Heart failure is a major health and economic burden, particularly in an ageing society. It is estimated that 5.8 million people in the USA alone have heart failure and approximately 23 million worldwide. Despite the improvements in therapy, progression of the disease results in frequent hospitalization and a survival rate of only 50% at 5 years with the risk of sudden death is 5 times more likely in heart failure patients compared to the general public [1, 2].

Heart failure occurs when there is an unresolved impairment of the heart that compromises its ability to work as a pump and may result from one or the sum of many causes. Once the heart is damaged, it can result in a cascade of events that damages other organs, which in turn worsens heart failure. Furthermore, when other conditions are present, such as diabetes, renal disease and hypertension, the problem can be exacerbated.

Patients at risk of many cardiovascular diseases are also at risk of heart failure. Early identification of those at risk of heart failure and subsequently monitor the effects of treatment could result in improved outcomes and ultimately help prevent or delay the progression of heart failure [3].

Background

Heart failure is generally defined as the inability of the heart to pump sufficient blood to meet the demands of the body and is caused over time by any condition that causes overloading of the heart or muscle damage. There are a number of underlying causes including hypertension, coronary artery disease, diabetes and obesity, -conditions that are considered to increase in prevalence in the future and are all related to increased central blood pressure and arterial stiffness.

As Heart Failure progresses and the heart continues to pump ineffectually, the effect of reduced cardiac output and increased strain ultimately results in damage from oxygen deprivation to vital organs, including the heart itself and thereby increasing the risk of cardiac arrest [1, 2]. Clinically, heart failure manifests itself as dyspnoea, fatigue, fluid retention and a decreased tolerance to exercise [1, 2]. In many cases, patients are hospitalized on numerous occasions and the quality of life steadily diminishes.

Hypertension is a very common risk factor for heart failure and it has been reported that 75% of heart failure cases have antecedent hypertension. Furthermore, the lifetime risk of developing heart failure for people with a blood pressure of 160/90 mmHg is double that of those with a blood pressure of 140/90 mmHg [4]. Diabetes has also been shown to be an important risk factor, with the prevalence increasing among older individuals diagnosed with heart failure [4].

Heart failure can often involve the left side, right side and both sides together; however heart failure typically starts in the left ventricle, the main pumping chamber. Heart failure is often classified as:

• Systolic heart failure – the left ventricle has impaired contractile function, resulting in increase in left ventricular cavity size and a reduced ejection fraction.



• Diastolic heart failure – results from impaired relaxation and an increase in left ventricular passive stiffness, resulting in increased left ventricular wall thickness; however the ejection fraction remains preserved. Also described as heart failure with preserved (or normal) ejection fraction (HFpEF).

Population studies have found that 40-50% of diagnosed heart failure patients have diastolic heart failure [5], and more recently that asymptomatic diastolic dysfunction to be as common as asymptomatic systolic dysfunction common in the community [6]. Left ventricular dysfunction (systolic or diastolic) has been shown to be a risk factor for developing overt heart failure and diastolic dysfunction has been associated with a marked increase in all cause mortality [6].

Management of heart failure includes treating underlying risk factors, pharmacological management and in some cases surgical intervention. However, much of the focus to date has been on systolic heart failure and proven therapies for diastolic heart failure are still yet to be fully studied [2].

Arterial stiffness and heart failure/ Central Pressure and Heat Failure.

Central haemodynamic measurements are important markers of early organ damage and are considered to be important when quantifying total cardiovascular risk [7, 8, 9, 10, 11]. Measures of central pressure and arterial stiffness have been commonly associated with conditions that are considered risk factors for developing heart failure, such as hypertension, diabetes, obesity and coronary artery disease [8, 9, 11, 12, 13, 14]. More recently, the contribution of arterial stiffness and pulsatile load to cardiovascular disease and the pathophysiology of heart failure have been recognised.

In healthy and compliant arteries, the pressure waveform generated in the left ventricle travels down the arterial tree and merges with the incident (reflected) wave during diastole and thereby augmenting coronary perfusion. In stiffer vessels, the pulse wave travels faster and the reflected wave returns while the cardiac cycle is still in systole, thereby increasing systolic pressure and thus increasing left ventricular load. As a result, normal ventricular relaxation and coronary filling are compromised. In this setting, late systolic load has deleterious effects on left ventricular structure and function [15, 16]. In a failing heart this negatively impacts cardiac systolic performance and efficacy, resulting in a further deterioration of the cardiovascular haemodynamics and clinical outcomes [17].

Measures of arterial stiffness have previously been shown to be associated with systolic heart failure [17] but more recent interest has been on diastolic heart failure (HFpEF) and asymptomatic patients with left ventricular dysfunction. Several small studies have found measurements of central pressure indices and arterial stiffness to be reduced in heart failure patients with HFpEF.

Patients with HFpEF have been shown to have increased central aortic stiffness compared to healthy and hypertensive subjects without heart failure. Aortic pulse wave velocity (PWV) steadily increases with progression from healthy to hypertensive to heart failure. Furthermore these were correlated with both left ventricular mass and filling pressure [18].

Aortic stiffness has also been shown in other studies to be increased in heart failure patients [19, 20, 21] but also in patients with LV dysfunction in the absence of heart failure [22, 23, 24]. Data from a study examining arterial stiffness in patients with HFpEF, systolic heart failure and a healthy control group showed that there was a marked increase in aortic PWV in HFpEF patients compared to the other two groups [19] , as shown in Figure 1.

Figure 1 Comparison of mean aortic pulse wave velocity in patients with reduced systolic function (HF-RSF), preserved systolic function (HF-PSF) and control group.

(From: Balmain S, Padmanabhan N, Ferrell WR, et al. Differences in arterial compliance, microvascular function and venous capacitance between patients with heart failure and either preserved or reduced left ventricular systolic function. Eur J Heart Fail 2007,9:865-871.)

A comparison of diastolic heart failure and systolic heart failure patients found that PWV and augmentation index (a measure of arterial stiffness), was significantly higher in HFpEF patients. The data showed that these parameters appeared to be influenced by simple haemodynamic parameters particularly in systolic heart failure however it was suggested that these parameters remain an important prognostic tool for heart failure patients [20].

Indices of central blood pressure have also been shown to be associated with left ventricular diastolic response in HFpEF patients both at rest and in response to exercise [25]. A study of 15 patients with HFpEF compared to a group of 15 age and sex matched individuals, demonstrated that the change in augmentation pressure and augmentation index, indices of central blood pressure and arterial stiffness, from rest to submaximal exercise were both highly associated with diastolic function, independent of age, sex and diabetes and brachial blood pressure. Brachial blood pressure has traditionally been used as a measure of left ventricular afterload but this study clearly showed there was no association between diastolic function and brachial blood pressure, highlighting the importance of measuring central pressures for a true estimation of left ventricular load.

In a relatively large study of patients with preserved EF being investigated for suspected coronary artery disease, the association between impaired arterial stiffness and impaired left ventricular function and symptomatic status was examined [21]. An increase in arterial wave reflections, AIx and AP along was associated with impaired systolic function and AIX and AP, along with PWV were inversely associated with diastolic function. Patients with increasing levels of exertional dyspnea had increasingly impaired arterial function. As compared to patients without functional limitation, patients with NYHA classes II and III had higher AIx, AP and PWV and worse diastolic function, as shown in Figure 2. They also happened to be mostly older females with hypertension, a group HFpEF is most prevalent in. This study raises the suggestion that due to the significant and independent association of measures of arterial stiffness with impaired systolic and diastolic function and exertional dyspnea, these measurements might add additional information in the diagnosis of HFpEF patients.

Figure 2. Association of AIx and PWV to functional limitation. AIx (P = 0.025), PWV (P = 0.001), where P values derived from Kruskal-Wallis analysis of variance.

(From: Weber T, O'Rourke MF, Ammer M, et al. Arterial stiffness and arterial wave reflections are associated with systolic and diastolic function in patients with normal ejection fraction. Am J Hypertens 2008,21:1194-1202.)

Similar findings of impaired arterial function have been found in other studies examining the association of arterial stiffness and suspected diastolic dysfunction in patients with essential hypertension [22, 23, 24] and patients with a high cardiovascular risk [{Weber, 2006 1197 /id}, 27, [28]. In one community based cross-sectional study comprising predominantly elderly women of Hispanic ethnicity and a high frequency of risk factors, arterial stiffness was significantly associated with worse left ventricular diastolic function in both men and women. The results showed that a higher ratio of central pulse pressure to LV stroke volume was a significant predictor of left ventricular diastolic function independent of age and cardiovascular risk factors. Arterial stiffness was also found to be higher in women compared to men and it was suggested that this may account for a more impaired left ventricular diastolic function and become a preclinical finding in HFpEF [28]. Importantly these studies demonstrate that increased arterial stiffness is closely associated with left ventricular diastolic function, and is present even in early stages of hypertension and in the absence of left ventricular hypertrophy. Identification of these patients may assist in risk stratification as a group with substantially increased risk of cardiovascular disease including the development of heart failure.

Pharmacological treatment and arterial stiffness in heart failure

The significant association of measures of arterial stiffness with heart failure provides a foundation for measures of central haemodynamics to be treatment targets. Measurement of central blood pressure and arterial stiffness are now being used to assess the efficacy of medication in cardiovascular disease and more recently in heart failure.

The pharmacological approach to heart failure includes use of ACE inhibitors and beta blockers, but also ARB's and a combination of hydralazine and nitrate. For those patients considered at an additional risk of thromboembolic events, warfarin or aspirin is also an option [3].

One early study [29] which examined the four major cardiovascular drug classes (calcium channel blockers, diuretic, ACE inhibitor and beta blocker) in hypertensive patients found that brachial blood pressure measurements did not accurately predict the effects in central blood pressure. Changes in central systolic blood pressure were underestimated for patients on ACE inhibitors and calcium channel blockers, while changes in central pulse pressure were underestimated on ACE inhibitors and overestimated on beta blockers, as shown in Figure 3.

Figure 3 The fall in systolic (A) and pulse (B) pressure blood pressure with different drug classes (ACE inhibitor, beta blocker, calcium channel blockers, diuretic). B – Brachial blood pressure, A – blood pressure at aortic root. *P<0.05 compared with brachial blood pressure.

(From: Morgan T, Lauri J, Bertram D and Anderson A. Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens 2004,17:118-123).

Two small studies have examined the effect of aspirin on arterial stiffness [30, 31] in heart failure patients. In a dose ranging study [30], it was found that after 1 week of aspirin of 325mg/day in heart failure patients on an ACE inhibitor there was a dose mediated alteration of arterial function compared to aspirin of 100mg/day or placebo. This was observed by an increase in reflection wave amplitude (AIx) and a shortening of the reflection wave time but with no change in brachial blood pressure. In a later study, the effect of clopidogrel, an alternative to aspirin, was examined. In a group of 45 patients, taking aspirin (325mg/day) for 2 weeks AIx increased significantly, whereas clopidogrel did not, without any significant change in brachial BP [31].

While some beta blockers may be similar in the survival rate of heart failure patients, they can have different pharmacological actions. This may have significant implications in patients with heart failure and coexisting chronic obstructive pulmonary disease. In a randomized triple cross over trial to examine the effect of changing between these different beta blockers, patients were administered each of the beta blockers for a 6 week period before resuming their original beta blocker. The results showed that while there was no change in brachial blood pressure, central augmented pressure was the lowest on carvedilol compared with metoprolol or bisoprolol.

These results are consistent with large trials that have found that antihypertensive drugs can have vastly different effect on central blood pressure and arterial properties despite a similar effect on brachial blood pressure. In large studies, such as CAFÉ and REASON, central systolic blood pressure was significantly lower in patients taking amlopdipine/perindopril therapy compared with atenolol/thiazide (or atenolol alone in the REASON trial), while no difference in brachial blood pressure was observed [32, 33].

Assessment of endothelial function (salbutamol-mediated changes in augmentation index, AIx) has also recently been used in heart failure patients to better understand the mechanisms by which certain pharmaceuticals may be having a beneficial effect. Many heart failure patients are considered to have nitric oxide resistance and this represents a therapeutic target for drugs considered to enhance nitric oxide responsiveness, such as hydralazine and folic acid. In two separate studies [34, 35] assessment of endothelial function was used to test the hypotheses that these drugs may be providing their reported beneficial effects through nitric oxide. While the results suggested that neither of the drugs was having an effect on nitric oxide, the ability to test the mechanism by which pharmaceuticals may be having a beneficial effect adds important information in this field.

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