Exploring the link between blood pressure variability and atrial fibrillation: current insights and future directions.

Atrial fibrillation (AF) is the most common heart rhythm disorder, especially in people over the age of 50, which affects more than 40 million people worldwide. Many studies have highlighted the association between hypertension with the development of AF. Blood pressure variability (BPV) is a dynamic size obtained by recording blood pressure oscillations using specific readings and at specific time intervals. A multitude of internal and external factors shape BPV while at the same time constituting a common pathogenetic pathway with the development of AF. Until recently, BPV has been applied exclusively in preclinical and clinical studies, without significant implications in clinical practice. Indeed, even from the research side, the determination of BPV is limited to patients without AF due to doubts about the accuracy of its measurement methods in patients with AF. In this review, we present the current evidence on common pathogenic pathways between BPV and AF, the reliability of quantification of BPV in patients with AF, the prognostic role of BPV in these patients, and discuss the future clinical implications of BPV in patients with AF.

Retinal Vessel Caliber Measurement Bias in Fundus Images in the Presence of the Central Light Reflex.

Purpose: To investigate the agreement between a fundus camera and a scanning laser ophthalmoscope in retinal vessel caliber measurements and to identify whether the presence of the central light reflex (CLR) explains potential discrepancies. Methods: For this cross-sectional study, we obtained fundus camera and scanning laser ophthalmoscope images from 85 eyes of 85 healthy individuals (aged 50-65 years) with different blood pressure status. We measured the central retinal artery equivalent (CRAE) and central retinal artery vein equivalent (CRVE) with the Knudtson-Parr-Hubbard algorithm and assessed the CLR using a semiautomatic grading method. We used Bland-Altman plots, 95% limits of agreement, and the two-way mixed effects intraclass correlation coefficient for consistency [ICC(3,1)] to describe interdevice agreement. We used multivariable regression to identify factors associated with differences in between-device measurements. Results: The between-device difference in CRAE (9.5  µm; 95% confidence interval, 8.0-11.1  µm) was larger than the between-device difference in CRVE (2.9  µm; 95% confidence interval, 1.3-4.5  µm), with the fundus camera yielding higher measurements (both P < 0.001). The 95% fundus camera-scanning laser ophthalmoscope limits of agreement were -4.8 to 23.9  µm for CRAE and -12.0 to 17.8  µm for CRVE. The corresponding ICCs(3,1) were 0.89 (95% confidence interval, 0.83-0.92) and 0.91 (95% confidence interval, 0.86-0.94). The between-device CRAE difference was positively associated with the presence of a CLR (P = 0.002). Conclusions: Fundus cameras and scanning laser ophthalmoscopes yield correlated but not interchangeable caliber measurements. The CLR induces bias in arteriolar caliber in fundus camera images, compared with scanning laser ophthalmoscope images. Translational Relevance: Refined measurements could yield better estimates of the association between retinal vessel caliber and ophthalmic or systemic disease.

Imaging of Left Main Coronary Artery; Untangling the Gordian Knot.

Left Main Coronary Artery (LMCA) disease is considered a standout manifestation of coronary artery disease (CAD), because it is accompanied by the highest mortality. Increased mortality is expected, because LMCA is responsible for supplying up to 80% of total blood flow to the left ventricle in a right-dominant coronary system. Due to the significant progress of biomedical technology, the modern drug-eluting stents have remarkably improved the prognosis of patients with LMCA disease treated invasively. In fact, numerous randomized trials provided similar results in one- and five-year survival of patients treated with percutaneous coronary interventions (PCI) -guided with optimal imaging and coronary artery bypass surgery (CABG). However, interventional treatment requires optimal imaging of the LMCA disease, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The aim of this manuscript is to review the main pathophysiological characteristics, to present the imaging techniques of LMCA, and, last, to discuss the future directions in the depiction of LMCA disease.

Retinal Oxygen Delivery and Extraction in Ophthalmologically Healthy Subjects With Different Blood Pressure Status.

PURPOSE: To compare retinal oxygen delivery (DO2) and oxygen extraction (VO2) in ophthalmologically healthy subjects with different blood pressure (BP) status. METHODS: In this case-control study, we prospectively included 93 eyes of 93 subjects (aged 50-65 years) from a Dutch cohort (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We estimated vascular calibers from fundus images and fractal dimension from optical coherence tomography angiography scans. We combined calibers, fractal dimension, BP, and intraocular pressure measurements in a proxy of retinal blood flow (RBF), using a Poiseuille-based model. We measured arterial and venous oxygen saturations (SaO2, SvO2) with a scanning laser ophthalmoscope. We calculated the DO2 and VO2 from the RBF, SaO2, and SvO2. We compared the DO2 and VO2 between groups and investigated the DO2-VO2 association. RESULTS: DO2 and VO2 were different between groups (P = 0.009, P = 0.036, respectively). In a post hoc analysis, the low BP group had lower DO2 than the untreated AHT group (P = 4.9 × 10-4). The low BP group and the treated AHT group had a lower VO2 than the untreated AHT group (P = 0.021 and P = 0.034, respectively). There was a significant DO2-VO2 correlation (Robs = 0.65, bobs = 0.51, P = 2.4 × 10-12). After correcting for shared measurement error, the slope was not significant. CONCLUSIONS: The DO2 and VO2 were altered in ophthalmologically healthy subjects with different BP status. Future studies could elucidate whether these changes can explain the increased risk of ophthalmic pathologies in those subjects. TRANSLATIONAL RELEVANCE: Understanding the baseline interplay between BP, retinal perfusion, and oxygenation allows for improved evaluation of retinal disease manifestation.

U-Shaped Effect of Blood Pressure on Structural OCT Metrics and Retinal Perfusion in Ophthalmologically Healthy Subjects.

Purpose: We wanted to investigate the association of blood pressure (BP) status with the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thickness of nonglaucomatous eyes and to elucidate whether this effect is related to vascular metrics proxying retinal perfusion. Methods: For this case-control study, we prospectively included 96 eyes of 96 healthy subjects (age 50-65) from a large-scale population-based cohort in the northern Netherlands (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We measured macular GCIPL and RNFL (mRNFL) and peripapillary RNFL (pRNFL) thicknesses with optical coherence tomography (OCT). We estimated retinal blood flow (RBF), retinal vascular resistance (RVR), and autoregulatory reserve (AR) from quantitative OCT-angiography, fundus imaging, BP, and intraocular pressure. We compared structural and vascular metrics across groups and performed mediation analysis. Results: Compared to controls, GCIPL was thinner in the low BP group (P = 0.013), treated hypertensives (P = 0.007), and untreated hypertensives (P = 0.007). Treated hypertensives exhibited the thinnest mRNFL (P = 0.001), temporal pRNFL (P = 0.045), and inferior pRNFL (P = 0.034). The association of GCIPL thickness with BP was mediated by RBF within the combined low BP group and controls (P = 0.003), by RVR and AR within the combined treated hypertensives and controls (P = 0.001, P = 0.032), and by RVR within the combined untreated antihypertensives and controls (P = 0.022). Conclusions: Inner retinal thinning was associated with both tails of the BP distribution and with ineffective autoregulation. Longitudinal studies could clarify whether these defects can explain the reported glaucomatous predisposition of these population groups.

Combined Multi-Modal Assessment of Glaucomatous Damage With Electroretinography and Optical Coherence Tomography/Angiography.

Purpose: To compare the diagnostic performance and to evaluate the interrelationship of electroretinographical and structural and vascular measures in glaucoma. Methods: For 14 eyes of 14 healthy controls and 15 eyes of 12 patients with glaucoma ranging from preperimetric to advanced stages optical coherence tomography (OCT), OCT-angiography (OCT-A), and electrophysiological measures (multifocal photopic negative response ratio [mfPhNR] and steady-state pattern electroretinography [ssPERG]) were applied to assess changes in retinal structure, microvasculature, and function, respectively. The diagnostic performance was assessed via area-under-curve (AUC) measures obtained from receiver operating characteristics analyses. The interrelation of the different measures was assessed with correlation analyses. Results: The mfPhNR, ssPERG amplitude, parafoveal (pfVD) and peripapillary vessel density (pVD), macular ganglion cell inner plexiform layer thickness (mGCIPL) and peripapillary retinal nerve fiber layer thickness (pRNFL) were significantly reduced in glaucoma. The AUC for mfPhNR was highest among diagnostic modalities (AUC: 0.88, 95% confidence interval: 0.75-1.0, P < 0.001), albeit not statistically different from that for macular (mGCIPL: 0.76, 0.58-0.94, P < 0.05; pfVD: 0.81, 0.65-0.97, P < 0.01) or peripapillary imaging (pRNFL: 0.85, 0.70-1.0, P < 0.01; pVD: 0.82, 0.68-0.97, P < 0.01). Combined functional/vascular measures yielded the highest AUC (mfPhNR-pfVD: 0.94, 0.85-1.0, P < 0.001). The functional/structural measure correlation (mfPhNR-mGCIPL correlation coefficient [rs]: 0.58, P = 0.001; mfPhNR-pRNFL rs: 0.66, P < 0.001) was stronger than the functional-vascular correlation (mfPhNR-pfVD rs: 0.29, P = 0.13; mfPhNR-pVD rs: 0.54, P = 0.003). Conclusions: The combination of ERG measures and OCT-A improved diagnostic performance and enhanced understanding of pathophysiology in glaucoma. Translational Relevance: Multimodal assessment of glaucoma damage improves diagnostics and monitoring of disease progression.

Microcirculatory model predicts blood flow and autoregulation range in the human retina: in vivo investigation with laser speckle flowgraphy.

In this study, we mathematically predict retinal vascular resistance (RVR) and retinal blood flow (RBF), we test predictions using laser speckle flowgraphy (LSFG), we estimate the range of vascular autoregulation, and we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, optical coherence tomography (OCT), and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained from 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregulation limits (LARL/HARL), using retinal vessel calibers, fractal dimension, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R2 = 0.77/P = 6.9·10-9) and RBF (R2 = 0.65/P = 1.0·10-6), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P = 4.0·10-4) and GCC (P = 0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies.NEW & NOTEWORTHY We describe and test a new approach to quantify retinal blood flow, based on standard clinical examinations and imaging techniques, linked together with a physiological model. We use these findings to generate individualized estimates of the autoregulation range. We provide evidence that healthy subjects are closer to the lower autoregulation limit than thought before. This suggests that some retinas are less prepared to withstand hypoperfusion, even after small intraocular pressure rises or blood pressure drops.

Association of Systemic Medication Exposure With Glaucoma Progression and Glaucoma Suspect Conversion in the Groningen Longitudinal Glaucoma Study.

Purpose: To determine the association of statins, five classes of antihypertensive medications, and proton pump inhibitors with (1) primary open-angle glaucoma (POAG) progression and (2) conversion of POAG suspects to POAG. Methods: We retrospectively investigated the records of a cohort with POAG cases and suspects from the Groningen Longitudinal Glaucoma Study. To quantify visual field (VF) deterioration in cases, we used the rate of progression of the mean deviation (MD). Suspects were considered to have converted at the time point after which two consecutive VF tests for at least one eye were abnormal (glaucoma hemifield test outside normal limits). Progression and conversion were analyzed with quantile and logistic regression, respectively, with the systemic medications as predictors, controlling for age, sex, body mass index, pretreatment IOP, corneal thickness, and baseline MD. The multivariable models were built with and without IOP intervention. Results: No systemic medications were associated with POAG progression in the final IOP/treatment-adjusted or unadjusted model. However, angiotensin II receptor blockers (ARBs) appeared to slow progression in older patients (b = 0.014, P = 0.0001). Angiotensin-converting enzyme inhibitors (ACEIs) were significantly associated with a decrease in POAG suspect conversion in both the IOP/treatment-adjusted and -unadjusted model (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.07-0.79, P = 0.012; OR=0.24, 95% CI 0.07-0.78, P = 0.021, respectively), as were ARBs (OR 0.12, 95% CI 0.01-0.98, P = 0.014; OR 0.11, 95% CI 0.01-0.87, P = 0.005, respectively). Conclusions: No overall association of VF progression with systemic medication was found; ARBs delayed progression in older patients. ACEIs and ARBs were associated with lower risk of suspect conversion. The pathophysiology of this relationship is to be disentangled.

Quantification and Repeatability of Vessel Density and Flux as Assessed by Optical Coherence Tomography Angiography.

PURPOSE: To determine the intrasession repeatability (test-retest variability) of parafoveal and peripapillary perfused capillary density (PCD) and normalized flux index (NFI) as assessed with Canon OCT-HS100 angiography. METHODS: Pairs of optical coherence tomography angiography (OCT-A) images were obtained from the parafoveal and peripapillary region of 30 eyes of 30 healthy subjects. PCD and NFI were calculated using generic image-processing software. Macular ganglion-cell complex thickness (GCC) and peripapillary retinal nerve fiber layer thickness (RNFLT) were also recorded. Bland-Altman analysis was performed and the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) were calculated. Correlations of parafoveal PCD/NFI with GCC and of peripapillary PCD/NFI with RNFLT were also computed. RESULTS: Mean (standard deviation) parafoveal and peripapillary PCD were 40.0% (1.8%) and 44.5% (1.3%), respectively. Corresponding values for NFI were 151.2 (6.8) and 164.2 (3.9). For PCD, ICC was 0.76 for parafoveal and 0.79 for peripapillary measurements; corresponding CoRs were 2.7% and 1.8%. Corresponding values for NFI were 0.62 and 0.67 for ICC and 13.3 and 7.0 for CoR. Average measures ICC was 0.87/0.88 and 0.76/0.80 for the parafoveal/peripapillary PCD and NFI, respectively. PCD and NFI were weakly correlated with GCC (r = 0.39, P = 0.035; r = 0.33, P = 0.077) and moderately correlated with RNFLT (r = 0.43, P = 0.017; r = 0.55, P = 0.002). CONCLUSIONS: Repeatability of a commercially available OCT-A with generic image-processing software was good (NFI) to excellent (PCD). Our results indicate that changes surpassing the variability in healthy subjects should be easily detectable in a clinical setting. TRANSLATIONAL RELEVANCE: Repeatability estimates provide information regarding the relevance of changes in retinal perfusion.