Peripheral arterial occlusive disease (PAOD) is an ischemic disease characterized by narrowing of the peripheral arteries due to the accumulation of atherosclerotic plaque in the inner lining of the vessels, which disrupts blood flow to downstream tissues. Blood can be redirected into collateral vessels, natural bypasses around arterial occlusions, causing shear-induced outward remodeling of the vessels. The enlarged vessels facilitate transfer of increased blood flow to downstream tissues. The remodeling process, however, may impair vasodilation, which in turn may cause or contribute to intermittent claudication- transient pain brought on by locomotion. To stimulate the growth of collateral arteries, the femoral arteries of young, otherwise healthy mice were ligated distally to the profunda femoris, the stem to the gracilis collateral circuit. The diameter of the profunda femoris artery was measured at rest and following gracilis muscle contraction 7 and 28 days post-surgery using intravital microscopy. Enlarged resting diameter, consistent with collateral enlargement, and impaired vasodilation was observed at day 7, but not at day 28. To determine if impaired functional vasodilation is due to impaired endothelial- or smooth muscle-dependent responses during outward remodeling, cell-dependent vasodilators were applied to the hindlimb. Endothelial- and smooth muscle-dependent vasodilation was significantly impaired 7 days post-ligation, but not 28 days after. This data supports the hypothesis that smooth muscle dysfunction causes impaired functional vasodilation in the early stages of collateral enlargement.

Peripheral arterial occlusive disease (PAOD) is a globally-prevalent cardiovascular disease in which atherosclerotic plaques narrow arterial lumen diameters and restrict blood flow to downstream tissues. The impact of these occlusions can be mitigated by collateral vessels that connect parallel arterial branches and act as natural bypasses to maintain perfusion. In animal models that lack collateral arterioles, capillaries that connect terminal arteriolar segments can arterialize and form functional collaterals following an ischemic event; however, in the early stages of development, vasodilation is impaired. We explored the mechanism of impaired vasodilation in arterialized collateral capillaries (ACCs) and pre-existing collaterals (PECs) by evaluating endothelial-dependent vasodilation and endothelial-independent reactivity at day seven following the ischemic event. We also evaluated functional vasodilation in mature ACCs and PECs at day 21 by applying vasodilation inhibitors during the electrical stimulation of muscle contraction. Arterial occlusion was performed by ligating the cranial-lateral spinotrapezius feed artery in Balb/C mice, a strain that either lacks native arteriolar collaterals or contains a single collateral arteriole (~50% of mice), as opposed to the C57Bl/6 strain, which each contain 10 or more collateral arterioles. At seven days post-surgery, both vasodilation and vasoconstriction were impaired in ACCs when compared to terminal arterioles of similar size in unoperated limbs, but still exhibited significant changes when compared to baseline. The comparable reactivity in both endothelial-dependent and independent vasodilation at day-seven in ACCs indicates that vascular smooth muscle cells are likely responsible for the impairment, as they may still be developing, rearranging, or both, and are not yet fully capable of regulating diameter in immature ACCs. However, by 21 days post-ligation, ACCs regained the capacity to dilate in response to muscle contraction, and utilized similar vasodilation pathways as control vessels. At seven days post-ligation, PECs had impaired endothelialindependent dilation, but successful endothelial-dependent dilation, indicating the use of alternative pathways to dilate. Unlike ACCs, the PECs never completely restored vasodilation capabilities by day 21, which may be due to a variation in smooth muscle phenotype, sensitivity to vasoactive agents, and/or limited growth factor expression. For future work, evaluating collateral formation and vasodilation in a diseased model and investigating molecular variations in the smooth muscle may yield additional knowledge that can improve therapies for patients during ischemic events.

Since the 1900s, the number of deaths attributable to cardiovascular disease has steadily risen. With the advent of antihypertensive drugs and non-invasive surgical procedures, such as intravascular stenting, these numbers have begun to level off. Despite this trend, the number of patients diagnosed with some form of cardiovascular disease has only increased. By 2030, prevalence of coronary heart disease is expected to increase approximately by 18% in the United States. By 2050, prevalence of peripheral arterial occlusive disease is expected to increase approximately by 98% in the U.S. No single drug or surgical intervention offers a complete solution to these problems. Thus, a multi-faceted regimen of lifestyle changes, medication, and device or surgical interventions is usually necessary. A potential adjunct therapy and cost-effective solution for treating cardiovascular disease that has been overlooked is neurostimulation. Recent studies show that using neurostimulation techniques, such as transcutaneous electrical nerve stimulation (TENS), can help to reduce ischemic pain, lower blood pressure, increase blood flow to the periphery, and decrease systemic vascular resistance. The mechanisms by which these hemodynamic changes occur is still under investigation. The primary aim of this thesis is to elucidate these mechanisms through a thorough synthesis of the existing literature on this subject. Neurostimulation, specifically TENS, is thought to modulate both the metaboreflex and norepinephrine release from sympathetic nerve terminals. To test the hypothesis that TENS increases local blood flow, decreases mean arterial pressure, and decreases cutaneous vascular resistance compared to placebo, in which the electrodes are attached but no electrical stimulation is applied, a protocol was developed to test the effect of neurostimulation on healthy subjects. Implementation of this protocol in a pilot study will determine if neurostimulation causes significant changes in blood flow using the most relevant perfusion measurement instrumentation. Before conducting this study, pre-pilot comparison studies of interferential current therapy (IFC) versus TENS, low frequency (4 Hz) TENS versus high frequency (100 Hz) TENS, and electrode placement on the back versus the forearm were conducted. The only statistically significant difference found was that the application of IFC on the back decreased the reperfusion time, meaning that the time required to reach the average baseline perfusion unit value after occlusion decreased. Further pre-pilot work investigating these different modalities and parameters is necessary to ensure that favorable hemodynamic changes can be detected in the pilot study.

Made available in DSpace on 2016-12-06T17:07:18Z (GMT). No. of bitstreams: 1 Ana P Damiano.pdf: 1573878 bytes, checksum: c1d4586f2c9d815e5179472918435bc3 (MD5) Previous issue date: 2008-09-05 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Intermittent claudication (IC) is the main symptom of peripheral arterial occlusive disease (PAOD) and it can severely affect the walking capacity. This study aimed to investigate the effects of a short-course physical exercise program on intermittent claudication of PAOD patients. Twelve out of the 34 recruited subjects were excluded for several reasons. Twenty-two subjects (14 males, mean age 64.4 ± 10.4 years, ankle-brachial index &#8804; 0.8) with varied clinical characteristics were included, and all have participated in Programa de Reabilitação de Doenças Vasculares Periféricas do Núcleo de Cardiologia e Medicina do Exercício (NCME) of the CEFID/UDESC. The physical performance was objectively assessed by means of a 6-minute walk test and subjectively assessed by means of the walking impairment questionnaire. The primary walking test was carried out in order to assess the initial and absolute claudication distances, and lasted up to 15 minutes. The final test lasted up to 30 minutes, if necessary. The results showed that 3 out of the 22 participants had no claudication, being able to walk up to one hour without pain. The mean improvement of the initial claudication distance for the 19 remaining participants was 74.15% (67.6 ± 61.4m, p<0.05). Eleven patients (50%) did not report absolute claudication pain during the primary test; 3 patients, with prior absolute claudication pain, completed the final walking test without reporting pain, and the 8 remaining patients, who still reported absolute claudication pain, had a mean improvement of 48.61% (84.3 ± 58.8m, p<0.05) in walking distance. Regarding the distance walked in 6 minutes, the mean improvement of the 22 patients was 17% (41.1 ± 62.5, p<0.05). It was also possible to notice mean improvement (n = 22) of 14.30% (p<0.05) in walking capacity impairment; 17.56% (p<0.05) in walking distance; 4.59% (p=0.258) in walking speed and 5.49% (p=0.468) in stair climbing. In conclusion, a short-course physical exercise program is effective in PAOD and IC patients. Throughout the walking test, the initial and absolute claudication distances and the distance walked in 6 minutes were significantly improved. The walking impairment questionnaire showed considerable improvements related to walking impairment and walking distance, however, concerning walking speed and stair climbing, the improvements were not statistically significant. / A claudicação intermitente (CI) é o principal sintoma da doença arterial obstrutiva periférica (DAOP) e pode comprometer severamente o desempenho de caminhada. O objetivo do estudo foi investigar os efeitos de um programa de exercício físico a curto prazo na claudicação intermitente de pacientes com DAOP. Dos 34 indivíduos selecionados, 12 foram excluídos por diversos motivos. Os 22 incluídos (14 do gênero masculino, média de idade 64,4 + 10,4 anos, índice tornozelo braquial < 0,8), todos participantes do Programa de Reabilitação de Doenças Vasculares Periféricas do Núcleo de Cardiologia e Medicina do Exercício (NCME) do CEFID/UDESC, apresentavam características clínicas heterogêneas. O desempenho físico foi avaliado objetivamente por meio do teste de caminhada de 6 minutos e subjetivamente pelo questionário de dificuldade para caminhar. O teste inicial de caminhada, destinado à avaliação das distâncias de claudicação inicial e absoluta, foi prolongado até 15 minutos e o final, quando necessário, até 30 minutos. Os resultados demonstraram que, dos 22 participantes do estudo, 3 deixaram de sentir a claudicação, caminhando até uma hora no programa de exercícios sem referir dor. Nos 19 pacientes restantes, a melhora média da distância de claudicação inicial foi de 74,15% (67,6 ± 61,4m, p<0,05). Dos 22 pacientes incluídos no estudo, 11 (50%) não apresentaram dor da claudicação absoluta no teste inicial; 3 pacientes, antes com dor da claudicação absoluta, completaram o teste de caminhada final sem essa manifestação e nos restantes (8 pacientes), que ainda apresentavam dor da claudicação absoluta, foi observada melhora média na distância caminhada de 48,61% (84,3 ± 58,8m, p<0,05). Quanto à distância percorrida em 6 minutos, a melhora média dos 22 pacientes foi de 17% (41,1 ± 62,5, p<0,05). Foi ainda constatado melhora média (n = 22) de 14,30% (p<0,05) na dificuldade para caminhar; 17,56% (p<0,05) na distância de caminhada; 4,59% (p = 0,258) na velocidade de caminhada e 5,49% (p = 0,468) na subida de degraus. Conclui-se que um programa de exercício físico a curto prazo é eficiente no tratamento de pacientes com DAOP e CI. Foi possível observar, por meio do teste de caminhada, melhora significativa na distância para claudicação inicial e absoluta e na distância percorrida em 6 minutos. A aplicação do questionário de dificuldade para caminhar demonstrou melhoras significativas relacionadas à dificuldade para caminhar e à distância de caminhada, sendo, entretanto, as melhoras relacionadas à velocidade de caminhada e subida de degraus consideradas estatisticamente não significativas.