Global longitudinal strain and plasma biomarkers for prognosis in heart failure complicated by diabetes: a prospective observational study.

BACKGROUND: Heart failure (HF) and diabetes are associated with increased incidence and worse prognosis of each other. The prognostic value of global longitudinal strain (GLS) measured by cardiovascular magnetic resonance (CMR) has not been established in HF patients with diabetes. METHODS: In this prospective, observational study, consecutive patients (n = 315) with HF underwent CMR at 3T, including GLS, late gadolinium enhancement (LGE), native T1, and extracellular volume fraction (ECV) mapping. Plasma biomarker concentrations were measured including: N-terminal pro B-type natriuretic peptide(NT-proBNP), high-sensitivity troponin T(hs-TnT), growth differentiation factor 15(GDF-15), soluble ST2(sST2), and galectin 3(Gal-3). The primary outcome was a composite of all-cause mortality or HF hospitalisation. RESULTS: Compared to those without diabetes (n = 156), the diabetes group (n = 159) had a higher LGE prevalence (76 vs. 60%, p < 0.05), higher T1 (1285±42 vs. 1269±42ms, p < 0.001), and higher ECV (30.5±3.5 vs. 28.8±4.1%, p < 0.001). The diabetes group had higher NT-pro-BNP, hs-TnT, GDF-15, sST2, and Gal-3. Diabetes conferred worse prognosis (hazard ratio (HR) 2.33 [95% confidence interval (CI) 1.43-3.79], p < 0.001). In multivariable Cox regression analysis including clinical markers and plasma biomarkers, sST2 alone remained independently associated with the primary outcome (HR per 1 ng/mL 1.04 [95% CI 1.02-1.07], p = 0.001). In multivariable Cox regression models in the diabetes group, both GLS and sST2 remained prognostic (GLS: HR 1.12 [95% CI 1.03-1.21], p = 0.01; sST2: HR per 1 ng/mL 1.03 [95% CI 1.00-1.06], p = 0.02). CONCLUSIONS: Compared to HF patients without diabetes, those with diabetes have worse plasma and CMR markers of fibrosis and a more adverse prognosis. GLS by CMR is a powerful and independent prognostic marker in HF patients with diabetes.

Multiparametric exercise stress cardiovascular magnetic resonance in the diagnosis of coronary artery disease: the EMPIRE trial.

BACKGROUND: Stress cardiovascular magnetic resonance (CMR) offers assessment of ventricular function, myocardial perfusion and viability in a single examination to detect coronary artery disease (CAD). We developed an in-scanner exercise stress CMR (ExCMR) protocol using supine cycle ergometer and aimed to examine the diagnostic value of a multiparametric approach in patients with suspected CAD, compared with invasive fractional flow reserve (FFR) as the reference gold standard. METHODS: In this single-centre prospective study, patients who had symptoms of angina and at least one cardiovascular disease risk factor underwent both ExCMR and invasive angiography with FFR. Rest-based left ventricular function (ejection fraction, regional wall motion abnormalities), tissue characteristics and exercise stress-derived (perfusion defects, inducible regional wall motion abnormalities and peak exercise cardiac index percentile-rank) CMR parameters were evaluated in the study. RESULTS: In the 60 recruited patients with intermediate CAD risk, 50% had haemodynamically significant CAD based on FFR. Of all the CMR parameters assessed, the late gadolinium enhancement, stress-inducible regional wall motion abnormalities, perfusion defects and peak exercise cardiac index percentile-rank were independently associated with FFR-positive CAD. Indeed, this multiparametric approach offered the highest incremental diagnostic value compared to a clinical risk model (χ2 for the diagnosis of FFR-positive increased from 7.6 to 55.9; P < 0.001) and excellent performance [c-statistic area under the curve 0.97 (95% CI: 0.94-1.00)] in discriminating between FFR-normal and FFR-positive patients. CONCLUSION: The study demonstrates the clinical potential of using in-scanner multiparametric ExCMR to accurately diagnose CAD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03217227, Registered 11 July 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03217227?id=NCT03217227&draw=2&rank=1&load=cart.

The application of exercise stress cardiovascular magnetic resonance in patients with suspected dilated cardiomyopathy.

OBJECTIVES: The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM. METHODS: Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; PeakCI). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events. RESULTS: No patients with confirmed G+P+ DCM had PeakCI exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with PeakCI below 35th percentile had characteristics similar to confirmed DCM while patients with higher PeakCI were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004). CONCLUSIONS: In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.

Cardiac magnetic resonance T1 and extracellular volume mapping with motion correction and co-registration based on fast elastic image registration.

OBJECTIVE: Our aim was to investigate the technical feasibility of a novel motion compensation method for cardiac magntic resonance (MR) T1 and extracellular volume fraction (ECV) mapping. MATERIALS AND METHODS: Native and post-contrast T1 maps were obtained using modified look-locker inversion recovery (MOLLI) pulse sequences with acquisition scheme defined in seconds. A nonrigid, nonparametric, fast elastic registration method was applied to generate motion-corrected T1 maps and subsequently ECV maps. Qualitative rating was performed based on T1 fitting-error maps and overlay images. Local deformation vector fields were produced for quantitative assessment. Intra- and inter-observer reproducibility were compared with and without motion compensation. RESULTS: Eighty-two T1 and 39 ECV maps were obtained in 21 patients with diverse myocardial diseases. Approximately 60% demonstrated clear quality improvement after motion correction for T1 mapping, particularly for the poor-rating cases (23% before vs 2% after). Approximately 67% showed further improvement with co-registration in ECV mapping. Although T1 and ECV values were not clinically significantly different before and after motion compensation, there was improved intra- and inter-observer reproducibility after motion compensation. CONCLUSIONS: Automated motion correction and co-registration improved the qualitative assessment and reproducibility of cardiac MR T1 and ECV measurements, allowing for more reliable ECV mapping.

Fractal analysis of left ventricular trabeculations is associated with impaired myocardial deformation in healthy Chinese.

BACKGROUND: Left ventricular (LV) non-compaction (LVNC) is defined by extreme LV trabeculation, but is measured variably. Here we examined the relationship between quantitative measurement in LV trabeculation and myocardial deformation in health and disease and determined the clinical utility of semi-automated assessment of LV trabeculations. METHODS: Cardiovascular magnetic resonance (CMR) was performed in 180 healthy Singaporean Chinese (age 20-69 years; males, n = 91), using balanced steady state free precession cine imaging at 3T. The degree of LV trabeculation was assessed by fractal dimension (FD) as a robust measure of trabeculation complexity using a semi-automated technique. FD measures were determined in healthy men and women to derive normal reference ranges. Myocardial deformation was evaluated using feature tracking. We tested the utility of this algorithm and the normal ranges in 10 individuals with confirmed LVNC (non-compacted/compacted; NC/C ratio > 2.3 and ≥1 risk factor for LVNC) and 13 individuals with suspected disease (NC/C ratio > 2.3). RESULTS: Fractal analysis is a reproducible means of assessing LV trabeculation extent (intra-class correlation coefficient: intra-observer, 0.924, 95% CI [0.761-0.973]; inter-observer, 0.925, 95% CI [0.821-0.970]). The overall extent of LV trabeculation (global FD: 1.205 ± 0.031) was independently associated with increased indexed LV end-diastolic volume and mass (sß = 0.35; p < 0.001 and sß = 0.13; p < 0.01, respectively) after adjusting for age, sex and body mass index. Increased LV trabeculation was independently associated with reduced global circumferential strain (sß = 0.17, p = 0.013) and global diastolic circumferential and radial strain rates (sß = 0.25, p < 0.001 and sß = -0.15, p = 0.049, respectively). Abnormally high FD was observed in all patients with a confirmed diagnosis of LVNC. Five out of 13 individuals with suspected LVNC had normal FD, despite NC/C > 2.3. CONCLUSION: This study defines the normal range of LV trabeculation in healthy Chinese that can be used to make or refute a diagnosis of LVNC using the fractal analysis tool, which we make freely available. We also show that increased myocardial trabeculation is associated with higher LV volumes, mass and reduced myocardial strain.

Assessing exercise cardiac reserve using real-time cardiovascular magnetic resonance.

BACKGROUND: Exercise cardiovascular magnetic resonance (ExCMR) has great potential for clinical use but its development has been limited by a lack of compatible equipment and robust real-time imaging techniques. We developed an exCMR protocol using an in-scanner cycle ergometer and assessed its performance in differentiating athletes from non-athletes. METHODS: Free-breathing real-time CMR (1.5T Aera, Siemens) was performed in 11 athletes (5 males; median age 29 [IQR: 28-39] years) and 16 age- and sex-matched healthy volunteers (7 males; median age 26 [interquartile range (IQR): 25-33] years). All participants underwent an in-scanner exercise protocol on a CMR compatible cycle ergometer (Lode BV, the Netherlands), with an initial workload of 25W followed by 25W-increment every minute. In 20 individuals, exercise capacity was also evaluated by cardiopulmonary exercise test (CPET). Scan-rescan reproducibility was assessed in 10 individuals, at least 7 days apart. RESULTS: The exCMR protocol demonstrated excellent scan-rescan (cardiac index (CI): 0.2 ± 0.5L/min/m2) and inter-observer (ventricular volumes: 1.2 ± 5.3mL) reproducibility. CI derived from exCMR and CPET had excellent correlation (r = 0.83, p < 0.001) and agreement (1.7 ± 1.8L/min/m2). Despite similar values at rest (P = 0.87), athletes had increased exercise CI compared to healthy individuals (at peak exercise: 12.2 [IQR: 10.2-13.5] L/min/m2 versus 8.9 [IQR: 7.5-10.1] L/min/m2, respectively; P < 0.001). Peak exercise CI, where image acquisition lasted 13-17 s, outperformed that at rest (c-statistics = 0.95 [95% confidence interval: 0.87-1.00] versus 0.48 [95% confidence interval: 0.23-0.72], respectively; P < 0.0001 for comparison) in differentiating athletes from healthy volunteers; and had similar performance as VO2max (c-statistics = 0.84 [95% confidence interval = 0.62-1.00]; P = 0.29 for comparison). CONCLUSIONS: We have developed a novel in-scanner exCMR protocol using real-time CMR that is highly reproducible. It may now be developed for clinical use for physiological studies of the heart and circulation.

Computational medical imaging and hemodynamics framework for functional analysis and assessment of cardiovascular structures.

Cardiac dysfunction constitutes common cardiovascular health issues in the society, and has been an investigation topic of strong focus by researchers in the medical imaging community. Diagnostic modalities based on echocardiography, magnetic resonance imaging, chest radiography and computed tomography are common techniques that provide cardiovascular structural information to diagnose heart defects. However, functional information of cardiovascular flow, which can in fact be used to support the diagnosis of many cardiovascular diseases with a myriad of hemodynamics performance indicators, remains unexplored to its full potential. Some of these indicators constitute important cardiac functional parameters affecting the cardiovascular abnormalities. With the advancement of computer technology that facilitates high speed computational fluid dynamics, the realization of a support diagnostic platform of hemodynamics quantification and analysis can be achieved. This article reviews the state-of-the-art medical imaging and high fidelity multi-physics computational analyses that together enable reconstruction of cardiovascular structures and hemodynamic flow patterns within them, such as of the left ventricle (LV) and carotid bifurcations. The combined medical imaging and hemodynamic analysis enables us to study the mechanisms of cardiovascular disease-causing dysfunctions, such as how (1) cardiomyopathy causes left ventricular remodeling and loss of contractility leading to heart failure, and (2) modeling of LV construction and simulation of intra-LV hemodynamics can enable us to determine the optimum procedure of surgical ventriculation to restore its contractility and health This combined medical imaging and hemodynamics framework can potentially extend medical knowledge of cardiovascular defects and associated hemodynamic behavior and their surgical restoration, by means of an integrated medical image diagnostics and hemodynamic performance analysis framework.

Cardiovascular magnetic resonance reference ranges for the heart and aorta in Chinese at 3T.

BACKGROUND: Cardiovascular magnetic resonance (CMR) reference ranges have not been well established in Chinese. Here we determined normal cardiac and aortic reference ranges in healthy Singaporean Chinese and investigated how these data might affect clinical interpretation of CMR scans. METHODS: In 180 healthy Singaporean Chinese (20 to 69 years old; males, n = 91), comprehensive cardiac assessment was performed using the steady state free precision technique (3T Ingenia, Philips) and images were analysed by two independent observers (CMR42, Circle Cardiovascular Imaging). Measurements were internally validated using standardized approaches: left ventricular mass (LVM) was measured in diastole and systole (with and without papillary muscles) and stroke volumes were compared in both ventricles. All reference ranges were stratified by sex and age; and "indeterminate/borderline" regions were defined statistically at the limits of the normal reference ranges. Results were compared with clinical measurements reported in the same individuals. RESULTS: LVM was equivalent in both phases (mean difference 3.0 ± 2.5 g; P = 0.22) and stroke volumes were not significantly different in the left and right ventricles (P = 0.91). Compared to females, males had larger left and right ventricular volumes (P < 0.001 for all). Indexed LVM was significantly higher in males compared to females (50 ± 7 versus 38 ± 5 g/m2, respectively; P < 0.001). Overall, papillary muscles accounted for only ~2% of the total LVM. Indexed atrial sizes and aortic root dimensions were similar between males and females (P > 0.05 for all measures). In both sexes, age correlated negatively with left and right ventricular volumes; and positively with aortic sinus and sinotubular junction diameters (P < 0.0001 for all). There was excellent agreement in indexed stroke volumes in the left and right ventricles (0.1±5.7 mL/m2, 0.7±6.2 mL/m2, respectively), LVM (0.6±6.4 g/m2), atrial sizes and aortic root dimensions between values reported in clinical reports and our measured reference ranges. CONCLUSIONS: Comprehensive sex and age-corrected CMR reference ranges at 3T have been established in Singaporean Chinese. This is an important step for clinical practice and research studies of the heart and aorta in Asia.

Left ventricular diastolic function assessment using time differences between mitral annular velocities and transmitral inflow velocities in patients with heart failure.

BACKGROUND: Evaluation of left ventricular (LV) diastolic function is important in clinical echocardiography. The relationship between mitral annular velocities and transmitral inflow velocities provide additional information about LV filling and diastolic function. This study evaluates the relationships of time intervals between peaks E of mitral inflow velocities and E' of mitral annular velocities, and peaks A and A' in patients with heart failure (HF). METHODS: Eighty patients with HF and 50 age- and gender-matched normal healthy subjects were prospectively recruited and underwent full echocardiograms. The following time intervals were measured: (1) from the onset of R-wave on the ECG to the peak of E-wave on the transmitral flow (TMF) (R-pE); (2) from R to peak of E'-wave on the LV lateral wall of tissue Doppler imaging (TDI) (R-pE'); (3) from onset of P-wave to peak of A-wave on the TMF (P-pA); and (4) from onset of P-wave to peak of A'-wave (P-pA') of TDI. Early-diastolic temporal discordance (EDTD) and late-diastolic temporal discordance (LDTD) were calculated as the difference between the time intervals (R-E) and (R-E'), (P-pA) and (P-p A'). RESULTS: EDTD significantly decreased in patients with HF compared with normal subjects (18.0±54.1ms vs. 28.0±33.5ms, P<0.05). There was also a significant decrease in LDTD in HF patients compared with normal subjects (19.6±23.5ms vs. 34.8±20.6; P<0.05). CONCLUSIONS: EDTD and LDTD decreased in patients with heart failure, and they may be useful tools in identifying abnormal LV relaxation and left atrial contraction for LV diastolic function.

Assessment of left ventricular preload by cardiac magnetic resonance imaging predicts exercise capacity in adult operated tetralogy of Fallot: a retrospective study.

BACKGROUND: The optimal timing of pulmonary homograft valve replacement (PVR) is uncertain. Cardiopulmonary exercise testing (CPET) and cardiac magnetic resonance (CMR) are often used to guide the clinical decision for PVR in operated tetralogy of Fallot (TOF) patients with significant pulmonary regurgitation (PR). We aim to study the relationship between exercise capacity and CMR in these patients. METHODS: The study is a single-centre retrospective analysis of 36 operated TOF patients [median 21.4 (interquartile range 16.4, 26.4) years post-repair; 30 NYHA I, 6 NYHA II; median age 25.2 (interquartile range 19.5-31.7) years, 29 males] with significant PR on CMR who underwent CPET within 15 [median 2.0 (interquartile range 0.8-7.2)] months from CMR. CPET parameters were compared with 30 age- and sex-matched healthy controls [median age 27.8 (interquartile range 21.0-32.8) years; 24 males]. RESULTS: Peak systolic blood pressure (177 versus 192 mmHg, p = 0.007), Mets (7.3 versus 9.9, p < 0.001), peak oxygen consumption (VO2max) (29.2 versus 34.5 ml/kg/min, p < 0.001) and peak oxygen pulse (11.0 versus 13.7 ml/beat, p = 0.003) were significantly lower in TOF group versus control. Univariate analyses showed negative correlation between PR fraction and anaerobic threshold. There was a positive correlation between indexed left (LV) and right (RV) ventricular end-diastolic volumes, as well as indexed LV and effective RV stroke volumes, on CMR and VO2max and Mets achieved on CPET. These remained significant after adjustment for age and sex. CONCLUSIONS: TOF subjects have near normal exercise capacity but significantly lower Mets, VO2max and peak oygen pulse achieved compared to controls. Increased PR fraction in TOF subjects was associated with lower anaerobic threshold. Higher indexed effective RV stroke volume, a measure of LV preload, was associated with higher VO2max and Mets achieved, and may potentially be used as a predictor of exercise capacity.

Endothelial function is associated with myocardial diastolic function in women with systemic lupus erythematosus.

Endothelial dysfunction is associated with traditional and systemic lupus erythematosus (SLE)-specific risk factors, and early data suggest reversibility of endothelial dysfunction with therapy. The clinical relevance of endothelial function assessment has been limited by the lack of studies, demonstrating its prognostic significance and impact on early myocardial function. Therefore, we aimed to determine the association between endothelial and myocardial diastolic function in SLE women. Women with SLE and no coronary artery disease were prospectively recruited and underwent radionuclide myocardial perfusion imaging (MPI) (Jetstream, Philips, the Netherlands) to exclude subclinical myocardial ischemia. Cardiac and vascular functions were assessed in all patients (Alpha 10, Aloka, Tokyo). Diastolic function was assessed using pulse wave early (E) and late mitral blood inflow and myocardial tissue Doppler (mean of medial and lateral annulus e') velocities. Endothelial function was measured using brachial artery flow-mediated vasodilatation (FMD%). Univariate and multivariate linear regressions were used to assess the association between FMD% and myocardial diastolic function, adjusting for potential confounders. Thirty-eight patients without detectable myocardial ischemia on MPI were studied (mean age 44 ± 10 years; mean disease duration 14 ± 6 years). About 61 % of patients had normal diastolic function (E/e' ≤ 8), and 5 % of patients had definite diastolic dysfunction with E/e' > 13 (mean 7.1 ± 2.9). FMD% was associated with E/e' (regression coefficient ß = -0.35; 95 % CI -0.62 to -0.08; p = 0.01) independent of systolic blood pressure, age, and SLICC/ACR Damage Index.

Cardiovascular Magnetic Resonance Reference Ranges From the Healthy Hearts Consortium.

BACKGROUND: The absence of population-stratified cardiovascular magnetic resonance (CMR) reference ranges from large cohorts is a major shortcoming for clinical care. OBJECTIVES: This paper provides age-, sex-, and ethnicity-specific CMR reference ranges for atrial and ventricular metrics from the Healthy Hearts Consortium, an international collaborative comprising 9,088 CMR studies from verified healthy individuals, covering the complete adult age spectrum across both sexes, and with the highest ethnic diversity reported to date. METHODS: CMR studies were analyzed using certified software with batch processing capability (cvi42, version 5.14 prototype, Circle Cardiovascular Imaging) by 2 expert readers. Three segmentation methods (smooth, papillary, anatomic) were used to contour the endocardial and epicardial borders of the ventricles and atria from long- and short-axis cine series. Clinically established ventricular and atrial metrics were extracted and stratified by age, sex, and ethnicity. Variations by segmentation method, scanner vendor, and magnet strength were examined. Reference ranges are reported as 95% prediction intervals. RESULTS: The sample included 4,452 (49.0%) men and 4,636 (51.0%) women with average age of 61.1 ± 12.9 years (range: 18-83 years). Among these, 7,424 (81.7%) were from White, 510 (5.6%) South Asian, 478 (5.3%) mixed/other, 341 (3.7%) Black, and 335 (3.7%) Chinese ethnicities. Images were acquired using 1.5-T (n = 8,779; 96.6%) and 3.0-T (n = 309; 3.4%) scanners from Siemens (n = 8,299; 91.3%), Philips (n = 498; 5.5%), and GE (n = 291, 3.2%). CONCLUSIONS: This work represents a resource with healthy CMR-derived volumetric reference ranges ready for clinical implementation.

Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol.

Background: Diffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD. Methods: Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan. Discussion: REVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

Impact of Diabetes on Myocardial Fibrosis in Patients With Hypertension: The REMODEL Study.

BACKGROUND: Compared with patients with hypertension only, those with hypertension and diabetes (HTN/DM) have worse prognosis. We aimed to characterize morphological differences between hypertension and HTN/DM using cardiovascular magnetic resonance; and compare differentially expressed proteins associated with myocardial fibrosis using high throughput multiplex assays. METHODS: Asymptomatic patients underwent cardiovascular magnetic resonance: 438 patients with hypertension (60±8 years; 59% males) and 167 age- and sex-matched patients with HTN/DM (60±10 years; 64% males). Replacement myocardial fibrosis was defined as nonischemic late gadolinium enhancement on cardiovascular magnetic resonance. Extracellular volume fraction was used as a marker of diffuse myocardial fibrosis. A total of 184 serum proteins (Olink Target Cardiovascular Disease II and III panels) were measured to identify unique signatures associated with myocardial fibrosis in all patients. RESULTS: Despite similar left ventricular mass (P=0.344) and systolic blood pressure (P=0.086), patients with HTN/DM had increased concentricity and worse multidirectional strain (P<0.001 for comparison of all strain measures) compared to hypertension only. Replacement myocardial fibrosis was present in 28% of patients with HTN/DM compared to 16% of those with hypertension (P<0.001). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was the only protein differentially upregulated in hypertension patients with replacement myocardial fibrosis and independently associated with extracellular volume. In patients with HTN/DM, GDF-15 (growth differentiation factor 15) was independently associated with replacement myocardial fibrosis and extracellular volume. Ingenuity Pathway Analysis demonstrated a strong association between increased inflammatory response/immune cell trafficking and myocardial fibrosis in patients with HTN/DM. CONCLUSIONS: Adverse cardiac remodeling was observed in patients with HTN/DM. The novel proteomic signatures and associated biological activities of increased immune and inflammatory response may partly explain these observations.

The New Era of Retinal Imaging in Hypertensive Patients.

ABSTRACT: Structural and functional alterations in the microcirculation by systemic hypertension can cause significant organ damage at the eye, heart, brain, and kidneys. As the retina is the only tissue in the body that allows direct imaging of small vessels, the relationship of hypertensive retinopathy signs with development of disease states in other organs have been extensively studied; large-scale epidemiological studies using fundus photography and advanced semi-automated analysis software have reported the association of retinopathy signs with hypertensive end-organ damage includes the following: stroke, dementia, and coronary heart disease. Although yielding much useful information, the vessels assessed from fundus photographs remain limited to the larger retinal arterioles and venules, and abnormalities observed may not be that of the earliest changes. Newer imaging modalities such as optical coherence tomography angiography and adaptive optics technology, which allow a greater precision in the structural quantification of retinal vessels, including capillaries, may facilitate the assessment and management of these patients. The advent of deep learning technology has also augmented the utility of fundus photographs to help create diagnostic and risk stratification systems. Particularly, deep learning systems have been shown in several large studies to be able to predict multiple cardiovascular risk factors, major adverse cardiovascular events within 5 years, and presence of coronary artery calcium, from fundus photographs alone. In the future, combining deep learning systems with the imaging precision offered by optical coherence tomography angiography and adaptive optics could pave way for systems that are able to predict adverse clinical outcomes even more accurately.

Relationship of Quantitative Retinal Capillary Network and Myocardial Remodeling in Systemic Hypertension.

Background This study examined the associations between quantitative optical coherence tomography angiography (OCTA) parameters and myocardial abnormalities as documented on cardiovascular magnetic resonance imaging in patients with systemic hypertension. Methods and Results We conducted a cross-sectional study of 118 adults with hypertension (197 eyes). Patients underwent cardiovascular magnetic resonance imaging and OCTA (PLEX Elite 9000, Carl Zeiss Meditec). Associations between OCTA parameters (superficial and deep retinal capillary density) and adverse cardiac remodeling (left ventricular mass, remodeling index, interstitial fibrosis, global longitudinal strain, and presence of left ventricular hypertrophy) were studied using multivariable linear regression analysis with generalized estimating equations. Of the 118 patients with hypertension enrolled (65% men; median [interquartile range] age, 59 [13] years), 29% had left ventricular hypertrophy. After adjusting for age, sex, systolic blood pressure, diabetes, and signal strength of OCTA scans, patients with lower superficial capillary density had significantly higher left ventricular mass (ß=-0.150; 95% CI, -0.290 to -0.010), higher interstitial volume (ß=-0.270; 95% CI, -0.535 to -0.0015), and worse global longitudinal strain (ß=-0.109; 95% CI, -0.187 to -0.032). Lower superficial capillary density was found in patients with hypertension with replacement fibrosis versus no replacement fibrosis (16.53±0.64 mm-1 versus 16.96±0.64 mm-1; P=0.003). Conclusions We showed significant correlations between retinal capillary density and adverse cardiac remodeling markers in patients with hypertension, supporting the notion that the OCTA could provide a non-invasive index of microcirculation alteration for vascular risk stratification in people with hypertension.

Markers of Focal and Diffuse Nonischemic Myocardial Fibrosis Are Associated With Adverse Cardiac Remodeling and Prognosis in Patients With Hypertension: The REMODEL Study.

BACKGROUND: The prognostic significance of focal and diffuse myocardial fibrosis in patients with cardiovascular risk factors is unclear. METHODS: REMODEL (Response of the Myocardium to Hypertrophic Conditions in the Adult Population) is an observational cohort of asymptomatic patients with essential hypertension. All participants underwent cardiovascular magnetic resonance to assess for myocardial fibrosis: nonischemic late gadolinium enhancement (LGE), native myocardial T1, postcontrast myocardial T1, extracellular volume fraction including/excluding LGE regions, interstitial volume (extracellular volume×myocardial volume), and interstitial/myocyte ratio. Primary outcome was a composite of first occurrence acute coronary syndrome, heart failure hospitalization, strokes, and cardiovascular mortality. Patients were recruited from February 2016 and followed until June 2021. RESULTS: Of the 786 patients with hypertension (58±11 years; 39% women; systolic blood pressure, 130±14 mm Hg), 145 (18%) had nonischemic LGE. Patients with nonischemic LGE were more likely to be men, have diabetes, be current smokers, and have higher blood pressure (P<0.05 for all). Compared with those without LGE, patients with nonischemic LGE had greater left ventricular mass (66±22 versus 49±9 g/m2; P<0.001), worse multidirectional strain (P<0.001 for all measures), and elevated circulating markers of myocardial wall stress and myocardial injury, adjusted for potential confounders. Twenty-four patients had primary outcome over 39 (30-50) months of follow-up. Of all the cardiovascular magnetic resonance markers of myocardial fibrosis assessed, only nonischemic LGE (hazard ratio, 6.69 [95% CI, 2.54-17.60]; P<0.001) and indexed interstitial volume (hazard ratio, 1.11 [95% CI, 1.04-1.19]; P=0.002) demonstrated independent association with primary outcome. CONCLUSIONS: In patients with hypertension, myocardial fibrosis on cardiovascular magnetic resonance is associated with adverse cardiac remodeling and outcomes.

The Application of Optical Coherence Tomography Angiography in Systemic Hypertension: A Meta-Analysis.

Objective: Multiple studies have compared various optical coherence tomography angiography (OCTA) parameters in participants with systemic hypertension vs. controls and have presented discordant findings. We conducted a meta-analysis to pool together data from different studies to generate an overall effect size and find out whether OCTA parameter(s) significantly differed in participants with systemic hypertension as compared to controls. Methods: We conducted a literature search through a search of electronic databases to identify studies before 19 June 2021, which compared OCTA parameters in non-diabetic participants with systemic hypertension vs. controls. If the OCTA parameter had a minimum number of 3 studies that analyzed it, the mean difference between participants with systemic hypertension and controls were analyzed using a random-effects model. Results: We identified 11 eligible studies. At the macula, 9 studies analyzed vessel density at the superficial capillary plexus (SVD), 7 analyzed vessel density at the deep capillary plexus (DVD), and 6 analyzed the area of the superficial foveal avascular zone (FAZ). Participants with systemic hypertension had significantly lower SVD (standardized mean difference [SMD], -0.50 [-0.70, -0.30], P < 0.00001, I 2 = 63%), lower DVD (SMD, -0.38 [-0.64, -0.13], P = 0.004, I 2 = 67%) and larger superficial FAZ (SMD, 0.32 [0.04, 0.61], P = 0.020, I 2 = 77%). Conclusion: The eyes of people with systemic hypertension have robustly lower superficial and deep vascular densities at the macula when compared to control eyes. Our results suggest that OCTA can provide information about pre-clinical microvascular changes from systemic hypertension.

The remodelling index risk stratifies patients with hypertensive left ventricular hypertrophy.

AIMS: Hypertensive left ventricular hypertrophy (LVH) is associated with increased cardiovascular events. We previously developed the remodelling index (RI) that incorporated left ventricular (LV) volume and wall-thickness in a single measure of advanced hypertrophy in hypertensive patients. This study examined the prognostic potential of the RI in reference to contemporary LVH classifications. METHODS AND RESULTS: Cardiovascular magnetic resonance was performed in 400 asymptomatic hypertensive patients. The newly derived RI (EDV3t, where EDV is LV end-diastolic volume and t is the maximal wall thickness across 16 myocardial segments) stratified hypertensive patients: no LVH, LVH with normal RI (LVHNormal-RI), and LVH with low RI (LVHLow-RI). The primary outcome was a composite of all-cause mortality, acute coronary syndromes, strokes, and decompensated heart failure. LVHLow-RI was associated with increased LV mass index, fibrosis burden, impaired myocardial function and elevated biochemical markers of myocardial injury (high-sensitive cardiac troponin I), and wall stress. Over 18.3 ± 7.0 months (601.3 patient-years), 14 adverse events occurred (2.2 events/100 patient-years). Patients with LVHLow-RI had more than a five-fold increase in adverse events compared to those with LVHNormal-RI (11.6 events/100 patient-years vs. 2.0 events/100 patient-years, respectively; log-rank P < 0.001). The RI provided incremental prognostic value over and above a model consisting of clinical variables, LVH and concentricity; and predicted adverse events independent of clinical variables, LVH, and other prognostic markers. Concentric and eccentric LVH were associated with adverse prognosis (log-rank P = 0.62) that was similar to the natural history of hypertensive LVH (5.1 events/100 patient-years). CONCLUSION: The RI provides prognostic value that improves risk stratification of hypertensive LVH.

Choriocapillaris microvasculature dysfunction in systemic hypertension.

We examined the choriocapillaris microvasculature using a non-invasive swept-source optical coherence tomography angiography (SS-OCTA) in 41 healthy controls and 71 hypertensive patients and determined possible correlations with BP and renal parameters. BP levels, serum creatinine and urine microalbumin/creatinine ratio (MCR) specimens were collected. The estimated glomerular filtration rate (eGFR) was calculated based on CKD-EPI Creatinine Equation. The main outcome was choriocapillaris flow deficits (CFD) metrics (density, size and numbers). The CFD occupied a larger area and were fewer in number in the hypertensive patients with poor BP control (407 ± 10 µm2; 3260 ± 61) compared to the hypertensives with good BP control (369 ± 5 µm2; 3551 ± 41) and healthy controls (365 ± 11 µm2; 3581 ± 84). Higher systolic BP (ß = 9.90, 95% CI, 2.86-16.93), lower eGFR (ß = - 0.85; 95% CI, - 1.58 to - 0.13) and higher urine MCR (ß = 1.53, 95% CI, 0.32-2.78) were associated with larger areas of CFD. Similar significant associations with systolic BP, eGFR and urine MCR were found with number of CFD. These findings highlight the potential role of choriocapillaris imaging using SS-OCTA as an indicator of systemic microvascular abnormalities secondary to hypertensive disease.