Martyn Kingsbury

Capillary filtration is reduced in lungs adapted to chronic heart failure: morphological and haemodynamic correlates

OBJECTIVE To determine pulmonary capillary filtration in experimental chronic heart failure and to investigate some morphological and haemodynamic mechanisms that could account for reduced filtration in lungs adapted to chronic heart failure. METHODS We studied pulmonary capillary filtration, vascular resistances and morphology in lungs from guinea-pigs adapted to chronic heart failure. Heart failure was induced by banding of the ascending aorta (n=66) or sham control operation (n=78) in guinea-pigs which were studied at 150+/-8 days post-operation. RESULTS Reduced cardiac output, increased systemic vascular resistance and LV end diastolic pressure and increased LV and RV weight:body weight ratio (all P<0.05) indicated chronic heart failure at 5 months following aortic banding in guinea-pigs. Lung weight was increased (61%, P<0.05) in heart failure compared with controls, but lung water content was reduced (5.5%, P<0.05), a reversal of the pattern seen acutely. Studies in isolated perfused lungs demonstrated a reduced capillary filtration coefficient (0. 018+/-0.003 vs. 0.003+/-0.002 ml min(-1)mmHg(-1)g(-1), P<0.001), increased arterial (61%) and venous resistance (50%) in heart failure lungs, P<0.05. Wall thickness:lumen ratio was increased in small (<250 microm) pulmonary arterioles (0.15+/-0.02 vs. 0.08+/-0. 01) and venules (0.06+/-0.005 vs. 0.04+/-0.002) in heart failure, P<0.01. Alveolar septal volume fractions (35.2+/-5.1 vs. 23.1+/-2.7) and septal:air-space volume ratios (60.5+/-13.6 vs. 31.9+/-5.3) were also increased in heart failure, P<0.05. CONCLUSIONS Pulmonary adaptation to chronic heart failure is associated with vascular and alveolar remodelling that contributes to increased vascular resistance and reduced capillary filtration. These changes are likely to be important in mediating resistance to pulmonary oedema in chronic heart failure.

Structural remodelling of lungs in chronic heart failure

Abstract.In order to determine whether morphological changes could account for a previously reported reduction in pulmonary capillary filtration in heart failure, we studied pulmonary morphology in lungs from a guineapig chronic heart failure model. Heart failure was induced by banding the ascending aorta with sham operated animals serving as controls; all animals were studied at 158 ± 6 days post-operation. Following banding, a reduction in aortic flow, increased peripheral vascular resistance and raised left ventricular end diastolic, left atrial and right ventricular pressures together with increased right ventricle to body weight ratio (all p < 0.05) are indicative of established pulmonary hypertension and heart failure. This was associated with an increase in pulmonary septal volume fraction (38.1 ± 3.1% vs 24.6 ± 2.3 %, p < 0.01) and reticulin fibre density. There was also evidence of siderophage infiltration and examination of pulmonary ultra structure revealed a significantly thicker alveolar-capillary barrier in heart failure (1278 ±76 vs 638 ± 32 nm, p < 0.001), thickening of both the alveolar (89%, p < 0.01) and capillary (69%, p < 0.05) basal laminae with pericyte and collagen infiltration of the alveolar-capillary barrier. We hypothesise that these pulmonary adaptations provide protection from oedema formation, but whilst initially protective, are also likely to confer major long-term disadvantages in chronic heart failure.

Investigation of mechanisms that mediate reactive hyperaemia in guinea-pig hearts: role of KATP channels, adenosine, nitric oxide and prostaglandins

Reactive hyperaemia is a transient vasodilatation following a brief ischaemic period. ATP‐dependent K+ (KATP) channels may be important in mediating this response, however it is unclear whether mitochondrial KATP channels contribute to this in the heart. We examined the involvement of KATP channels and the relative role of mitochondrial channels as mediators of coronary reactive hyperaemia and compared them to mechanisms involving NO, prostaglandins and adenosine in the guinea‐pig isolated heart. Reactive hyperaemic vasodilatation (peak vasodilator response and flow debt repayment) were assessed after global zero‐flow ischaemia (5 – 120 s) in the presence of nitro‐L‐arginine methyl ester (L‐NAME, 10−5 M, n=9), 8‐phenyltheophylline (8‐PT, 10−6 M, n=12) and indomethacin (10−5 M, n=12). Glibenclamide (10−6 M, n=12) a non‐selective KATP channel inhibitor and 5‐hydroxy‐decanoic acid (5‐HD, 10−4 M, n=10) a selective mitochondrial KATP channel inhibitor were also used. The specificity of the effects of glibenclamide and 5‐HD (n=6 each) were confirmed using pinacidil (38 nmol – 10 μmol) and diazoxide (42 nmol – 2 μmol). Glibenclamide was most effective in blocking the hyperaemic response (by 87%, P<0.001) although 5‐HD and 8‐PT also had a marked effect (40% inhibition, P<0.001 and 32%, P<0.001, respectively). L‐NAME and indomethacin had little effect. Perfusion with L‐NAME and glibenclamide significantly reduced baseline coronary flow (22%, P<0.01 and 33%, P<0.01) while 8‐PT, indomethacin and 5‐HD had no effect. KATP channels are the major mediators of the coronary reactive hyperaemic response in the guinea‐pig. Although mitochondrial KATP channels contribute, they appear less important than sarcolemmal channels.

Left ventricular hypertrophy induced by aortic banding impairs relaxation of isolated coronary arteries

LVH (left ventricular hypertrophy) is associated with impaired coronary vascular reserve. In the present study, we examined the effect of pressure-overload hypertrophy on vasorelaxant responses of guinea-pig isolated coronary small arteries and compared them with mesenteric small arteries. Pressure-overload was induced by banding the ascending aorta of guinea-pigs. Haemodynamics, and ventricular, atrial and lung weights were measured 168 days after banding. Isolated coronary and mesenteric small arteries were contracted with a thromboxane mimetic (U46619) and relaxation to ACH (acetylcholine), ISO (isoprenaline), FSK (forskolin) and SNP (sodium nitroprusside) was examined. Arterial wall morphology was examined by light microscopy. Aortic banding reduced cardiac output and increased systemic vascular resistance; atrial, ventricular and lung weights were increased. Coronary artery adventitial and medial thickness were increased, but mesenteric arterial wall morphology was unaffected. Coronary artery relaxation to ACH, ISO, FSK and SNP were reduced in banded animals. In contrast, relaxation of mesenteric arteries to ACH, FSK and SNP were unaffected by banding, although ISO-induced relaxation was reduced. A COX (cyclo-oxygenase) inhibitor, indomethacin, had no effect on coronary artery responses to ACH in banded or sham animals, but the differences in relaxation of coronary arteries between banded and sham animals were no longer significant following pre-incubation with the NO inhibitors L-NMMA (N(G)-monomethyl-L-arginine) and oxyhaemoglobin. In conclusion, pressure-overload-induced LVH causes impaired relaxation of small coronary arteries to endothelium-dependent and -independent relaxants. These findings are indicative of alterations in vascular smooth muscle responsiveness to vasodilators. Impairment of coronary arterial vasodilation may contribute to the reduced coronary vascular reserve seen in LVH.

Recovery of coronary function and morphology during regression of left ventricular hypertrophy.

OBJECTIVES To investigate changes in coronary morphology and haemodynamic function during regression of established left ventricular hypertrophy (LVH) following surgical unloading. METHODS LVH was induced in guinea-pigs by aortic banding and sham operated animals served as controls. We examined the degree of LVH, coronary haemodynamic function and contemporaneous vessel morphology 42 days post-operation. Identically treated animals were debanded and the same parameters measured after 1, 3 and 6 weeks to assess haemodynamic and morphological changes as hypertrophy regressed. RESULTS Banding resulted in an aortic pressure gradient of 41+/-9 mmHg and increases in heart/body weight ratio (46%), myocyte size (26%) and a doubling of arteriolar wall thickness, all P<0.01. These changes were accompanied by a reduction in coronary reserve (38%) and significantly (P<0.01) decreased maximal response to acetylcholine (70%), sodium nitroprusside (87%), adenosine (70%) and reactive hyperaemia (52%). Surgical debanding normalised the systemic haemodynamics and removed the aortic gradient after 7 days. There was some limited improvement in coronary structure and, to a lesser extent, function despite the continued presence of significant LVH. This had completely regressed to normal levels 23 days after debanding and was accompanied by normalisation of coronary structure and function, although systolic impedance to flow remained significantly increased. After 44 days, debanding resulted in complete cardiac morphological and functional recovery. CONCLUSION Left ventricular haemodynamic unloading can result in complete normalisation of LVH, coronary morphology and haemodynamic function. Although morphological and functional recovery were closely correlated, recovery of coronary morphology and function slightly preceded that of the myocardium in this aortic banded/debanded model.

Why do people choose nephrology? Identifying positive motivators to aid recruitment and retention

ABSTRACT Increasing concerns about recruitment and retention of junior doctors have led to renewed interest in how and when trainees choose their specialties. To our knowledge, no study has yet reported what attracts UK applicants to nephrology nor how clinicians develop vocational interests or make occupational choices. With this in mind, we sought to explore the motivation behind current nephrologist’s career choices in the UK. We interviewed 11 nephrologists using a semi-structured face-to-face approach and used interpretative phenomenological analysis to conduct and analyse the interviews. We found role models were pivotal in encouraging specialization in nephrology, particularly those encountered in early postgraduate training. The diversity, diagnostic challenge and cross-specialty knowledge was highlighted as well as the ability to ‘make a difference to patients’ lives’. Nephrologists enjoyed the challenge of managing very sick, acutely unwell patients as well as the holistic continuity of long-term care offered to dialysis patients and their families. Academic and procedural components were attractive motivators to the specialty and the flexibility to have multiple interests was noted, with many nephrologists having ‘portfolio’ careers. Based on these results, we suggest strategies the specialty can use to aid policy decision making, promote recruitment and improve educational experiences within current training programmes.