Background-The presence of structural alterations in the microcirculation may be considered an important mechanism of organ damage; however, it is not currently known whether structural alterations of small arteries may predict fatal and nonfatal cardiovascular events. Methods and Results-One hundred twenty-eight patients were included in the present study. There were 59 patients with essential hypertension, 17 with pheochromocytoma, 20 with primary aldosteronism, 12 with renovascular hypertension, and 20 normotensive patients with non-insulin-dependent diabetes mellitus. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media-to-internal lumen ratio (M/L) was measured. The subjects were reevaluated after an average follow-up time of 5.4 years. Thirty-seven subjects had a documented fatal or nonfatal cardiovascular event (5.32 events/100 patients per year). In the subcutaneous small arteries of subjects with cardiovascular events, a smaller internal diameter and a clearly greater M/L was observed. Our subjects were subdivided according to the presence of an M/L greater or smaller than the mean and median values observed in the whole population (0.098) or mean value ϩ2 SD of our normal subjects (0.11). Life-

Objective-Angiotensin (Ang) II-induced vascular damage may be partially mediated by reactive oxygen species generation and inflammation. Homozygous osteopetrotic mice (Op/Op), deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We therefore investigated Ang II effects on vascular structure, function, and oxidant stress generation in this model. Methods and Results-Adult Op/Op, heterozygous (Op/ϩ), and wild type (ϩ/ϩ) mice underwent 14-day Ang II (1000 ng/kg per minute) or saline infusion. Blood pressure (BP) was assessed by radiotelemetry, mesenteric resistance artery vascular reactivity was studied on a pressurized myograph, and vascular superoxide and NAD(P)H oxidase activity by lucigenin chemiluminescence. Ang II increased BP in Op/ϩ and ϩ/ϩ mice but not in Op/Op. Ang II-treated Op/ϩ and ϩ/ϩ mice showed reduced acetylcholine-mediated relaxation (maximal relaxation, respectively, 64% and 67% versus 84% and 93% in respective controls; PϽ0.05), which was unaffected by L-NAME. Ang II-infused Op/Op mice arteries showed significantly less endothelial dysfunction than vehicle-infused counterparts (maximal relaxation 87% versus 96% in shams). Resistance arteries from Ang II-infused ϩ/ϩ and Op/ϩ mice had significantly increased media-tolumen ratio and media thickness, neither of which was altered in Op/Op mice compared with untreated littermates. Vascular media cross-sectional area, NAD(P)H oxidase activity and expression, and vascular cell adhesion molecule (VCAM)-1 expression were significantly increased by Ang II only in ϩ/ϩ mice (PϽ0.05). Key Words: hypertension Ⅲ macrophages Ⅲ reactive oxygen species I nflammation plays an important pathophysiological role in the development and progression of atherosclerosis, hypertension, and other conditions associated with vascular damage. 1 Macrophage colony-stimulating factor (m-CSF) functions as a chemotactic factor for monocytes, regulates effector functions of mature monocytes and macrophages, and modulates inflammatory responses by stimulating the production of other cytokines, adhesion molecules, and growth factors. 2,3 Macrophages have the ability to secrete various cytokines, including tumor necrosis factor (TNF)-␣ that can ultimately influence vascular inflammation. 4 Mice deficient in m-CSF, the result of a spontaneously occurring osteopetrotic mutation within the m-CSF gene, possess macrophage deficiency, monocytopenia, and defective bone formation. [5][6][7] Recently, it was demonstrated that m-CSF-deficient mice fed an atherogenic diet or crossed into a hypercholesterolemic apolipoprotein E-null background have significant reduction in atherosclerotic lesions. 8,9 However, whether reduced macrophage number as a result of the osteopetrotic mutation confers microvascular protection in hypertension remains to be determined. These mice may represent a good model to better understand mechanisms leading to vascular injury mediated by oxidative stress and inflammation in hypertension associated with the activation of the renin-angio...

Background Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID‐19) pandemic. However, there are still few data on COVID‐19 occurring in hematologic patients. Methods One hundred two patients with COVID‐19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID‐19 were analyzed by comparisons of patients with COVID‐19 and the standard hematologic population managed at the same institutions in 2019. Thirty‐day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID‐19. Results Male sex was significantly more prevalent in patients with COVID‐19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID‐19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune‐mediated anemia on immunosuppressive‐related treatments. The 30‐day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID‐19 (23.5%; P = .02) and uninfected hematologic controls (3%; P < .001). The severity of the respiratory syndrome at presentation and active hematologic treatment were independently associated with a worse prognosis. Neither diagnosis nor disease status affected the prognosis. The worst prognosis was demonstrated among patients on active hematologic treatment and those with more severe respiratory syndrome at COVID‐19 presentation. Conclusions During the COVID‐19 pandemic, patients should be advised to seek medical attention at the earliest signs of dyspnea and/or respiratory infection. Physicians should perform a risk‐benefit analysis to determine the impact of temporarily deferring nonlifesaving treatments versus the risk of adverse outcomes associated with COVID‐19. Lay Summary Coronavirus disease 2019 (COVID‐19) infection occurs across all different types of hematologic disease; however, the risk of acquiring it is lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune‐mediated anemia on immunosuppressive treatment. The 30‐day mortality rate is 39.2%, which is far higher than the rates for both uninfected hematologic controls (3%; P < .001) and nonhematologic patients with COVID‐19 (23.5%; P = .02) despite matching for age, sex, comorbidities, and severity of disease. Variables independently associated with a worse prognosis are the severity of the respiratory syndrome at presentation and any type of active hematologic treatment. Neither diagnosis nor disease status influence the prognosis.

Abstract-We hypothesized that resistance arteries from diabetic patients with controlled hypertension have less remodeling than vessels from untreated hypertensive subjects. Eight normotensive subjects (aged 44Ϯ3 years, 3 men; values are meanϮSEM), 19 untreated hypertensive subjects (46Ϯ2 years, 9 men), and 23 hypertensive subjects with type 2 diabetes mellitus under antihypertensive treatment (58Ϯ1 years, 15 men) were studied. Resistance arteries dissected from gluteal subcutaneous tissue were assessed on a pressurized myograph. Most diabetic patients (70%) were being treated with angiotensin-converting enzyme inhibitors. Although systolic blood pressure was still above the normotensive range in these patients (144Ϯ2 versus 150Ϯ3 mm Hg in hypertensive and 114Ϯ4 mm Hg in normotensive subjects), diastolic blood pressure was well controlled (83Ϯ2 mm Hg) and significantly lower compared with that in untreated hypertensives (100Ϯ1 mm Hg; PϽ0.001) but higher than in normotensives (76Ϯ3 mm Hg; PϽ0.05). Thus, pulse pressure was higher in diabetic patients (PϽ0.05). The media-to-lumen ratio of resistance arteries was greater in hypertensives (0.083Ϯ0.002) compared with normotensive controls (0.059Ϯ0.003; PϽ0.05) and was even higher in diabetic hypertensive subjects (0.105Ϯ0.004; PϽ0.001 versus normotensive controls). The medial cross-sectional area was greater in diabetic and hypertensive patients compared with normotensive controls (PϽ0.001). Acetylcholineinduced relaxation was impaired in vessels from hypertensive patients and from patients with both diabetes mellitus and hypertension (PϽ0.05 versus normotensive controls), whereas endothelium-independent vasorelaxation was similar in all groups. Despite effective antihypertensive treatment, resistance arteries from hypertensive diabetic patients showed marked remodeling, greater than that of vessels from untreated, nondiabetic, hypertensive subjects, in agreement with the high cardiovascular risk of subjects suffering from both diabetes and hypertension. Key Words: diabetes mellitus Ⅲ hypertension, detection and control Ⅲ angiotensin-converting enzyme inhibitors Ⅲ remodeling Ⅲ endothelium T ype 2 diabetes mellitus (DM-2) is a major cardiovascular risk factor. In the UKPDS study, the incidence of complications of diabetes was strongly associated with elevated blood pressure (BP). 1 Moreover, tight BP control substantially reduced the risk of macrovascular disease, stroke, and deaths related to diabetes. 2 Macrovessels and microvessels of diabetic patients show marked structural remodeling and impaired endothelial function. In a large, population-based cohort study, DM-2 was associated with increased stiffness of large arteries, as assessed by ultrasound. 3 Other ultrasound studies of large arteries have confirmed the presence of stiffer vessels in patients with DM-2. 4,5 In hypertensive patients, we previously reported that endothelial function of small arteries is correlated with that of large vessels, but ultrasound assessment of large arteries appeared to be less se...

Our results indicate that, in small resistance arteries of patients with primary aldosteronism, a pronounced fibrosis may be detected, even more evident than in blood-pressure-matched patients with essential hypertension.

Abstract-Lowering elevated blood pressure (BP) in diabetic hypertensive individuals decreases cardiovascular events. We questioned whether remodeling of resistance arteries from hypertensive diabetic patients would improve after 1 year of tight BP control with addition of either the angiotensin receptor blocker (ARB) valsartan or the ␤-blocker (BB) atenolol to previous therapy, which included angiotensin-converting enzyme inhibitors (ACEIs) and/or calcium channel blockers. Twenty-eight hypertensive type 2 diabetic patients treated with oral hypoglycemic and antihypertensive agents (not receiving ARBs or BBs) were randomly assigned to double-blind treatment for 1 year with valsartan (80 to 160 mg) or atenolol (50 to 100 mg) daily, added to previous therapy. Resistance arteries dissected from gluteal subcutaneous tissues were assessed on a pressurized myograph. After 1 year of treatment, systolic and diastolic BP and glycemia were equally well controlled in the valsartan and atenolol groups. Endothelium-dependent and independent relaxation did not change in the treated groups. After 1 year of treatment, resistance artery media:lumen ratio decreased in the valsartan group (7.9Ϯ0.5% after versus 9.8Ϯ0.6% before; PϽ0.05) but not in the atenolol-treated group (9.9Ϯ0.9% versus 10.6Ϯ1%; P value not significant). Artery walls from atenolol-treated patients became stiffer, with no change in the valsartan-treated patients. In conclusion, similar intensive BP control for 1 year with valsartan was associated with improved structure of resistance arteries in diabetic hypertensive patients, whereas vessels from atenolol-treated patients exhibited unchanged remodeling and a stiffer wall.

Our results indicate that structural alterations of small cerebral vessels are present in hypertensive patients compared with normotensive individuals, similar to those previously observed in subcutaneous small arteries.

Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus (NIDDM). However, no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM. Therefore, we have investigated the effect of an angiotensin-converting enzyme inhibitor, enalapril, and a highly selective angiotensin receptor blocker, candesartan cilexetil, on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM. Eight patients were treated with candesartan (8 to 16 mg per day) and 7 with enalapril (10 to 20 mg per day) for 1 year. Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment. Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated; moreover, endothelium-dependent vasodilation to acetylcholine was assessed. A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs. Vascular collagen content was reduced and metalloproteinase-9 was increased by candesartan, but not by enalapril. Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen. The 2 drugs equally improved endothelial function. In conclusion, antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct, at least in part, alterations in small resistance artery structure in hypertensive patients with NIDDM. Candesartan may be more effective than enalapril in reducing collagen content in the vasculature.