Journal of Human Hypertension (2009) 23, 295–306 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 www.nature.com/jhh REVIEW Hypertension and heart failure: a dysfunction of systole, diastole or both? GW Yip1, JWH Fung1, Y-T Tan2 and JE Sanderson2 1Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China and 2Department of Cardiovascular Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK The pathological myocardial hypertrophy associated and volume changes. Furthermore, dichotomizing heart with hypertension contains the seed for further mala- failure into systolic and diastolic clinical entities has led daptive development. Increased myocardial oxygen to a paucity of clinical trials of therapies for heart failure consumption, impaired epicardial coronary perfusion, with a normal ejection fraction. Therapies aimed at ventricular fibrosis and remodelling, abnormalities in reversing myocardial fibrosis, and targets outside the long-axis function and torsion, cause, to a varying heart such as enhancing vasodilator reserve and degree, a mixture of systolic and diastolic abnormalities. improving chronotropic incompetence deserve further In addition, chronotropic incompetence and peripheral study and may improve the exercise capacity of factors such as lack of vasodilator reserve and reduced hypertensive heart failure patients. Hypertension heart arterial compliance further affect cardiac output parti- disease with heart failure is simply not a dysfunction of cularly on exercise. Many of these factors are common systole and diastole. Other peripheral factors including to hypertensive heart failure with a normal ejection heart rate and vasodilator response with exercise may fraction as well as systolic heart failure. There is deserve equal attention in an attempt to develop more increasing evidence that these apparently separate effective treatments for this disorder. phenotypes are part of a spectrum of heart failure Journal of Human Hypertension (2009) 23, 295–306; differing only in the degree of ventricular remodelling doi:10.1038/jhh.2008.141; published online 27 November 2008 Keywords: heart failure; remodelling; pressure overload; volume overload Introduction heart failure (SHF) and contributes significant morbidity and mortality. It represents a chain of High blood pressure, including pre-hypertension, is pathological events starting with ageing and athero- a major global health economic issue, accounting for sclerosis, left ventricular hypertrophy (LVH), cor- about half of the total cases of stroke and ischaemic onary artery disease with or without myocardial heart disease. It is responsible for about 7.6 million infarction, to finally heart failure and end-stage deaths each year and costs over 92 million dis- heart disease. This cardiovascular disease conti- ability-adjusted life years, both of which represent nuum, by which common and overlapping patho- 13.5 and 6.0% of the respective global total in the physiological mechanisms are involved in multiple year 2001. Low-income and middle-income coun- steps in disease development across the entire tries, predominantly in eastern Europe, east and spectrum of cardiovascular disease as well as south Asia (China and India) and the Pacific regions, diseases of other target organs, including the brain shoulder about 80% of the cardiovascular disease 1 and kidneys, has received experimental and clinical burden, half of which is in people of working age. validation, with an increasing recognition of the The failing heart in hypertensive heart disease important roles of oxidative stress and nitric oxide (HHD) may present as predominant heart failure synthase, metalloproteinases and their inhibitors, with normal ejection fraction (HFNEF) or systolic renin–angiotensin–aldosterone system and sympa- thetic nervous system, in the development of heart failure.2–5 Correspondence: Professor JE Sanderson, Department of Cardio- A number of primary prevention trials demon- vascular Medicine, The Medical School, University of Birming- strated that treating hypertension can reduce the ham, Edgbaston, Birmingham B15 2TT, UK. development of heart failure up to 50%. In patients E-mail: [email protected] 6 Received 24 June 2008; revised 12 September 2008; accepted with left ventricular systolic dysfunction or LVH, 14 September 2008; published online 27 November 2008 control of blood pressure prevents or retards Hypertensive heart failure GW Yip et al 296 ventricular remodelling and decreases the incidence perfusion.31,32 The increased myocardial oxygen of overt heart failure.7 In patients with established demand from a combination of raised systolic heart failure, further decreases of blood pressure blood pressure, LVH and prolonged ejection time with therapy may lower the mortality rate, slow the in addition to compromised coronary perfusion progression of disease, reduce the number of predisposes hypertensive patients to coronary hospitalizations and exacerbations, and enhance ischaemia, which may be further jeopardized in quality of life and functional capacity.8 those with a pre-existing coronary artery disease.33 About half of the patients with symptoms of heart LVH is a strong predictor of cardiovascular morbid- failure have a normal ejection fraction. HFNEF is ity and mortality, regardless of blood pressure common among female elderly patients with a values or the presence of other cardiovascular risk history of hypertension or atrial fibrillation and factors.34–37 has an adverse prognosis similar to that of SHF.9–12 There is currently no evidence of the superiority of specific antihypertensive drugs in HHD presenting Ventricular fibrosis with HFNEF.13,14 Though a simple diuretic may be as efficacious as a combination with angiotensino- Biomechanical stretch and neurohumoral factors gen-converting enzyme inhibitor or angiotensin induce changes in intracellular signalling pathways, receptor antagonist in relieving symptoms and resulting in an increased protein synthesis and improving submaximal exercise capacity, there is activation of specific genes promoting cardiomyo- still a lack of convincing evidence of modern cyte growth, eventually leading to left ventricular pharmacological heart failure therapy that improves remodelling and cardiac dysfunction.38–40 Ventricu- prognosis in patients with HFNEF, and further lar remodelling describes structural changes in the clinical trial results are pending.15,16 The inefficacy LV in response to chronic alterations in volume of modern heart failure therapy on survival in overload or pressure loads. The remodelling process patients with HFNEF was also emphasized by large results from alterations in cardiac myocytes as well epidemiological surveys, which observed an im- as the extracellular matrix, including fibroblasts and proved prognosis over the last two decades in several different types of macromolecules, for patients with SHF, but not in patients with HFNEF.9 example, type I and III collagen, elastin and Furthermore, there is still no general consensus that fibronectin. Unlike in athletic training, there is a HFNEF and SHF are two distinct heart failure disproportionate growth of the extracellular matrix phenotypes,17 or just a precursor stage of SHF,18–20 and increased modification and enhancement of and that the role of systolic function in HFNEF is perivascular and interstitial (perimysial) collagen still a matter of debate.17–19,21–26 We will review the mass, in addition to the development of endothelial pathophysiology underlying the progression of HHD dysfunction, increasing vulnerability of the ventri- to congestive heart failure, in particular the func- cle to myocardial ischaemia, dysfunction, heart tional and morphological changes in both types of failure, arrhythmia and sudden death.41 Abnormal- heart failure. ities in the extent and distribution of collagen within the remodelling heart have been recognized as playing an important role in the pathogenesis of Cardiac hypertrophy heart failure. The collagen homoeostasis is deter- mined by the rate and extent of synthesis and The current view of HHD is that it first leads to degradation. increased cardiac hypertrophy, a maladaptive pro- Carboxy-terminal propeptide procollagen type I cess required to normalize wall stress and to (PICP), a breakdown product in a 1:1 stoichio- maintain cardiac output.27 It occurs in response to metric ratio to fibrillar collagen type I that accounts an increase in systolic blood pressure and, therefore, for 85–90% of myocardial collagen, can be measured ventricular loading throughout the ejection period from serum and reflect fibrogenesis.42 Type III due to a combination of increased proximal aortic collagen accounts for the majority of the remaining stiffening and augmentation of late systolic pressure myocardial collagen. Amino-terminal propeptide from early return of pulse wave reflection that is procollagen type III (PIIINP), an extension peptide commonly associated with ageing.28,29 A high base- that cleaved off from the procollagen type III in line left ventricular mass value in initially normo- the conversion to collagen type III, can also be tensive patients predicts subsequent increases in measured in the serum. However, in contrast blood pressure and the development of hyperten- to PICP, amino-terminal propeptide procollagen sion, independent of other risk factors.30 The