How important is blood pressure variability?

Arterial blood pressure (BP) is a continuous variable, with a physiology characterized by significant variability stemming from the complex interaction among haemodynamic factors, neuronal reflexes, as well as hormonal, behavioural, and environmental stimuli. The homoeostatic response accounts for the physiologic variability in BP in normotensive individuals, which is more evident in hypertensive patients. Blood pressure variability is a complex phenomenon, which could be classified in various types: very short term (beat to beat), short term (during 24 h), mid-term (day by day), long term (<5 years), and very long term (>5 years). Accurate measurement of BP variability represents a complex and often controversial endeavour, despite several methodological approaches are available. Albeit a prognostic significance has been demonstrated for some indicators of BP variability, the clinical significance of this measurement is still uncertain. In fact, none of the indicators presently available for BP variability, including early morning BP rise, substantially affects, and redefines, the cardiovascular risk of the hypertensive patient, over and beyond the mere BP values. Accordingly, in defining the cardiovascular risk, the focus should be on the absolute BP values, which remain the most relevant risk factor, and the one more susceptible to modification with both non-pharmacologic and pharmacologic treatment.

Prognostic significance of the wall to lumen ratio of retinal arterioles evaluated by adaptive optics.

OBJECTIVE: Microvascular structural alterations may be considered an important form of hypertension-mediated organ damage. An increased media-to-lumen ratio of subcutaneous small arteries evaluated with locally invasive techniques (micromyography) predicts the development of cardiovascular (CV) events. However, it is not known whether retinal arteriole structural alterations evaluated with a noninvasive approach (Adaptive Optics) may have a prognostic significance. DESIGN AND METHODS: Two-hundred and thirty-seven subjects (mean age 58.7 ± 16.1 years, age range 13-89 years; 116 males) were included in the study: 65 normotensive subjects (27.4 %) and 172 patients with essential hypertension or primary aldosteronism (72.6 %). All subjects underwent a non-invasive evaluation of retinal arteriolar wall-to-lumen ratio (WLR) by Adaptive Optics. Subjects were re-evaluated after an average follow-up time of 4.55 years in order to assess the occurrence of clinical events (non CV and/or CV death or events). RESULTS: Fifty-four events occurred in the study population:26 were cardio-cerebrovascular events (ischemic or hemorragic stroke, atrial fibrillation, heart failure, coronary artery disease, peripheral artery disease, cardiac valvular disease) while the remaining were deaths for any cause, or neoplastic diseases. Subjects with events were older and had a WLR of retinal arterioles significantly greater than those without events. The event-free survival was significantly worse in those with a baseline WLR above the median value of the population (0.28) according to Kaplan-Mayer survival curves and multivariate analysis (Cox's proportional hazard model). The evidence was confirmed after restricting the analysis to CV events. CONCLUSIONS: Structural alterations of retinal arterioles evaluated by Adaptive Optics may predict total and CV events.

Retinal microvascular alterations in patients with active rheumatoid arthritis without cardiovascular risk factors: the potential effects of T cell co-stimulation blockade.

Background: The evaluation of microvascular alterations might provide clinically useful information for patients with an increased cardiovascular (CV) risk, such as those with rheumatoid arthritis (RA), being the small artery remodeling the earliest form of target organ damage in primary CV diseases, such as arterial hypertension. The evaluation of retinal arterioles is a non-invasive technique aimed to identify an early microvascular damage, represented by the increase of the wall-to-lumen ratio (WLR) index. Abatacept (ABA), a T-cell co-stimulator blocker, is used to treat RA. A CV protective action was hypothesized for its peculiar mechanism of action in the modulation of T-cells, potentially involved in the pathogenesis of CV comorbidity. The study aimed to non-invasively investigate morphological characteristics of retinal arterioles in a cohort of RA patients treated with ABA. Materials and methods: Seventeen RA patients [median (25th-75thpercentile) age = 58 (48-64) years, baseline 28-joint Disease Activity Score DAS28-C-reactive protein (DAS28-CRP) = 4.4 (3.9-4.6), body mass index (BMI) = 24.2 (23.4-26) kg/m2, rheumatoid factor positive:52.9%, anti-citrullinated peptide autoantibodies positive:76.5%] without known CV risk factors (arterial hypertension, diabetes, hypercholesterolemia, previous CV events, smoking) were evaluated by the adaptive optics imaging system of retinal arterioles before and every 6 months of therapy with ABA (T0, T6 and T12). Office blood pressure evaluation, 24-h ambulatory blood pressure monitoring and tissue-doppler echocardiography were also performed. Results: A progressive significant reduction of the WLR of retinal arterioles was observed [T0 = 0.28 (0.25-0.30), T6 = 0.27 (0.24-0.31), T12 = 0.23 (0.23-0.26); p T0 vs. T6 = 0.414; p T6 vs. T12 = 0.02; p T0 vs. T12 = 0.009], without significant variations in other parameters. The T0-T12 reduction of WLR was correlated with that of DAS28-CRP (r:0.789; p = 0.005). Moreover, a significant reduction of diastolic office blood pressure and a trend for reduction of daily pressure measured by ambulatory monitoring were observed. Conclusion: In a cohort of RA patients without known CV risk factors, a reduction of retinal microvascular alterations was demonstrated after treatment for 12 months with ABA, in parallel with the reduction of disease activity. These results might suggest the possibility of microvascular abnormalities regression induced by the immune system modulation.

Atypical Varicella-Zoster Virus Reactivation: A Case Report.

Varicella-zoster virus (VZV) commonly causes benign skin manifestations in children; it then establishes a latent infection and may reactivate, causing herpes zoster. The most common zoster complication is postherpetic neuralgia, but complications can also occur without a rash. VZV infection may cause neurological manifestations and even vasculopathy may occur, in both primary and reactivated VZV infection. Thrombotic complications are mainly described in children, while a few case reports have described cerebral venous sinus thrombosis (CVST), deep-vein thrombosis of the lower limbs and pulmonary embolism in adults. In this article we report the case of a young woman who developed systemic thromboembolic sequelae due to a hypercoagulable state following VZV reactivation. She had deep venous lower-limb thrombosis extended to the inferior vena cava (IVC), massive pulmonary embolism and CVST. Moreover, VZV reactivation caused an acute hepatitis and clinical manifestations suggesting viral encephalitis. LEARNING POINTS: Varicella-zoster virus (VZV) commonly causes self-limiting skin manifestation, but even neurological manifestations and thrombotic complications may occur.Only few isolated cases of VZV-related cerebral venous sinus thrombosis (CVST) and other types of deep-vein thrombosis have been reported in adults.Early diagnosis of VZV-related thrombosis and prompt anticoagulant and antiviral therapy can prevent a potentially fatal outcome and produce a good prognosis.

Skin capillary alterations in patients with acute SarsCoV2 infection.

BACKGROUND: Acute SarsCov2 infection is associated with endothelial dysfunction and 'endothelitis', which might explain systemic microvascular impairment. The presence of endothelial damage may promote vasoconstriction with organ ischemia, inflammation, tissue oedema and a procoagulant state resulting in an increase in the incidence of cardiovascular and cerebrovascular events. Microvascular thrombosis has been demonstrated in postmortem autopsy of COVID-19 patients; however, few data are available about skin capillary alterations in these patients. MATERIALS AND METHODS: We evaluated skin microvascular alteration in 22 patients admitted to our hospital with SarsCov2 infection. Capillary density was evaluated by capillaroscopy in the nailfold and the dorsum of the finger in the acute phase of the disease. Capillaroscopy was repeated after 3 months (recovery phase). In addition, blood chemistry parameters and inflammatory markers were obtained during acute infection and at the recovery after 3 months. RESULTS: Patients with COVID-19 showed skin microvascular complications, such as thrombosis, microhaemorrhages and neoangiogenesis, which were not detected after 3 months from the discharge. A significant reduction of capillary density in the dorsum was observed after 3 months from the acute infection (97.2 ±â€Š5.3 vs. 75.81 ±â€Š3.9 n/mm 2P  < 0.05). A significant inverse correlation between C-reactive protein and capillary density was observed in patients with acute SarsCov2 infection ( r  = 0.44, P  < 0.05). Conversely a direct correlation between capillary density during the acute phase and lymphocyte number was detected ( r  = 0.49, P  < 0.05). CONCLUSION: This is the first in-vivo evidence of skin capillary thrombosis, microhaemorrhages and angiogenesis in patients with acute SarsCov2 infection, which disappeared after 3 months, supporting the presence of endothelial dysfunction and inflammation. Capillary alterations might reflect systemic vascular effects of viral infection.

Comparison of the characteristics, morbidity and mortality of COVID-19 between first and second/third wave in a hospital setting in Lombardy: a retrospective cohort study.

Coronavirus disease 2019 (COVID-19) represents a major health problem in terms of deaths and long-term sequelae. We conducted a retrospective cohort study at Montichiari Hospital (Brescia, Italy) to better understand the determinants of outcome in two different COVID-19 outbreaks. A total of 634 unvaccinated patients admitted from local emergency room to the Internal Medicine ward with a confirmed diagnosis of SARS-CoV-2 infection and a moderate-to-severe COVID-19 were included in the study. A group of 260 consecutive patients during SARS-CoV-2 first wave (from February to May 2020) and 374 consecutive patients during SARS-CoV-2 2nd/3rd wave (from October 2020 to May 2021) were considered. Demographic data were not significantly different between waves, except a lower prevalence of female sex during first wave. Mortality was significantly higher during the 1st wave than in the following periods (24.2% vs. 11%; p < 0.001). Time from symptoms onset to hospital admission was longer during first wave (8 ± 6 vs. 6 ± 4 days; p < 0.001), while in-hospital staying was significantly shorter (10 ± 14 vs. 15 ± 11 days; p < 0.001). Other significant differences were a larger use of corticosteroids and low-molecular weight heparin as well less antibiotic prescription during the second wave. Respiratory, bio-humoral and X-ray scores were significantly poorer at the time of admission in first-wave patients. After a multivariate regression analysis, C-reactive protein and procalcitonin values, % fraction of inspired oxygen on admission to the Internal Medicine ward and length of hospital stay and duration of symptoms were the strongest predictors of outcome. Concomitant anti-hypertensive treatment (including ACE-inhibitors and angiotensin-receptor blockers) did not affect the outcome. In conclusion, our data suggest that earlier diagnosis, timely hospital admission and rational use of the therapeutic options reduced the systemic inflammatory response and were associated to a better outcome during the 2nd/3rd wave.

Microvascular Structural Alterations in Cancer Patients Treated With Antiangiogenic Drugs.

Objective: Antiangiogenic therapies (tyrosine kinase inhibitors-TKI and direct anti-VEGF monoclonal antibodies) are being increasingly used in the treatment of solid tumors; hypertension represents a common side effect of these agents. Several mechanisms are involved in the development of hypertension, including microvascular rarefaction and other microvascular alterations. Therefore, the aim of our study was to evaluate whether TKI and direct anti-VEGF agents may affect the structure of retinal arterioles or capillary density. Design and Methods: We investigated 20 patients with a diagnosis of cancer who underwent a treatment with either a TKI or an anti-VEGF antibody. Patients were submitted to ambulatory monitoring blood pressure for blood pressure evaluation. Basal and total capillary density were assessed by capillaroscopy whereas, retinal arteriole morphology was measured by Adaptive Optics. Patients were evaluated before starting the antiangiogenic therapy (T0) and re-evaluated after 3 (T3) and 6 (T6) months after treatment. Fourteen patients completed the study. Results: Systolic and diastolic blood pressure values were similar in all patients at T3 and T6 compared to T0. However, during the study antihypertensive treatment was optimized (increased dose and/or addition of drugs) in 57% of patients (n = 8). No differences were observed in retinal arteriole structural parameters and in large artery stiffness. Basal capillary density was reduced by antiangiogenic drugs after 3 or 6 months. Conclusions: Our data suggest that an increase of antihypertensive treatment is necessary in patients treated with a TKI or a direct VEGF inhibitor, confirming pro-hypertensive effects of these drugs. However, under adequate blood pressure control, microvascular structure seem to be partially preserved, since a worsening of basal capillary density but no changes in retinal arteriole morphology were observed.

Short-Term Consequences of SARS-CoV-2-Related Pneumonia: A Follow Up Study.

The aim of the study was to assess the short-term consequences of SARS-CoV-2-related pneumonia, also in relation to radiologic/laboratory/clinical indices of risk at baseline. This prospective follow-up cohort study included 94 patients with confirmed COVID-19 admitted to a medical ward at the Montichiari Hospital, Brescia, Italy from February 28th to April 30th, 2020. Patients had COVID-19 related pneumonia with respiratory failure. Ninety-four patients out of 193 survivors accepted to be re-evaluated after discharge, on average after 4 months. In » of the patients an evidence of pulmonary fibrosis was detected, as indicated by an altered diffusing capacity of the lung for carbon monoxide (DLCO); in 6-7% of patients the alteration was classified as of moderate/severe degree. We also evaluated quality of life thorough a structured questionnaire: 52% of the patients still lamented fatigue, 36% effort dyspnea, 10% anorexia, 14% dysgeusia or anosmia, 31% insomnia and 21% anxiety. Finally, we evaluated three prognostic indices (the Brixia radiologic score, the Charlson Comorbidity Index and the 4C mortality score) in terms of prediction of the clinical consequences of the disease. All of them significantly predicted the extent of short-term lung involvement. In conclusion, our study demonstrated that SARS-CoV-2-related pneumonia is associated to relevant short-term clinical consequences, both in terms of persistence of symptoms and in terms of impairment of DLCO (indicator of a possible development of pulmonary fibrosis); some severity indices of the disease may predict short-term clinical outcome. Further studies are needed to ascertain whether such manifestations may persist long-term.

Prognostic factors and predictors of outcome in patients with COVID-19 and related pneumonia: a retrospective cohort study.

The aim of the present study was to simultaneously assess several potential predictors of outcome (co-morbidity, previous and in-hospital treatment, radiologic Brixia score) in patients with COVID-19. This retrospective cohort study included 258 consecutive patients with confirmed COVID-19 admitted to a medical ward at Montichiari Hospital, Brescia, Italy from February 28th to April 30rd, 2020. Patients had SARS-CoV-2 related pneumonia with respiratory failure, and were treated with hydroxychloroquine and lopinavir plus ritonavir. In some patients, additional treatment with tocilizumab, dexamethasone and enoxaparin was adopted. Outcomes (death or recovery) were assessed at the end of the discharge period or at the end of the follow-up (August 2020). During hospitalization, 59 patients died, while 6 died after discharge. The following variables were demonstrated to be associated with a worse prognosis: Radiologic Brixia score higher than 8, presence at baseline of hypertension, diabetes, chronic obstructive pulmonary disease, heart disease, cancer, previous treatment with ACE-inhibitors or anti-platelet drugs. Anticoagulant treatment during hospital admission with enoxaparin at a dose higher than 4000 U once daily was associated with a better prognosis. In conclusion, our study demonstrates that some co-morbidities and cardiovascular risk factors may affect prognosis. The radiologic Brixia score may be a useful tool to stratify the risk of death at baseline. Anticoagulant treatment with enoxaparin might be associated to a clinical benefit in terms of survival in patients with COVID-19.

Vascular Aging and Disease of the Small Vessels.

Cardiovascular events are the consequence of vascular damage at both the macro and microcirculatory level. The relationship between large stiffening artery and microvascular disease may be bidirectional, since wave reflection from microvascular sites could increase systolic blood pressure and pulse pressure, while transmission of increased arterial pulsatility to microvessels could represent a mechanism of damage. Hypertension and aging share similar mechanisms of vascular dysfunction. In fact, vascular remodelling, endothelial dysfunction and vascular stiffness are common features in hypertension and aging. Structural and functional changes in small arteries occur during normal and accelerated aging, possibly triggered by hypertension. A cross-talk may be present between large and small artery changes, interacting with pressure wave transmission and reflection, exaggerating cardiac, brain and kidney damage, and finally leading to cardiovascular and renal complications.