therapeutic has completed a reverse merger with Avrobio and will begin trading on the Nasdaq global market as Tectonic Therapeutic (ticker symbol 'TECX') on 21 June.
Coinciding with the merger, the new company also completed a private placement of $130.7m with multiple US and European investors. Following the placement, Tectonic reported total cash reserves of $181m, before payment of final transaction-related expenses, which is expected to fund operations until mid-2027.
As part of the merger, Avrobio enacted a 1-for-12 reverse stock split of its common shares, along with an issuance of a non-transferable contingent value right. Under that, shareholders will have the rights to cash payments received by Tectonic, if any, related to Avrobio's pre-transaction legacy assets.
Avrobio's stockholders will own approximately 24.8% of the new company while old Tectonic shareholders, including the investors in the private placement, will hold 75.2% of the combined company's outstanding common stock. The merged company's stock debuted at a share price of $16.80 on the Nasdaq.
The companies first announced the merger back in January, prompted by Avrobio's cash-strapped coffers. The company's money woes started last year when it stopped development work on its gene therapy programmes. Avrobio also sold its investigational haematopoietic stem cell (HSC) gene therapy programme, designed to treat cystinosis, to Novartis in an all-cash deal valued at $87.5m.
Tectonic's lead asset, TX000045 (TX45), is a G protein-coupled receptor (GCPR) targeting the Fc-relaxin fusion molecule. It activates relaxin family peptide receptor 1 (RXFP1) in cardiovascular cells and its overexpression can have a cardioprotective effect. The therapy is being evaluated in a Phase Ia trial in patients with group 2 pulmonary hypertension due to left-sided heart disease, one of the most common forms of pulmonary hypertension.
"We expect to initiate a randomised Phase II clinical trial for our lead program, TX45, in group 2 pulmonary hypertension in the setting of left heart disease with preserved ejection fraction in the second half of this year," said Dr Alise Reicin, president and CEO of Tectonic.
"Results from the ongoing Phase Ia clinical trial in this patient population are expected in mid-2024, to be followed by Phase Ib results expected in 2025 and results from the Phase II clinical trial expected in 2026."
The company's second programme targets hereditary haemorrhagic telangiectasia (HHT), a genetic bleeding disorder that causes vessel enlargement and malformations. Tectonic plans to select a development asset for HHT later this year and start clinical trials in the fourth quarter (Q4) of 2025 or Q1 2026.
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"Tectonic bets on GPCR heart failure drug following reverse merger with Avrobio" was originally created and published by Clinical Trials Arena, a GlobalData owned brand.
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Study Reveals Link Between Protein In Skeletal Muscle And PH-HFpEF
A SIRT3 protein deficiency in skeletal muscles, which are attached to bones, was related to pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF), a study shows.
A lack of SIRT3 triggered the release of LOXL2, a protein that promotes lung tissue scarring, which stimulated the CNPY2 pathway related to the thickening of pulmonary arteries and PH. Suppressing LOXL2 improved PH signs in a mouse model.
The findings identify skeletal muscle SIRT3, LOXL2, and CNPY2 in the pulmonary vasculature as potential molecular targets for developing PH-HFpEF therapies, a research team led by scientists at the Indiana University School of Medicine wrote in "Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction," which was published in Circulation.
PH is a major complication in heart failure with preserved ejection fraction (HFpEF), which is when patients have heart failure, but the percentage of blood pumped out of the left ventricle with each heartbeat is normal or near normal. PH in HFpEF develops due to stiffness in the muscles of the left side of the heart and an inability to meet the body's demands.
SIRT3 and PH-HFpEF severityUsing a rat model of PH-HFpEF, researchers discovered decreased levels of the enzyme SIRT3 (Sirtuin 3) in skeletal muscles, which are attached to bones and are responsible for voluntary movements.
What stood out, however, was that SIRT3 levels were normal in the muscles of the heart and the pulmonary arteries. Also, restoring SIRT3 in skeletal muscle reduced PH-HFpEF severity, "indicating a critical role of skeletal muscle SIRT3 in regulating pulmonary vascular remodeling and PH-HFpEF," said the researchers, who selectively deleted SIRT3 from the skeletal muscles of mice and assessed PH-related parameters and tissues to better understand the connection between SIRT3 and PH-HFpEF.
Without SIRT3, mice had elevated pulmonary blood pressure, increased pulmonary vascular remodeling, and fewer pulmonary arteries per area of lung tissue.
Molecular experiments revealed that SIRT3-deficient skeletal muscle cells secreted LOXL2, a protein that promotes lung tissue scarring and drives lung diseases like idiopathic pulmonary fibrosis (IPF). In fact, LOXL2 is a potential biomarker and a therapeutic target for IPF. At the same time, LOXL2 was significantly higher in the bloodstream of mice without SIRT3 and a rat model of PH-HFpEF.
More importantly, people with PH-HFpEF had elevated levels of LOXL2 in their bloodstream compared with unaffected people. Consistently, muscle biopsies of PH-HFpEF patients had higher LOXL2 production alongside reduced SIRT3, compared to HFpEF patients without PH.
Treating lung tissue isolated from mice with lab-made LOXL2 triggered the increase of several proteins, particularly CNPY2, which was also significantly elevated in the lungs of a rat model of PH-HFpEF. CNPY2 has recently been identified as an initiator of the unfolded protein response pathway, a protein quality-control mechanism, and was found to promote tumor growth.
LOXL2 treatment also significantly increased CNPY2 in cultured human pulmonary artery endothelial cells (PAECs), which line the arteries, and pulmonary artery smooth muscle cells (PASMCs), which surround and provide structure to PAECs. Furthermore, LOXL2, via the CNPY2 pathways, stimulated PAEC migration and the growth of both PAECs and PASMCs.
Lastly, the researchers selectively deleted LOXL2 from mice skeletal muscles. To induce PH-HFpEF, the mice were fed a high-fat diet, which reduces SIRT3 in skeletal muscle and leads to developing PH-HFpEF associated with metabolic syndrome, a group of risk factors specific to cardiovascular disease.
Mice lacking skeletal muscle-secreted LOXL2 had decreased CNPY2 and eased PH, results showed. Consistent with these data, blocking LOXL2 with a small molecule also eased PH signs via CNPY2 in PAECs and PASMCs, compared with mice fed with a high-fat diet alone.
"Our studies have uncovered several processes by which skeletal muscle SIRT3 deficiency can affect pulmonary vascular health in PH-HFpEF," the researchers said. "Our findings also provide new insights into the mechanistic basis of the skeletal muscle-lung communication and identify skeletal muscle SIRT3, [LOXL2], and CNPY2 in the pulmonary vasculature as potential molecular targets for the development of therapeutic treatments in PH-HFpEF."
How To Conduct A Cardiovascular Assessment In Advanced Practice
Read this article to learn how to conduct an advanced cardiovascular assessment to reveal heart abnormalities and associated symptoms and risk factors
AbstractCardiovascular disease remains one of the leading causes of death in developed countries, accounting for a quarter of UK deaths and morbidity. A cardiovascular assessment can reveal cardiac abnormalities and give an understanding of associated symptoms and risk factors to aid early diagnosis. This article, the sixth in a series on assessment and interpretation for advanced clinical practitioners, shows how to take an accurate history and complete a structured physical examination. This includes inspection, palpation and auscultation of the heart, arteries and veins.
Citation: Coaten J, North Z (2024) How to conduct a cardiovascular assessment in advanced practice. Nursing Times [online]; 120: 7.
Authors: Josey-Marie Coaten is programme leader MSc advanced clinical practice and Zach North is MSc head of school: paramedical, peri-operative and advanced practice (interim); both at the University of Hull.
The cardiovascular system comprises the heart and a network of blood vessels (Waugh and Grant 2022). Its function is to distribute oxygen to the cells of the body and remove waste products such as carbon dioxide (Martini et al, 2018).
The heart is hollow with four chambers and four valves (Fig 1) and sits in the thoracic cavity between the lungs and mediastinum. Deoxygenated blood from the right side of the heart is pumped to the lungs where gas exchange takes place. Carbon dioxide diffuses into the alveoli and is subsequently exhaled as a waste product; the blood also collects and transports oxygen to oxygenate cells in the body (Waugh and Grant, 2022).
In the cardiovascular system, veins carry blood to the heart and arteries carry it away, with capillaries being the gas exchange point for oxygen and carbon dioxide (Waugh and Grant, 2022). Blood enters the right atrium of the heart via the superior and inferior vena cava, before moving into the right ventricle via the tricuspid valve. It is then pumped through the pulmonary valve into the pulmonary artery and then the lungs for gas exchange. Blood from the lungs travels into the left atrium then goes through the mitral valve into the left ventricle, where it passes through the aortic valve and is pumped to the rest of the body via the aorta (Martini et al, 2018).
The heart wall is made up of three layers:
A specialist group of cells emit impulses that ensure atrial and ventricular contraction, allowing blood to be pumped through the heart and around the body (Innes et al, 2023).
History takingCardiovascular disease remains one of the leading causes of death in developed countries, accounting for a quarter of UK deaths and morbidity (National Institute for Health and Care Excellence (NICE), 2023). Taking a comprehensive history is essential to explore the patient's symptoms and risk factors, and determine their likely cause and whether it the problem originates within the heart or cardiovascular system (Kumar and Clark, 2020).
IntroductionFor every patient encounter, first introduce yourself and your role, and anyone else present. Confident and appropriate introductions can help build the much-needed rapport between practitioner and patient (Peart, 2022).
Start by using open questioning (for example, "How can I help today?") to allow patients to give their version of their complaint; this can also help patients feel valued and listened to (Peart, 2022). Closed questions are often only used for clarification (for example, "So the pain is in the centre of your chest?").
Presenting complaintAs cardiovascular conditions can be life-threatening, ensure you fully explore each presenting symptom (NICE, 2023). Using a mnemonic such as SOCRATES, adapting it for the specific presentation, gives a framework to the practitioner and allows a systematic approach (Simon et al, 2020) (see article in this series on history taking).
Past medical historyBuilding a picture of the patient and their past medical history will help determine any specific risk factors; for example, hypertension, high cholesterol or type 2 diabetes increase the risk of cardiovascular disease (Innes et al, 2023). Some connective tissue diseases also have specific links and risk factors; for example, Marfan syndrome carries an increased risk of aortic dissection.
Drug historyMany prescribed, herbal or over-the-counter medications can cause or aggravate cardiovascular symptoms (Kumar and Clark, 2017). For example, amlodipine used to treat hypertension may cause ankle oedema, beta blockers for asthma may cause breathlessness and thyroxine may cause arrythmias, so ensure you explore medications the patient is taking and their potential side-effects (Innes et al, 2023).
Family historyhe risk of cardiovascular disease is higher in patients with a family history (NHS, 2022). For example, cardiomyopathies (diseases of the heart wall) are often genetic; note that a family history of cardiovascular disease or sudden unexplained deaths may increase the risk of cardiomyopathies or arrythmias in younger people (<55 years) (Kumar and Clark, 2020). Another risk factor for cardiovascular disease is a history of familial hypercholesterolemia (high cholesterol) (Innes, et al, 2023). Make sure you consider ethnicity, as people from South Asian, Black African or African Carribean backgrounds are more likely to develop hypertension or type 2 diabetes, already noted as risk factors (NHS, 2022).
Social historyTaking a social history includes lifestyle and environmental factors. Table 1 highlights elements to consider.
Systems review As well as presenting symptoms, you will also need to review other bodily systems for associated symptoms the patient may not have mentioned. This can also help identify any red flags that need to be dealt with urgently.
For cardiovascular symptoms, ask about oedema and shortness of breath, as this could indicate heart failure (Kumar and Clark, 2020). Dizziness and vasovagal episodes (faints) could suggest aortic stenosis, while hypotension, postural hypotension or calf pain when walking could indicate peripheral vascular disease (Kumar and Clark, 2020). Table 2 gives a general overview of cardiovascular symptoms.
Cardiovascular examination The next step is to examine the patient. Before you start:
The clinical examination should be structured and follow an inspect, palpate and auscultate format (Bickley, 2020).
Initial inspectionStart by gaining an overall impression of the health of the patient. Measure and assess the patient's vital signs – blood pressure, heart rate, oxygen saturation, respiratory rate and overall level of consciousness – as this will provide vital information and enable you to assess the urgency of the patient's presentation (Penman et al, 2023). Check for signs of visible pain, distress or confusion, cyanosis (blue hue around the mouth or extremities), pallor (lighter skin complexion than is usual), shortness of breath, sweating or oedema.
For the acutely deteriorating patient, you will need to take a more urgent approach, such as the ABCDE (airway, breathing, circulation, disability, exposure) approach for assessing and treating critically ill patients (RCUK, 2021).
This article describes the approach to take for a non-deteriorating patient.
Inspect the handsAssess the patient's hands, correlating any clinical signs with others in your examination and the patient's history. Certain abnormalities can suggest cardiovascular disease but may also be found in other disease processes.
Temperature and colourCompare the temperature of both hands. Cold hands might suggest peripheral vasoconstriction (narrowing of the blood vessels) as in patients with hypertension.
Cyanosis (bluish tint to the skin) can suggest poor circulation or deoxygenated blood, which can be due to heart failure or congenital heart diseases.
Capillary refill timeAssess peripheral perfusion and cardiac output by pressing down on a fingernail until it turns white for approximately 5 seconds, then releasing. The pink colour should return in less than 2 seconds. A prolonged capillary refill time could suggest poor perfusion or hypoxia, which can be due to heart failure or shock.
Finger clubbingA bulbous enlargement of the distal phalanges of the fingers and toes, while often associated with lung diseases, can be seen in certain cardiovascular conditions like infective endocarditis, heart failure and atrial myxoma.
Splinter haemorrhagesTiny blood clots running vertically under the nails can be seen in infective endocarditis and can be caused by trauma to the nail bed.
Janeway lesionsNon-tender and small, red nodular lesions on the palms or soles of the feet are indicative of infective endocarditis.
Osler nodesTender nodules found on the fingertips or toes are associated with infective endocarditis.
Palmar erythemaReddening of the palms can be a sign of liver disease, which can affect the heart or be a consequence of right heart failure.
XanthomasYellow, fatty deposits often found on the elbows, knees, or palms might suggest hyperlipidemia (high cholesterol or triglycerides), which is a risk factor for atherosclerotic cardiovascular disease.
Inspect the faceCarefully inspect the face, including eyes, mouth and lips:
Colour
Eyes
Mouth and lips
The JVP can give a visual representation of the pressures in the right atrium. This can be used to understand the function of the right side of the heart, fluid status (such as overload or hypovolemia) and pathologies such as tricuspid valve disease, cardiac tamponade (fluid build-up in the sac around the heart) and superior vena cava obstruction. To check the patient's JVP:
Interpretating the JVP can be challenging, so seek advice from a senior colleague if need be. A raised JVP (>4cm) can be seen in conditions where the right side of the heart is not pumping blood efficiently into the pulmonary circulation, such as right heart failure, tricuspid valve disease, pulmonary hypertension or cardiac tamponade (Kumar and Clark, 2020).
Assessing the pulsesPulses are palpable wave forms in the arteries as a result of systole, where the beating heart forces blood from the left ventricle through the aortic valve into the aorta and onwards to the rest of the body (Agur and Dalley, 2023). Assessing the pulses allows assessment of the rate (beats/min), rhythm (regular or irregular) and volume/character (strength and quality) of the pulse (Innes et al, 2023). There are three general principles to consider when assessing the pulses:
First palpate the radial pulses - the six pulses in the arms, legs and feet. Start by assessing rate, followed by rhythm and finally volume/character, comparing right and left extremities (Innes et al, 2023). Table 3 describes radial pulse locations and reasons for assessment.
Next assess the carotid pulse. There are two carotid arteries on either side of the neck but these should never be palpated simultaneously as this could restrict blood flow to the brain.
Prior to palpating, first auscultate each artery. Use the diaphragm of your stethoscope to listen to high frequency sounds and the bell to listen to low frequency sounds (Innes et al, 2020). If the patient's carotid arteries are normal, you may not hear anything. In this case it is fine to palpate the carotid artery. Conversely, an audible sound on auscultation due to turbulent blood flow may indicate a bruit (Penman et al, 2023). This can be caused by plaques in the artery or aortic stenosis (narrowing of the artery), which can lead to stroke (Penman et al, 2023). If a bruit is detected do not palpate as there may be a risk of loosening a plaque and causing a stroke.
Auscultation and palpation of the heartPalpation gives information about the position, size and activity of the heart (Innes et al, 2020). From this, it is also possible to assess any abnormal masses or pain from trauma.
The heart has four valves (aortic, pulmonary, tricuspid and mitral). Placement of the hands or stethoscope to assess a particular valve is not where the valve is located anatomically but is in the direction of blood flow to or from the valve (Kumar and Clark, 2020).
AuscultationTo auscultate the heart valves, use both the diaphragm (high frequency sounds) and the bell (low frequency sounds) of the stethoscope, as this will give a more accurate assessment. Assessment points are as follows:
Be systematic and take your time. It helps to have a quiet environment, as sometimes heart sounds can be quite difficult to distinguish. If you are struggling to hear over the patient's breathing, consider asking them to hold their breath for a few seconds (Talley and O'Connor, 2022).
The terms S1 and S2 are often used in relation to heart auscultation. These refer to the sound the heart makes ('lub, dub, lub, dub') when the valves snap shut (Kumar et al, 2020). S1 is the 'lub' sound produced by the closure of the mitral and tricuspid valve, and S2 is the 'dub' sound generated by the closure of the aortic and pulmonary valve.
While you auscultate, try to identify S1 and then S2. Then look out for added sounds, which may signify abnormalities. These are commonly called S3 and S4 and are explained below:
You may also hear a murmur. Murmurs are due to turbulent blood flow, which causes a sound that is audible with a stethoscope (or in severe cases, without one). There are three main causes of murmurs:
Once you have heard a murmur, if you or a colleague are experienced enough, you should try to classify it (Talley and O'Connor, 2022) (Box 1).
Box 1. Classification of heart murmurs
Timing in the cardiac cycle
Intensity (grade 1-6)
Quality
Descriptions such as 'blowing', 'harsh', 'rumbling', or 'musical' can be used
Location
The best place on the chest to hear the loudest component
Source: Innes et al (2023)
PalpationEnsure the patient is supine and at a 45-degree angle; this helps palpation by bringing the heart closer to the chest wall (Penman et al, 2023). Palpate the following:
Auscultation of the lung fields are important in the assessment of the cardiovascular system. The technique of auscultation of the respiratory system has been covered already in this series. However, in the context of the cardiovascular system we are looking for crackles. These are short, high-pitched sounds heard more commonly on inspiration (Bickley, 2020). In the context of cardiovascular disease, they often indicate fluid overload or heart failure, especially when heard at the lung bases (Bickley, 2020).
Wheezing, although common in respiratory conditions such as asthma, can also be present in heart failure where there is significant pulmonary oedema (Bickley, 2020).
Assessment of oedemaPeripheral oedema is swelling of the ankles, feet, legs and sacrum caused by a build-up of fluid. Causes can range from standing or sitting in the same position for too long, to renal or liver disease and malnutrition (Kumar and Clark, 2020). Bilateral oedema is often a sign of systemic fluid overload and is seen in right-sided heart failure (Kumar and Clark, 2020).
If oedema is apparent on inspection, palpate by pressing gently but firmly with your thumb on the bony area and holding for a couple of seconds. This will determine if the oedema is pitting (pressure leaves a lasting indentation or pit) or non-pitting (pressure leaves no lasting indentation) as pitting oedema is more likely to be a sign of liver, heart or kidney problems.
InvestigationsFollowing on from the history and clinical examination, advanced nurse practitioners may choose a watch and wait approach or consider investigating further to confirm a diagnosis.
Table 4 details common investigations of cardiac disease.
Conclusion As heart disease is highly prevalent and a leading cause of morbidity and mortality, advanced nurse practitioners need to be competent in conducting cardiovascular assessments. Taking a thorough history is important and the clinical examination should be structured and follow an inspect, palpate and auscultate format. If in doubt, refer to a specialist.
Advanced practitionersThis series is aimed at nurses and midwives working at, or towards, advanced practice. Advanced practitioners are educated at master's level and are assessed as competent to make autonomous decisions in assessing, diagnosing and treating patients. Advanced assessment and interpretation is based on a medical model, and the role of advanced practitioners is to integrate this into a holistic package of care.
Professional responsibilitiesThis procedure should be undertaken only after approved training, supervised practice and competency assessment, and carried out in accordance with local policies and protocols.
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