Targeting the myocardium in hypertensive left ventricular hypertrophy

KEYWORDS:

• Heart failure
• hypertensive heart disease
• left ventricular hypertrophy
• myocardial fibrosis

The diagnosis and management of hypertension rely primarily on the accurate assessment of peripheral arterial pressure. However, the challenges associated with all noninvasive techniques of measuring blood pressure are well recognized. Significant variability and inaccurate measurements exceeding 15 mmHg have been documented, leading to diagnostic misclassification and inappropriate treatment for some patients [1,2]. Contemporary management of hypertension places great emphasis on achieving blood pressure targets, but specific targets (particularly in elderly patients) remain controversial [3–5]. Compared to previous recommendations, less stringent but different blood pressure targets were recently proposed by all major organizations. Adding to this complexity, a more recent trial demonstrated significant reduction in mortality in patients (including those >75 years old) intensely treated to achieve systolic blood pressure <120 mmHg, challenging the new targets and increasing uncertainty among physicians [6].

The ambiguity of optimal blood pressure targets coupled with the inherent limitations of measuring peripheral arterial pressure signals a critical need of a more reliable marker to monitor disease progression and assess treatment response in patients with hypertensive heart disease. In vulnerable hypertensive patients, the myocardium hypertrophies in response to elevated arterial pressure. These changes are initially adaptive by minimizing wall stress and maintaining cardiac output and function. As the disease progresses, the left ventricle decompensates and ultimately, the heart fails [7]. Two processes drive this transition from ventricular adaptation to decompensation: (1) myocyte dysfunction/death and (2) myocardial fibrosis [8]. Myocardial fibrosis, defined as an increase in collagen volume fraction of myocardial tissue, is a final common pathway in most chronic causes of heart failure [9]; and it is associated with impaired cardiac performance and adverse outcomes in a variety of cardiac conditions [10–14]. The development and persistence of left ventricular hypertrophy demonstrated important association with not only arterial blood pressures but also common comorbidities such as increased body mass index, metabolic syndrome, and obstructive sleep apnea [15–17].

Conventionally, four patterns of left ventricular geometry have been described: normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy [18]. Although concentric and eccentric hypertrophies are associated with adverse outcomes, ventricular geometric patterns have limited incremental value when myocardial mass and other cardiovascular factors are considered [19–23]. Recently, a more complex classification based on left ventricular mass, concentricity, and end-diastolic volume was proposed: normal, concentric dilated/non-dilated left ventricle, and eccentric dilated/non-dilated left ventricle [24]. All patterns of hypertrophy, except eccentric non-dilated hypertrophy, were associated with worse outcomes [25].

Myocardial biopsy remains the gold standard for assessing myocardial fibrosis. However, it is invasive, susceptible to sampling errors and unable to assess the fibrotic burden of the whole heart. Unfortunately, circulating markers of fibrosis (such as markers of collagen metabolism and galectin-3) lack sensitivity and specificity. The use of gadolinium contrast in cardiovascular magnetic resonance has dramatically improved tissue characterization of the myocardium. Indeed, contrast-enhanced cardiovascular magnetic resonance is currently the only noninvasive approach of diagnosing and quantifying myocardial fibrosis. Recent novel myocardial T1 mapping techniques further allowed quantification of abnormal extracellular volume expansion due to collagen accumulation. Such techniques demonstrated excellent reproducibility and they have been validated against histological fibrosis [14,26].

While excessive left ventricular hypertrophy in hypertensive heart disease carries an increased risk of cardiac events, regression of left ventricular hypertrophy is associated with improved outcomes [19,27–30]. Importantly, the increased cardiovascular risk directly relates to the extent of myocardial hypertrophy, in excess of blood pressure. Of note, the correlation between peripheral blood pressure and left ventricular mass is modest, particularly in treated individuals [31,32]. In addition to more aggressive blood pressure control, the management of other metabolic aspects is just as critical in the regression of left ventricular hypertrophy [33]. For these reasons, it is perhaps not surprising that recommending optimal blood pressure targets in hypertensive patients with left ventricular hypertrophy is challenging, again underscoring the limitations of using peripheral blood pressure as treatment goals and the complexity of ventricular remodeling in hypertensive heart disease. The mechanisms and mediators as well as the long-term prognosis associated with ventricular remodeling (including myocardial fibrosis) in hypertensive heart disease are currently being examined in an ongoing prospective study (Response of the Myocardium in Hypertrophic Conditions in the Adult Population [REMODEL]; clinicaltrials.gov identifier: NCT02670031).

Stratified and personalized treatment aims at improving the classification of advanced disease that reflects the specific biology in order to better guide targeted therapies. This is particularly relevant in hypertensive heart disease and heart failure. While heart failure is more commonly known by the signs and symptoms related to impaired systolic function, heart failure with preserved ejection fraction (HFpEF) is an increasingly recognized complex entity characterized by the clinical syndrome of heart failure in the presence of preserved left ventricular ejection fraction [34]. To date, therapies that improve outcomes in heart failure with reduced ejection fraction (HFrEF) have not unequivocally shown similar benefits in patients with HFpEF. There is no single explanation for these negative findings, but one potential reason may relate to the heterogeneity of patients recruited in these trials, and thus supporting a more targeted approach to specific phenotypes rather than a standard treatment strategy for all HFpEF patients [35,36]. Of importance, as in HFrEF, hypertension is the single most common risk factor with the highest population attributable risk in HFpEF; and more than 80% of patients have hypertension in many HFpEF trials [37]. Therefore, alternative therapies targeting the myocardium may hold promise in the treatment of hypertensive heart disease, and may influence the design of future HFpEF trials.

It is well established that the different classes of antihypertensive medications do not have the same effects on the myocardium. Upregulation of the renin–angiotensin–aldosterone system (RAAS) is a major determinant of left ventricular hypertrophy and myocardial fibrosis. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are effective at reducing left ventricular mass and regressing myocardial fibrosis [38,39]. The constitutive release of cardiac natriuretic peptides represents the most important endogenous system shown to have anti-hypertrophic and anti-fibrotic effects. A key regulator of the natriuretic peptide system is the neutral endopeptidase (neprilysin; NEP). Therefore, the net result of inhibiting NEP and RAAS (such as valsartan/sacubitril combination: Entresto, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) will potentially best reflect the beneficial effects of augmenting the natriuretic peptides that have multiple desirable anti-heart failure effects (including cardiac anti-hypertrophic and anti-fibrotic effects) while suppressing the deleterious effects of angiotensin [40]. Other emerging novel molecules targeting cardiac fibrosis are being investigated [41].

The important relationship between the myocardium and arterial pressure justifies a paradigm shift in the management of hypertensive heart disease. Instead of relying solely on peripheral blood pressure targets, greater emphasis should be placed on identifying at risk individuals with advanced hypertrophy and myocardial fibrosis, targeting treatment to ameliorate adverse changes in the myocardium irrespective of the effects on blood pressure. Clinical trials guided by imaging-driven endpoints (or other reliable markers) of fibrosis will better inform treatment goals with such a strategy.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.