Advanced Hypertensive Heart Disease Research Articles

Left Atrial Myocardium in Arterial Hypertension.

Arterial hypertension affects ≈ 1 billion people worldwide. It is associated with increased morbidity and mortality and responsible for millions of deaths each year. Hypertension mediates damage of target organs including the heart. In addition to eliciting left ventricular hypertrophy, dysfunction and heart failure, hypertension also causes left atrial remodeling that may culminate in atrial contractile dysfunction and atrial fibrillation. Here, we will summarize data on the various aspects of left atrial remodeling in (essential) hypertension gathered from studies on patients with hypertension and from spontaneously hypertensive rats, an animal model that closely mimics cardiac remodeling in human hypertension. Analyzing the timeline of remodeling processes, i.e., distinguishing between alterations occurring in prehypertension, in early hypertension and during advanced hypertensive heart disease, we will derive the potential mechanisms underlying left atrial remodeling in (essential) hypertension. Finally, we will discuss the consequences of these remodeling processes for atrial and ventricular function. The data imply that left atrial remodeling is multifactorial, starts early in hypertension and is an important contributor to the progression of hypertensive heart disease, including the development of atrial fibrillation and heart failure.

Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.

The significance of plasma collagen degradation products as biomarkers for advanced hypertensive heart disease.

The significance of plasma collagen degradation products as biomarkers for advanced hypertensive heart disease.

Changes in the number of mast cells, expression of fibroblast growth factor-2 and extent of interstitial fibrosis in established and advanced hypertensive heart disease

IntroductionAn increasing number of studies have shed light on the role of cardiac mast cells in the pathogenesis of hypertension-induced myocardial remodeling. Mast cells promote fibroblast activation, myofibroblast differentiation and subsequent collagen accumulation through the action of tryptase, chymase, histamine and fibroblast growth factor-2. The aim of the present study was to report on the changes in the number of mast cells as evaluated through toluidine blue, tryptase and c-kit staining, to assess the extent of interstitial fibrosis and correlate it with the changes in the number of mast cells and to analyze the immunohistochemical expression of fibroblast growth factor-2 in two groups of spontaneously hypertensive rats indicative of established and advanced hypertensive heart disease. A novel aspect of our work was the analysis of all parameters in the right ventricle. Material and methodsFor the present study, we used 6- and 12-month-old spontaneously hypertensive rats. A light microscopic study was conducted on sections stained with hematoxylin and eosin and toluidine blue. For the immunohistochemical study we used monoclonal antibodies against mast cell tryptase and fibroblast growth factor-2 and a polyclonal antibody against c-kit. The expression of fibroblast growth factor-2 was assessed semi-quantitatively through ImageJ. The number of mast cells was evaluated on toluidine blue-, tryptase- and c-kit-stained sections and a comparative statistical analysis with the Mann-Whitney test was conducted between the two age groups. A separate statistical analysis between results obtained through immunostaining for tryptase and for c-kit was conducted in each age group with the Wilcoxon signed-rank test. The extent of fibrosis was assessed quantitatively on slides stained with Mallory’s trichrome stain as a percentage of the whole tissue and compared between the two age groups. Spearman’s correlation was used to test whether a correlation exists between the number of mast cells and the percentage of interstitial fibrosis. ResultsMast cells with typical cytoplasmic granules were visualized in the interstitial tissue and in the perivascular zone in both age groups. In both ventricles, their number increased significantly in 12-month-old animals as evaluated through all three staining methods. Moreover, immunostaining for tryptase and for c-kit yielded comparable results. The immunoreactivity of fibroblast growth factor-2 increased in both ventricles in older animals. Expression of this protein was particularly intensive in the cytoplasm of connective tissue cells with the characteristic features of mast cells mainly found in the areas of fibrotic alterations in 12-month-old spontaneously hypertensive rats. In both ventricles, interstitial fibrosis was more extensive throughout the myocardium of older animals and was positively correlated with the changes in the number of mast cells in both age groups. ConclusionThe present study reported for the first time that the increase in the number of mast cells, observed as hypertension-induced myocardial changes progress, is statistically significant and confirmed that this process takes place in both ventricles. This increase is accompanied by a higher expression of fibroblast growth factor-2 and is more strongly correlated with the more pronounced interstitial fibrosis in older animals, further supporting the role of mast cells in the structural changes taking place in the myocardium in response to systemic hypertension.

Interplay of cardiac remodelling and myocardial stiffness in hypertensive heart disease: a shear wave imaging study using high-frame rate echocardiography

To determine myocardial stiffness by means of measuring the velocity of naturally occurring myocardial shear waves (SWs) at mitral valve closure (MVC) and investigate their changes with myocardial remodelling in patients with hypertensive heart disease. Thirty-three treated arterial hypertension (HT) patients with hypertrophic left ventricular (LV) remodelling (59 ± 14 years, 55% male) and 26 aged matched healthy controls (55±15 years, 77% male) were included. HT patients were further divided into a concentric remodelling (HT1) group (13 patients) and a concentric hypertrophy (HT2) group (20 patients). LV parasternal long-axis views were acquired with an experimental ultrasound scanner at 1266 ± 317 frames per seconds. The SW velocity induced by MVC was measured from myocardial acceleration maps. SW velocities differed significantly between HT patients and controls (5.83 ± 1.20 m/s vs. 4.04 ± 0.96 m/s; P < 0.001). In addition, the HT2 group had the highest SW velocities (P < 0.001), whereas values between controls and the HT1 group were comparable (P = 0.075). Significant positive correlations were found between SW velocity and LV remodelling (interventricular septum thickness: r = 0.786, P < 0.001; LV mass index: r = 0.761, P < 0.001). SW velocity normalized for wall stress indicated that myocardial stiffness in the HT2 group was twice as high as in controls (P < 0.001), whereas values of the HT1 group overlapped with the controls (P = 1.00). SW velocity as measure of myocardial stiffness is higher in HT patients compared with healthy controls, particularly in advanced hypertensive heart disease. Patients with concentric remodelling have still normal myocardial properties whereas patients with concentric hypertrophy show significant stiffening.

Progressive impairment of atrial myocyte function during left ventricular hypertrophy and heart failure

Hypertensive heart disease (HHD) can cause left ventricular (LV) hypertrophy and heart failure (HF). It is unclear, though, which factors may contribute to the transition from compensated LV hypertrophy to HF in HHD. We hypothesized that maladaptive atrial remodeling with impaired atrial myocyte function would occur in advanced HHD and may be associated with the emergence of HF. Experiments were performed on atrial myocytes and tissue from old (15–25months) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with advanced HHD. Based on the absence or presence of elevated lung weight, a sign of lung congestion and heart failure, SHR were divided into a non-failing (SHR-NF) and failing (SHR-HF) group. Compared with WKY, SHR exhibited elevated blood pressure, LV hypertrophy and left atrial (LA) hypertrophy with increased LA expression of markers of hypertrophy and fibrosis. SHR-HF were distinguished from SHR-NF by aggravated hypertrophy and fibrosis. SHR-HF atrial myocytes exhibited reduced contractility and impaired SR Ca2+ handling. Moreover, in SHR the expression and phosphorylation of SR Ca2+-regulating proteins (SERCA2a, calsequestrin, RyR2 and phospholamban) showed negative correlation with increasing lung weight. Increasing stimulation frequency (1-2-4Hz) of atrial myocytes caused a progressive increase in arrhythmogenic Ca2+ release (including alternans), which was observed most frequently in SHR-HF. Thus, in old SHR with advanced HHD there is profound structural and functional atrial remodeling. The occurrence of HF in SHR is associated with LA and RA hypertrophy, increased atrial fibrosis, impaired atrial myocyte contractility and SR Ca2+ handling and increased propensity for arrhythmogenic Ca2+ release. Therefore, functional remodeling intrinsic to atrial myocytes may contribute to the transition from compensated LV hypertrophy to HF in advanced HHD and an increased propensity of atrial arrhythmias in HF.

Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis.

Left ventricular (LV) hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG), echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m2), severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%), accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease.

Ventricular remodeling in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and causes substantial morbidity and mortality. HFpEF has commonly been viewed as an expression of advanced hypertensive heart disease, with a cardiac phenotype characterized by an increase in wall thickness-to-chamber radius ratio (concentric hypertrophy). However, marked clinical heterogeneity within this syndrome is now well appreciated, and is mirrored in the variability in left ventricular (LV) structure. A review of larger imaging studies from epidemiology and clinical trial cohorts demonstrate that while concentric LV remodeling is common, it is by no means universal and many patients demonstrate normal LV geometry or even an eccentric pattern. More detailed assessment of cardiac structure and function in broader HFpEF populations will be necessary to better define the prevalence, determinants, and prognostic relevance of these measures, which may in turn serve as a foundation to identify pathophysiologically relevant sub-phenotypes within this diverse syndrome.

Herzinsuffizienz mit erhaltener linksventrikulärer Auswurffraktion

Heart failure with preserved left ventricular ejection fraction (LVEF; HFpEF) is a common type of heart failure in the elderly, and it typically represents advanced hypertensive heart disease. The left ventricle in patients with HFpEF is characterized by concentric remodeling, normal LVEF, but reduced left longitudinal shortening, and importantly diastolic dysfunction. Dyspnoe and fatigue in patients with HFpEF are due to impaired left ventricular filling with a rapid increase in filling pressures and the lack of an increase in stroke volume during exercise. The diagnosis of HFpEF requires the careful exclusion of non-cardiac causes of dyspnoe as well as cardiac causes of dyspnoe associated with preserved LVEF other than HFpEF, primarily coronary artery disease and valve disease. Then, the following findings are required to make a diagnosis of HFpEF: a non-dilated left ventricle with an LVEF >50% and the presence of a significant diastolic impairment, which can be assessed using invasive haemodynamics, echocardiography, natriuretic peptides, or a combination of these tools. In contrast to patients with heart failure and reduced LVEF there is still no established treatment for patients with HFpEF, which prolongs survival or reduces the rate of hospitalizations for heart failure. There is currently however intense research going on in this field, and results from large trials evaluating the effects of various interventions on clinical endpoints are expected within the next years.

Primary Aldosteronism With Right-Dominant Heart Failure

A 48 year-old obese male with hypertension was admitted to our department because of severe right-dominant heart failure. His heart rhythm was 2:1 atrial flutter and the left ventricle was diffusely hypertrophic and hypokinetic. Primary aldosteronism was diagnosed based on severe hypokalemia (2.6 mEq/L) and a low renin-high aldosterone state with hypertension despite the use of an angiotensin-II receptor blocker, but its etiology could not be clarified with computed tomography, adrenal scintigraphy, and adrenal vein sampling. Ascites and edema rapidly worsened. Ascites aspiration was performed daily, until serum potassium was normalized by a full dose of an aldosterone receptor blocker (spironolactone 100 mg/day). A diuretic (furosemide) was then added. Rate control of atrial flutter was obtained with a beta-adrenergic blocker, and anticoagulation therapy was started. His heart failure was successfully controlled. Coronary arteries were normal on coronary arteriograms, and an endomyocardial biopsy sample obtained from the left ventricle did not show any specific pathological findings. Blood pressure was well controlled with the full dose of the aldosterone receptor blocker, but he died one year later due to intracerebral hemorrhage. As his heart failure was right dominant, we believe that its etiology may have been hyperaldosteronism-induced cardiomyopathy, and not advanced hypertensive heart disease.

Relation of circulating markers of fibrosis and progression of left and right ventricular dysfunction in hypertensive patients with heart failure

To study the association of circulating markers of fibrosis: procollagen type III amino-terminal propeptide (PIIINP), procollagen type I carboxy-terminal propeptide (PIP) and collagen type I carboxy-terminal telopeptide (CITP): with left (LV) and right ventricular (RV) longitudinal and LV radial systolic function in patients with heart failure in the course of essential hypertension. The study population consisted of 81 patients with hypertension divided into four groups according to NYHA classification and 20 healthy controls. Cardiac function was estimated by myocardial deformation indices assessed by tissue Doppler imaging. Serum PIIINP, PIP and CITP levels were quantified by radioimmunoassay. Progressive LV longitudinal function impairment was demonstrated in all hypertension groups as indicated by reduced peak systolic strain and strain rate and increased postsystolic strain index. The respective indicators of LV radial function were deteriorated only in NYHA classes III-IV. Concurrently, RV longitudinal function was found abnormal in NYHA classes II-IV. PIIINP concentration was higher in NYHA class III and IV, whereas CITP level was increased and PIP/CITP ratio was decreased in the NYHA IV individuals. PIIINP was an independent correlate of LV and RV longitudinal strain (R = 0.52, beta = -0.34, P < 0.001; R = 0.25, beta = -0.27, P < 0.01, respectively). PIP/CITP ratio independently determined LV radial strain in patients with LV ejection fraction less than 50% (R = 0.44, beta = 0.52, P < 0.008). In hypertensive patients, the progressive decline in cardiac longitudinal function is related to increased collagen III synthesis, whereas the changes in collagen I turnover favoring its increased degradation might contribute to LV radial and global systolic dysfunction seen in the advanced hypertensive heart disease.

Linoleate-Rich High-Fat Diet Decreases Mortality in Hypertensive Heart Failure Rats Compared With Lard and Low-Fat Diets

Recent studies indicate that high-fat diets may attenuate cardiac hypertrophy and contractile dysfunction in chronic hypertension. However, it is unclear whether consuming a high-fat diet improves prognosis in aged individuals with advanced hypertensive heart disease or the extent to which differences in its fatty acid composition modulate its effects in this setting. In this study, aged spontaneously hypertensive heart failure rats were administered a standard high-carbohydrate diet or high-fat diet (42% of kilocalories) supplemented with high-linoleate safflower oil or lard until death to determine their effects on disease progression and mortality. Both high-fat diets attenuated cardiac hypertrophy, left ventricular chamber dilation, and systolic dysfunction observed in rats consuming the high-carbohydrate diet. However, the lard diet significantly hastened heart failure mortality compared with the high-carbohydrate diet, whereas the linoleate diet significantly delayed mortality. Both high-fat diets elicited changes in the myocardial fatty acid profile, but neither had any effect on thromboxane excretion or blood pressure. The prosurvival effect of the linoleate diet was associated with a greater myocardial content and linoleate-enrichment of cardiolipin, an essential mitochondrial phospholipid known to be deficient in the failing heart. This study demonstrates that, despite having favorable effects on cardiac morphology and function in hypertension, a high-fat diet may accelerate or attenuate mortality in advanced hypertensive heart disease depending on its fatty acid composition. The precise mechanisms responsible for the divergent effects of the lard and linoleate-enriched diets merit further investigation but may involve diet-induced changes in the content and/or composition of cardiolipin in the heart.

Simple criteria for differentiation of Fabry disease from amyloid heart disease and other causes of left ventricular hypertrophy

Aims Fabry disease may be difficult to differentiate from other causes of left ventricular hypertrophy such as other myocardial storage diseases (including amyloidosis), hypertrophic cardiomyopathy (HCM), or hypertensive heart disease (HHD). We sought to determine simple criteria to best differentiate the above mentioned cardiac diseases. Methods and results All patients in a six-year time period with left ventricular hypertrophy due to Fabry disease (13 patients), biopsy proven cardiac amyloidosis (16 patients), non-obstructive HCM (17 patients), and 22 randomly selected patients with advanced HHD were compared. Retrospective analysis of clinical characteristics, findings of electrocardiogram (ECG) and echocardiography by blind review was performed. Results No single clinical characteristic or findings of ECG or echocardiography could reliably differentiate between the various diseases. Increased echogenicity/granular sparkling, valvular abnormalities, abnormal renal function, and diastolic function were not helpful discriminators. In a univariate analysis, four criteria (acroparesthesia, anhydrosis, absence of hypertension and presence of Sokolow criteria for left ventricular hypertrophy in the ECG) were significant for Fabry disease. By logistic regression analysis, the following most suitable discriminative parameters were identified: hypertension in HHD (specificity 82%), orthostasis and/or pericardial effusion for amyloidosis (specificity 93%), papillary muscle anomaly in non-obstructive HCM (specificity 92%), and Fabry disease if neither hypertension orthostatis, pericardial effusion nor a papillary muscle anomaly was present (specificity 87%). Conclusion A combination of symptoms, echocardiographic findings and ECG in unexplained left ventricular hypertrophy may help to differentiate amyloidosis, non-obstructive HCM and hypertensive heart disease from Fabry disease. The results of this preliminary study will have to be confirmed in a prospective study.

Morphologic, hemodynamic and coronary perfusion characteristics in severe left ventricular hypertrophy secondary to systemic hypertension and evidence for nonatherosclerotic myocardial ischemia

Patients with the clinical diagnosis of ischemic heart disease who were found to be free of significant coronary artery atherosclerotic disease (n = 150) underwent coronary vasodilator reserve testing, 2-dimensional echocardiography, and dipyridamole limited-stress thallium testing. After exclusions (predominantly for technically poor coronary artery Doppler signals or suboptimal echocardiography), 100 patients formed the study population. The purpose was to characterize typical cardiac and coronary artery findings in hypertensive patients with severe left ventricular (LV) hypertrophy (n = 15) and to investigate the evidence for myocardial ischemia unrelated to coronary atherosclerosis in early and advanced hypertensive heart disease. Normotensive and hypertensive control groups without LV hypertrophy (n = 12 and 34, respectively) were used for comparison. Severe LV hypertrophy was defined as LV mass index ≥50% above established gender specific norms using 2-dimensional-directed M-mode echocardiography and the cube equation corrected to agree with necropsy estimates of mass. Clinical characteristics more often associated with severe LV hypertrophy were black race (67%), diabetes mellitus (33%), proteinuria (47%) and elevated creatinine (1.5 ± 0.9 mg/dl). Baseline electrocardiograms and dipyridamole limited-stress thallium scans were highly likely to be abnormal (94 and 73%, respectively). Both eccentric and concentric cardiac hypertrophies were found in the severe group. Ejection fraction was significantly lower (0.51 vs 0.68, p = 0.002) and basal coronary flow velocity higher (12.0 vs 5.0 cm/s, p = 0.0004) among these patients when compared with normotensive control patients. Coronary flow reserve did not differ between control groups but was significantly depressed in patients with severe LV hypertrophy (2.5 vs 3.9, p = 0.001). This, together with the prevalent evidence of resting and stress-induced ischemia, strongly supports the concept of myocardial ischemia unrelated to coronary atherosclerosis in this group.

Prevention of the development of heart failure and the regression of cardiac hypertrophy by captopril in the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) exhibits both a compensated phase of cardiac hypertrophy in which forward output is maintained despite persistently elevated systemic arterial pressures and a decompensated phase in which cardiac performance has deteriorated in spite of further hypertrophic growth. To determine whether chronic antihypertensive therapy prevents the development of heart failure and the progression of cardiac hypertrophy in SHR with advanced hypertension, captopril (2 g/l of drinking water), a converting enzyme inhibitor, was administered to 14 month old female SHR and normotensive American Wistar rats (NWR) for 10 months. The severe left ventricular hypertrophy of the 24 month old untreated SHR (4.37 +/- 0.2 mg/g v. 2.50 +/- 0.06 mg/g, untreated NWR) was markedly reduced (P less than 0.02) by captopril (3.01 +/- 0.1 mg/g). Chronic therapy prevented the reduction of both baseline and maximal cardiac indices in SHR, but did not alter blood flow in NWR. Left ventricular dilatation was present in 24 month old SHR and, as peak stroke volume index was diminished, the ejection fraction index of the SHR was reduced. Captopril restored this index in SHR to normal. The relation of ejection fraction index and afterload (peak systolic wall stress) was depressed in untreated SHR, but was normal in treated SHR. Thus, chronic therapy with captopril prevented the development of severe cardiac dysfunction and produced a marked regression of cardiac hypertrophy in SHR with advanced hypertensive heart disease.