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Improving RISK stratification in hypertensive heart disease: What is in the horizon?
Hypertension is a major contributor to heart failure and other cardiovascular complications. Integrating markers of adverse myocardial features (fibrosis and exaggerated hypertrophy) in hypertension management may improve risk stratification and informed therapeutic options for hypertensive patients, says Asst Prof Calvin Woon Loong Chin.

The burden of heart failure is a global pandemic. An estimated 26 million people are living with heart failure worldwide, of which nine million are in Southeast Asia (Savarese 2017). Despite substantial improvement in therapeutic strategies, heart failure remains a leading cause of death worldwide, indicating an urgent need for innovative approaches to risk stratification and treatment (Ponikowski 2016).

In major heart failure trials, the prevalence of hypertension is reported to be as high as 80% (Lam 2014; McMurray 2014). Indeed, hypertension remains one of the most important preventable contributors to cardiovascular disease and death. In Singapore, one in every two Singaporeans older than 60 years has hypertension and it is one of the major contributors to the total burden of cardiovascular diseases in Singapore. As life expectancy of the ageing population increases, hypertensive heart disease is expected to impose an increasing burden on the healthcare system.

Current challenges in managing hypertensive heart disease

Currently, the diagnosis and management of hypertension relies primarily on the accurate assessment of peripheral arterial pressure. However, the challenges associated with all non-invasive techniques of measuring blood pressure are well recognised (Marshall 2004; Pater 2005). Significant variability and inaccurate measurements exceeding 15mmHg have been reported; this leads to diagnostic misclassification and inappropriate treatment in some patients (Campbell 1994). Contemporary management of hypertension places great emphasis on achieving blood pressure targets, but the specific targets (particularly in older patients) remain controversial and differ among major cardiovascular societies (Table 1; Mancia 2013; James 2014; Weber 2014; Whelton 2017). Adding to this complexity, a more recent trial demonstrated a significant reduction in mortality in patients (including those more than 75 years old) who were intensely treated to achieve systolic arterial pressures of less than 120mmHg (Wright 2015), challenging these new targets and increasing uncertainty amongst physicians. The ambiguity of optimal blood pressure targets coupled with the inherent limitations of measuring peripheral blood pressure signal a critical need of a more reliable marker to monitor progression and assess treatment response in patients with hypertensive heart disease.

Rationale to focus on the myocardium

In response to the increased arterial pressure and wall stress, the myocardial wall thickens to maintain cardiac function. This process is initially adaptive. With time, the left ventricle (LV) decompensates and ultimately, heart failure ensues. The transition from adaptation to decompensation is mediated by myocyte death and myocardial fibrosis (Hein 2003).

Myocardial fibrosis (defined as an increased in collagen accumulation in the myocardial tissue) is the final common pathology in most chronic causes of heart failure. Myocardial biopsy remains the gold standard for assessing fibrosis. However, it is invasive, susceptible to sampling errors and unable to assess the fibrotic burden of the whole heart. Instead, contrast-enhanced cardiovascular magnetic resonance (CMR) is currently the only non-invasive approach for diagnosing and quantifying myocardial fibrosis. Newer CMR techniques such as myocardial T1 mapping improve sensitivity and reproducibility of quantifying fibrosis that has been validated with fibrosis on histology (Chin 2016; Figure 1).

Indeed, fibrosis on CMR predicts an adverse prognosis in ischaemic and non-ischaemic causes of heart disease. For instance, about 30% of patients with dilated cardiomyopathy and myocardial fibrosis died over five years of follow-up (Gulati 2013). Similarly, about 19% of patients with aortic stenosis (another common cardiac disease causing myocardial hypertrophy and heart failure in the adult population) and myocardial fibrosis died within two years (Dweck 2011).

Remodelling Index: Marker to improve risk stratification in hypertensive heart disease

Hypertensive heart disease is defined as a clinical syndrome characterised by left ventricular hypertrophy, systolic and diastolic dysfunction and evidence of heart failure (Drazner 2011). By definition, this is a late-stage diagnosis. The point where adaptive LV hypertrophy decompensates to heart failure in hypertensive heart disease is not well defined, and it is an area of emerging interest so that management can be prioritised to retard or arrest heart failure.

To address this, we have recently developed a novel CMR index (Remodelling Index; Figure 2) based on the LaPlace's Law of wall stress (σ):

where P is the LV pressure, R is the LV radius and t is the myocardial wall thickness. Assuming the LV to be spherical, LV volume is related to radius,

Substituting equation (3) into equation (1), we have:

as the Remodelling Index that describes the geometric relationship between LV EDV and wall thickness, and it is proportionate to the myocardial wall stress
(σ∝P.RI ). A normal age and sex specific reference range for the Remodelling Index was established in 180 healthy volunteers (Goh 2017). Subsequently, we applied this Index to a cohort of 256 hypertensive patients. Increasing hypertrophy was associated with progressive reduction in the Index because of increased wall thickening. Despite the absence of heart failure symptoms, hypertensive patients with abnormally low Remodelling Index had increased LV mass and fibrosis volume measured on CMR. Circulating markers of myocardial injury and heart failure were also elevated in hypertensive patients with abnormally low Remodelling Index. This Index therefore holds potential in defining the transition before heart failure occurs in hypertensive patients with myocardial hypertrophy. Our next step is to examine the prognostic value of the Remodelling Index in predicting progression of adverse myocardial remodelling and adverse outcomes in hypertensive patients.

Impact on hypertension management and therapies

It is well established that different classes of anti-hypertensive medications do not have the same effects on the myocardium. The myocardial interstitium is an attractive treatment target because the apparent amelioration of myocardial fibrosis improves outcomes. Upregulation of the renin-angiotensin-aldosterone system (RAAS) is a major determinant of LV hypertrophy and myocardial fibrosis. In limited studies, angiotensin converting enzyme inhibitors and angiotensin II receptor blockers have demonstrated encouraging potential in regressing myocardial fibrosis (Brilla 2000; Diez 2002) with some indication that mineralocorticoid receptor antagonists may also foster reverse remodelling in heart failure (Zannad 2012; Pandey 2015).

The important relationship between the myocardium and blood pressure justifies a paradigm shift in the management of hypertensive heart disease. Integrating myocardial assessment in hypertension management will improve risk stratification and informed management of hypertensive patients beyond simply considering blood pressure in isolation. Future clinical trials guided by imaging driven endpoints (or other reliable markers) of fibrosis will help physicians develop better treatment strategies.


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About the Author

Asst Prof Calvin Chin
Department of Cardiology
National Heart Centre Singapore

Asst Prof Calvin Chin is a Consultant with the Department of Cardiology at the National Heart Centre Singapore, and an Assistant Professor at the Duke-NUS Medical School. Having a sub-specialty interest in echocardiography, Asst Prof Chin is certified in echocardiography and cardiovascular magnetic resonance imaging. Asst Prof Chin graduated from Loma Linda University, California, USA, in 2003 and completed his cardiology training at the National Heart Centre Singapore in 2012. With the support from the National Medical Research Council (NMRC), he completed the Master of Clinical Investigation at the University of Singapore and a PhD programme at the University of Edinburgh in 2010 and 2015 respectively.

Recently, he was awarded the Transition Award by the NMRC for his research in the mechanisms mediating myocardial hypertrophy and fibrosis in patients with hypertensive heart disease, using non-invasive imaging techniques and biochemical markers. Asst Prof Chin has also received several other national and international awards in recognition of his research, including the American College of Cardiology Young Investigator Award (2015), British Heart Valve Society Young Investigator Award (2015) and the SingHealth Publish Award (2015 and 2016).

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