Systemic diseases

15.1

Arterial systemic hypertension

Arterial systemic hypertension is a well established, leading cardiovascular (CV) risk factor for morbidity and mortality in the general population. Myocardial infarction, heart failure, and sudden death are the main fatal and non-fatal complications in hypertensive patients [ ]. The clinical consequences of hypertension on the heart derive from chronic pressure overload, such as to induce left ventricular (LV) structural and functional alterations, which define hypertensive heart disease. The development of LV hypertrophy (LVH) is of hinge importance since it increases the risk for CV outcomes by a factor of 3–5-fold [ ]. Hypertensive heart disease is clinically asymptomatic but manifests at a more advanced stage as angina pectoris, dyspnoea, and palpitation. These symptoms can be attributed to a reduced coronary flow reserve (CFR), impaired diastolic function, and arrhythmias [ , ].

Echocardiographic examination is the first-step imaging technique for diagnosing hypertensive heart disease because of its relatively low cost, prompt availability, and suitability for serial examinations and patient follow-up. Echo-Doppler examination is currently used to detect LV remodelling and LVH [ ] as well as LV diastolic dysfunction (DD) [ ] and also to unmask regional wall motion abnormalities [ ] and the onset of coronary artery disease (CAD).

The estimation of LV geometry and LV mass (LVM) has been one of the most studied issues by echocardiography in the epidemiologic studies and treatment trials in the last three decades [ , ]. LV geometric patterns of hypertensive heart are identified according to a classification which combines the values of relative wall thickness (RWT) and LVM index ( Figure 15.1 ) [ ]. LVM (indexed for body surface area [BSA] or, better, for height) identifies LVH according to standardized cut-off point values ( Table 15.1 ) [ ]. LV concentric remodelling and LVH are independent predictors of morbidity and mortality in the general population [ , , ]. Reduction of LVM can be obtained by different kinds of anti-hypertensive treatments [ , ] and improves prognosis in hypertensive patients [ ]. Further information could be added by the calculation of midwall fractional shortening, obtainable by mathematical model from linear measures of LV cavity size and wall thickness at end-diastole and end-systole [ ]. Midwall shortening should be preferred to ejection fraction (EF) in the presence of LV concentric geometry, in which the prognostic power of this parameter has been reported [ , ]. The assessment of LV systolic function in hypertensive heart disease, however, does not add prognostic information to the assessment of LVM, at least in the context of a normal LV systolic function [ ].

The progression of hypertensive heart towards heart failure includes serial LV structural and geometric abnormalities (mainly myocardial fibrosis) [ ] corresponding to LV concentric remodelling and LVH. In presence of these abnormalities, parallel alterations in LV diastolic properties occur and are globally defined as LV DD. DD includes alterations of both relaxation and filling [ ], precede LV chamber systolic dysfunction, and can per se induce symptoms/signs of heart failure even when EF is still normal (heart failure with normal EF). In this context, the simple Doppler transmitral inflow pattern is not sufficient to stratify the hypertensive prognosis and should be combined with further manoeuvers (Valsalva) applied to the assessment of LV filling and/or additional Doppler parameters (i.e., difference between pulmonary flow atrial reverse and mitral inflow A velocity, ratio between mitral inflow E velocity and early relaxation velocity of the mitral annulus on pulsed tissue Doppler [ E / e ′ ratio] and left atrial volume index) [ ]. E / e ′ ratio is highly feasible and accurate in the clinical setting [ ] ( Figure 15.2 ) and its value is highlighted in the recent ESC/ESH guidelines on arterial hypertension to detect early cardiac organ damage of hypertensive patients [ ] ( Table 15.2 ). The prognostic value of e ′ is recognized in the hypertensive setting [ ]. Recently, the ASCOT Study highlighted the prognostic value of E / e ′ ratio, independent on traditional echocardiographic measurements (including LVM index and RWT) during a mean follow-up of 4.2 years of 980 hypertensive patients [ ].

Among the advanced echocardiographic techniques, important insights can be gained by 2-D speckle tracking echocardiography, which allows the quantifying of the regional and global longitudinal strain (GLS) of subendocardial fibres with good accuracy [ ]. An early impairment of GLS has been observed in pre-hypertensive stages [ ] and in firstly diagnosed hypertensives [ ] when EF is still normal ( Figure 15.3 ). GLS progressively deteriorates in hypertensive heart disease, passing from NYHA I to IV class while LV circumferential systolic reduction becomes overt only in NYHA III and IV classes [ ].

All LVM algorithms (M-mode, 2-D, 3-D) are based upon the subtraction of LV cavity volume from the volume enclosed by LV epicardium (“shell” volume) to obtain a myocardial volume, which is then multiplied by the specific weight of the myocardium (1.055 g/ml). The original ASE formula, which is based on M-mode linear measurements [ ], is still currently used for the estimation of LVM. It may be considered appropriate for evaluating patients with normal LV geometry, but its accuracy is suboptimal (standard error of estimate from 29 to 97 g, 95% confidence interval [CI] 57–190 g) in comparison with post-mortem LVM [ , ]. The calculation of LVM from real-time three-dimensional echocardiography (RT3DE) removes geometric assumptions of LV shape and reduces errors due to foreshortened views [ , ] ( Figure 15.4 ). RT3DE-derived LVM has been validated against post-mortem measurement and cardiac magnetic resonance ( K = 0.92 and 0.91, respectively) [ ]. A much lower LVM underestimation versus cardiac magnetic resonance has been found using RT3DE rather than 2D echocardiography [ ]. The very good reproducibility of LVM with RT3DE (intra-observer variability = 7–12.5%) [ , ] could significantly reduce sample size to assess LVM changes as compared to M-mode/and 2-D echocardiography [ ]. However, nowadays, due to the superior inter- and intra-observer repeatability cardiac magnetic resonance is considered the gold standard in the assessment of LVM and is used to this purpose in modern clinical trials to evaluate the drug capability in reducing LVM [ ].

Another possible application of cardiac magnetic resonance (CMR) is the evaluation of RV free wall mass, as the right sections can also be involved in the hypertrophic process. In fact, systemic hypertension might be associated with concentric right ventricular remodelling independently from the haemodynamic stress. Structural and functional right ventricular adaptation to systemic hypertension tends to parallel the homologous modifications induced by systemic haemodynamic overload on the left ventricle [ ].

Specific procedures are reserved for the diagnosis of myocardial ischemia in hypertensive patients [ ]. This is very challenging because hypertension strongly lowers the specificity of exercise ECG and perfusion scintigraphy. When exercise-ECG is positive (or ambiguous), an imaging test of inducible ischemia [ , ] is requested for a reliable identification of epicardial coronary artery stenosis. Stress echocardiography has higher specificity than exercise ECG or perfusion scintigraphy, with a similar sensitivity. Among the different types of stress, pharmacological stressors (dobutamine, dipyridamole, and adenosine) have higher feasibility than exercise testing, especially vasodilator testing. Stress-induced wall motion abnormalities are highly specific for the diagnosis of epicardial coronary artery stenosis, whereas myocardial perfusion abnormalities are frequently found also in presence of angiographically normal coronary arteries. This can occur in patients with LVH because of coronary microvascular disease [ ]. Recent recommendations suggest the use of dual echo imaging of regional wall motion and CFR on left anterior descending artery to differentiate obstructive CAD (reduced coronary reserve + inducible wall motion abnormalities) from isolated coronary microcirculatory damage (reduced coronary reserve without wall motion abnormalities) [ ]. While the use of stress cardiac magnetic resonance (dobutamine, adenosine, and dipyridamole) has been proven to be very accurate in ischemic heart disease, it is still under development in non-ischemic heart diseases. However, it might be already considered as a possible alternative to echocardiography and nuclear medicine.

Positron emission tomography (PET) offers the unique capability of measuring absolute myocardial flow (flow per unit of mass) in vivo by means of a regional, tridimensional, non-invasive approach. Using PET, myocardial perfusion abnormalities secondary to microvascular disorders have been investigated in arterial hypertension as well as in hypertrophic cardiomyopathy. In arterial hypertension, regional perfusion at rest is within the normal range, while the coronary reserve and flow response to increase in metabolic demand are blunted ( Figure 15.5 ). These flow abnormalities are independent of the degree of cardiac hypertrophy and the severity of arterial hypertension; appropriate anti-hypertensive therapy is able to improve the perfusion abnormalities after long-term treatment, independently of the effect on myocardial hypertrophy. Hypertrophic cardiomyopathy demonstrates abnormal vasodilating capability, which has been shown to be present in the subclinical form of dilated cardiomyopathy; the reduction of coronary reserve is not related to the presence and extent of the haemodynamic impairment, and involves also non-hypertrophied myocardium in asymmetric hypertrophic cardiomyopathy. These findings indicate a primary involvement of coronary microcirculation in non-advanced forms of dilated and hypertrophic cardiomyopathy [ ].

15.2

Diabetic cardiomyopathy

The first demonstration of a distinct diabetic cardiomyopathy occurred in the early 1990s, when the Framingham Study demonstrated an increase of LVM in diabetic women, independent of the effects of other common risk factors [ ]. Subsequent studies confirmed these results in both genders, pointing out associations of both type 2 diabetes mellitus (DM2) and glucose intolerance (GI) with LV structure abnormalities (LV concentric remodelling/hypertrophy), independent of the influence of relevant covariates [ ]. GI and DM2 were also found to negatively affect midwall systolic mechanics [ ] and LV diastolic filling [ ], even in the presence of normal chamber function [ ], with an impact amplified by the coexistence of hypertension [ ]. These findings have now been complemented by the ability of echo-Doppler techniques to identify, categorize, and quantify alteration of LV function and CFR.

15.2.2

Diabetes and coronary microvascular dysfunction

Alterations of myocardial composition and, thus, of diastolic properties and LVFP might be mediated by changes in the coronary microcirculation. Microvascular damage of DM2 [ ] may lead to myocardial cell injury and reactive fibrosis/hypertrophy. Although focal microvascular alterations have not appeared sufficient to account for diffuse interstitial fibrosis [ ], these observations looked at structure but not dynamics of coronary microvessels. Today, the function of coronary circulation may be evaluated by transthoracic echocardiography, by visualizing the distal left anterior descending artery [ , ], and measuring CFR as hyperemic to resting velocities ratio [ , ]. CFR has excellent concordance with intracoronary Doppler flow wire-derived CFR, high feasibility, and reproducibility [ ]. In the absence of epicardial coronary stenosis, impaired CFR indicates coronary microvascular dysfunction [ ]. A reduction of CFR has been documented in both type 1 and 2 DM ( Figure 15.6 ) and appears as a direct consequence of elevated glycemia, as demonstrated by PET [ ]. An alternative explanation is insulin resistance, which alters CFR during cold pressure test, a completely endothelium-dependent stimulus [ ]. Endothelial function, another possible determinant of CFR, is impaired in early DM [ ]. Also, increased cardiac sympathetic activity may account for abnormal CFR in diabetics [ ].