cron-web.org

[A1CR]

The previous http://tinyurl.com/glo4a paper found, it
seemed, that CR
improved diastolic function among us CRers. The paper below
(0) is related
to these previous studies, and refers to the
http://tinyurl.com/glo4a paper
as reference [1]. A paper http://tinyurl.com/qlcjt that
discussed [1] is
designated reference [2]. It might be useful for someone
who communicates
with Dr. Fontana to bring (0) to his attention, should he
not be aware of
this study is being published. He may wish to provide
comments to the
journal, since (0) critically commented of the study of Dr.
Fontana. We human CRONiess eat less salt than those eating
a typical Western style diet, and this may have impacted
our beneficial heart functions. Maybe it did not. The use
of a
salt-sensitive model to study heart functions may have benefits.

0. Seymour EM, Parikh RV, Singer AA, Bolling SF.

Moderate calorie restriction improves cardiac remodeling and
diastolic
dysfunction in the Dahl-SS rat.

J Mol Cell Cardiol. 2006 Aug 22; [Epub ahead of print]

PMID: 16934290

Abstract:

Caloric restriction extends longevity and reduces the onset
of chronic disease in many animal models. Recently, caloric
restriction was shown in humans to be associated with lower
blood pressure, decreased systemic inflammation, and
improved cardiac diastolic parameters. However, the
causation and mechanisms of caloric restriction were
obscured by the varied diet composition of the participants.
The Dahl salt-sensitive rat which develops gradual,
hypertension-associated diastolic dysfunction was used in
this study to assess the impact of caloric restriction upon
decompensated pressure-overload hypertrophy. Male Dahl
salt-sensitive rats were provided either a low-salt diet or
a high-salt diet to initiate heart failure progression. A
further subset of high-salt rats underwent 15% calorie
restriction, with salt load held constant. Parameters
measured included serial systolic blood pressure, body
weight, and changes of left ventricular systolic and
diastolic parameters and ventricular geometry by
echocardiography. After 18 weeks, fasting glucose, blood
lipids, heart weight, kidney weight, lung weight, plasma
interleukin-6 and TNF-alpha, and cardiac lipid peroxidation
were measured. Low-salt rats did not develop heart failure.
While high-salt rats displayed features of decompensated
pressure-overload hypertrophy, moderate calorie restriction
remarkably reduced morbidity. Compared to the high-salt fed
group, the high-salt, calorie-restricted group showed
reduced blood pressure, delayed onset of cachexia, lower
fasting hyperlipidemia, lower cardiac, renal and lung
weight, less plasma IL-6 and TNF-alpha, less cardiac
oxidative damage, and improved diastolic chamber function
and cardiac index. Modest calorie restriction, independent
of salt intake, reduced pathogenesis in this well described
model of decompensated pressure-overload hypertrophy.


Excerpts:

... Recently, caloric restriction was shown in humans
to be associated
with lower blood pressure, decreased systemic inflammation,
and improved
cardiac diastolic parameters. However, the causation and
mechanisms of
caloric restriction were obscured by the varied diet
composition of the
participants. The Dahl salt-sensitive rat which develops
gradual,
hypertension-associated diastolic dysfunction ... Male Dahl
salt-sensitive
rats were provided either a low-salt diet or a high-salt
diet to initiate
heart failure progression. A further subset of high-salt
rats underwent 15%
calorie restriction, with salt load held constant. ... After
18 weeks ...
Low-salt rats did not develop heart failure. While high-salt
rats displayed
features of decompensated pressure-overload hypertrophy,
moderate calorie
restriction remarkably reduced morbidity. Compared to the
high-salt fed
group, the high-salt, calorie-restricted group showed
reduced blood
pressure, delayed onset of cachexia, lower fasting
hyperlipidemia, lower
cardiac, renal and lung weight, less plasma IL-6 and
TNF-alpha, less cardiac
oxidative damage, and improved diastolic chamber function
and cardiac index.
Modest calorie restriction, independent of salt intake,
reduced pathogenesis
...
... A recent human study published by Meyer et al. [1]
suggested that
calorie restriction lowers blood pressure, lowers systemic
oxidative stress,
and improves diastolic function. This important study was
the first to
examine the effect of long-term calorie restriction, with
optimal nutrition,
on cardiac function in non-obese humans. However, the study
design was
complicated and limited by multiple dietary differences
between the study
groups [1] and [2]. The calorie-restricted group, mostly on
a "Mediterranean
diet" was compared to a mostly "Western Diet" control group.
Collectively,
the calorie-restricted group consumed less calories, sodium,
total fat and
saturated fat, while consuming more protein and more complex
versus simple
carbohydrates. The authors note that it is not possible to
imply causation
in regards to the specific effects of calorie restriction
with this design.
However, their results implied that in the population
studied, reduced
calorie intake was associated with improved clinical
parameters of cardiac
health. ...
.
[...]

... Dahl rats fed 6.0% NaCl experience 100% mortality
by 24 weeks. When
the rats in this study were sacrificed at 18 weeks, there
were observed
qualitative differences in heart failure phenotypes between
HS and HS-CR
rats in terms of lethargy and respiratory effort. ... onset of
http://en.wikipedia.org/wiki/Cachexia coincides with the
development of
decompensated pressure-overload hypertrophy in the Dahl-SS
rat model. The HS
group displayed the onset of cachexia at 13 weeks, but the
HS-CR did not
begin to lose body weight until 15-16 weeks (Fig. 1). In
addition, the final
degree of body weight loss was larger in the HS group at the
18-week time
point. HS rats lost 25% of body weight as compared to the LS
control group,
while HS-CR rats only lost 12% as compared to the LS control
group.
... (Fig. 2). The first statistically significant
decrease in systolic
blood pressure between the HS-CR group and HS group was
detected at the
6-week time point measure, and this effect was sustained
until the 12-week
time point, after which there is no statistical difference
between HS and
HS-CR [and none at weeks].

[...]


... Compared with LS rats at 18 weeks, left
ventricular dimension at
end diastole (LVEDD) and end systole (LVEDS) was greater in
the HS rats
(Table 1), but LVEDD was significantly reduced by CR (-27%
versus HS, p <
0.05). Indices of wall thickness and left ventricular weight
relative to
body weight show that HS diets increased wall thickness,
changes first
evident at the 8-week compensated hypertrophy stage. In the
Dahl-SS rat,
increasing relative wall thickness (RWT, or 2 × posterior
wall thickness
during diastole/LVEDD) is found to correlate strongly with
contractile
failure, more so than increasing LV mass [10]. When measured
at 18 weeks, CR
reduced RWT (-29% versus HS, p < 0.05) and left ventricular
mass/body weight
(-25% versus HS, p < 0.05). Regarding systolic function
(Table 2), the %
mid-wall fractional shortening and ejection fraction was not
significantly
altered by treatment. Cardiac index reflects cardiac
contractile efficiency
by measuring the volume of blood moved per minute (stroke
volume × heart
rate), per unit of body weight. The 8-week measures in all
groups did not
show significantly impaired cardiac index, which is expected
during
compensated hypertrophy. However, at 18 weeks, cardiac index
was
significantly lower in the HS fed group, but was
significantly improved by
CR (+ 16% versus HS, p < 0.05).


[...]
... In the Dahl-SS rat, heart, kidney and lung weight
relative to body
weight and tibial length are elevated by a high-salt diet.
While renal
hypertrophy is present early in Dahl-SS pathogenesis,
increased lung weight
heralds the onset of pulmonary congestion and decompensated
pressure-overload hypertrophy. Our results in Table 4 show
that CR
significantly reduced changes in heart, kidney and lung
weight. Table 4 also
shows that while not significantly impacting fasting glucose
levels, CR
lowered total cholesterol and triglyceride levels. CR also
reduced plasma
TNF-alpha and IL-6.


[...]

... CR reduced oxidative stress ... high-salt ...
elevates oxidative
stress ... elevating tissue
http://en.wikipedia.org/wiki/Angiotensin_II#Angiotensin_II
and activating
downstream NADPH-oxidase and subsequent superoxide ...
converted to hydrogen
peroxide ... high-salt feeding ... increased cardiac
oxidative ... increased
lipid peroxide marker, MDA. ..., CR significantly reduced
MDA ... [the free
full-text http://tinyurl.com/ow5we paper]. ... By reducing
oxidative stress,
CR could impact hypertrophic ... reduce cardiac
http://en.wikipedia.org/wiki/Fibrosis ... reduced cardiac
remodeling and
improved cardiac function. ... [1], subjects in the
calorie-restricted group
(-33% kcal) had an average systolic blood pressure 30% lower
than the
Western Diet group. ... here ... 15% calorie restriction
also had a
depressor effect, but more modest and variable than that
observed in the
human study. ... current study ... depressor effect of CR
waned as
pathogenesis progressed, without a parallel loss of cardiac
function
relative to HS. ... CR has lasting effects on cardiac
hypertrophy and
function, independent of a sustained depressor effect. ...
affect myocardial
stiffness and diastolic filling parameters. ... decompensated,
pressure-overload hypertrophy ... CR reduced the degree of
change rather
than preventing it. CR ... lower E/A ... prolonged early
filling
deceleration time, and shortened relaxation time. Meyer
showed that CR
benefited diastolic function, as the E/A ratio was greater
in the CR group
than in the Western diet group, with no significant
differences in ejection
fraction or fractional shortening. Taffet ... [45] [in 45,
the pdf-unavailed
http://tinyurl.com/qfbvo paper shown below for its Medline
description] ...
diastolic parameters were significantly improved (higher E/A
ratio, no
apparent relaxation abnormality) in the CR ... resembled
that of younger
mice. ... this ... model was not a model of heart failure
... ... here
displays clinical indices of heart failure, including renal
impairment and
hypertrophy, lung hypertrophy, lethargy, labored
respiration, and cachexia.
... improved diastolic parameters by CR appears to be
conserved across
diverse models. ... Changes in wet heart weight, left
ventricular mass, and
wall thickness were attenuated by CR. ... Renal impairment
... component of
Dahl-SS ... [1] also showed that calorie-restricted humans
also displayed
reduced hyperlipidemia. ... Dahl-SS rat is not typically
used to study
systolic impairment ...

Taffet GE, Pham TT, Hartley CJ.

The age-associated alterations in late diastolic function in
mice are
improved by caloric restriction.

J Gerontol A Biol Sci Med Sci. 1997 Nov;52(6):B285-90.

PMID: 9402929

Caloric restriction reduces the magnitude of many
age-related changes in rodents. Cardiac function is altered
with senescence in mice, rats, and healthy humans. We
examined the effects of life-long caloric restriction on
diastolic and systolic cardiac function in situ using
Doppler techniques in ad libitum-fed 30- to 32-month-old
(AL) and calorically restricted (CR) 32- to 35-month-old
female B6D2-F1 hybrid mice. The heart weight to body weight
ratio was similar in AL (5.74 +/- .24 mg/g) and CR (5.68 +/-
.20 mg/g) mice. Two systolic functional parameters known to
decrease with age in both humans and mice, peak aortic
velocity and aortic acceleration, were unchanged by CR
compared to AL. In contrast, diastolic function was altered
by caloric restriction. Although left ventricular peak early
filling velocity (E) was not different between CR and AL,
peak atrial filling velocity (A) was 50% lower in CR
compared to AL (p < .001). The ratio of early diastolic
filling to atrial filling (E/A ratio) was 64% higher in the
CR (2.74 +/- .31) than the AL (1.55 +/- .07; p = .004). The
fraction of ventricular filling due to atrial systole, the
atrial filling fraction, was also reduced in CR (.21 +/-
.04) compared to AL (.36 +/- .02; p = .007). These changes
occurred in CR without alteration in E deceleration time,
which is consistent with improved diastolic function in CR.
Through mechanisms that remain unknown, lifelong caloric
restriction may prevent the age-related impairments in late
diastolic function but does not alter the impairments in
systolic or early diastolic cardiac function.


... ad libitum-fed 30- to 32-month-old (AL) and
calorically restricted
(CR) 32- to 35-month-old female B6D2-F1 hybrid mice. The
heart weight to
body weight ratio was similar in AL (5.74 +/- .24 mg/g) and
CR (5.68 +/- .20
mg/g) mice. Two systolic functional parameters known to
decrease with age in
both humans and mice, peak aortic velocity and aortic
acceleration, were
unchanged by CR compared to AL. In contrast, diastolic
function was altered
by caloric restriction. Although left ventricular peak early
filling
velocity (E) was not different between CR and AL, peak
atrial filling
velocity (A) was 50% lower in CR compared to AL (p < .001).
The ratio of
early diastolic filling to atrial filling (E/A ratio) was
64% higher in the
CR (2.74 +/- .31) than the AL (1.55 +/- .07; p = .004). The
fraction of
ventricular filling due to atrial systole, the atrial
filling fraction, was
also reduced in CR (.21 +/- .04) compared to AL (.36 +/-
.02; p = .007).
These changes occurred in CR without alteration in E
deceleration time,
which is consistent with improved diastolic function in CR.
... lifelong
caloric restriction may prevent the age-related impairments
in late
diastolic function but does not alter the impairments in
systolic or early
diastolic cardiac function.