A Novel Paradigm For Heart Failure With Preserved Ejection Fraction
A Novel Paradigm For Heart Failure With Preserved Ejection Fraction
A Novel Paradigm For Heart Failure With Preserved Ejection Fraction
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Figure 1
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the inamed microvascular endothelium (5,59,60). Microvascular inammation also directly favors proliferation of
broblasts and myobroblasts because of reduced NO
bioavailability (42), which leaves probrotic action of
growth-promoting hormones such as endothelin-1, angiotensin II, and aldosterone unopposed (61).
Myocardial Afterload Excess
Arterial hypertension is the most prevalent comorbidity in
HFPEF (62). Although arterial hypertension has been
associated with oxidative stress and vascular inammation
(63), arterial hypertension is usually perceived to induce
HFPEF through myocardial afterload excess (64). The new
HFPEF paradigm proposed in this review shifts emphasis to
microvascular inammation, which lowers myocardial NO
bioavailability and removes the brake on prohypertrophic
stimuli triggered by myocardial afterload excess. This shift of
emphasis is further supported by the following arguments.
1. In all HFPEF registries and large outcome trials
(62,65,66), arterial hypertension in HFPEF consists
of increased systolic pressure (148 mm Hg) but
normal diastolic pressure (83 mm Hg). In HFPEF,
LV cavity dimensions are small, and, especially in the
presence of LV hypertrophy, the left ventricle operates
at a favorable Laplace relationship. LV systolic wall
stress therefore remains low despite increased LV
systolic pressure (67).
Figure 2
In HFPEF, myocardial dysfunction and remodeling are driven by endothelial inammation and oxidative stress. In HFREF, oxidative stress originates in the cardiomyocytes
because of ischemia, infection, or toxic agents. ROS trigger cardiomyocyte autophagy, apoptosis, or necrosis. The latter attracts leukocytes. Dead cardiomyocytes are replaced
by brous tissue. cGMP cyclic guanosine monophosphate; HFREF heart failure with reduced ejection fraction; other abbreviations as in Figure 1.
Figure 3
267
Furthermore, electron microscopic images of LV myocardium revealed lower myolamentary density in HFREF than
in HFPEF, with some HFREF cardiomyocytes showing
areas of complete myobrillar loss (3). These biopsy ndings
are consistent with cell death occurring in HFREF but not in
HFPEF. Potential bias of these results by the low frequency
of biopsy procurement in HFPEF patients cannot, however,
be excluded.
Apoptotic cardiomyocyte death also appears in late eccentric LV remodeling of transverse aortic constriction
mouse models (76). Oxidative stress because of upregulated
cardiac nicotinamide adenine dinucleotide phosphate oxidase
activity appears to be involved. These studies support a
sequence of events whereby myocardial pressure overload
initially triggers concentric hypertrophy followed later by
eccentric remodeling because of high oxidative stress and cell
death. This evolution has also been postulated in human
hypertension (77) but seriously questioned by longitudinal
cohort studies with sequential cardiac imaging (78). In these
studies, the evolution from concentric to eccentric remodeling appeared to be rare in the absence of interval myocardial
infarction.
In advanced HFREF, systemic and coronary endothelial
dysfunction is also present and attributed to increased
plasma levels of TNF-a and IL-6 (79,80) (Fig. 3). However,
in contrast to HFPEF, the increased plasma levels of TNFa and IL-6 do not result from pre-existing comorbidities but
are reactive to the severity of HFREF as they relate to both
In HFPEF, myocardial dysfunction and remodeling are driven by endothelial oxidative stress. In HFREF, oxidative stress originates in the cardiomyocytes. In advanced HFREF,
both mechanisms get superimposed. Abbreviations as in Figures 1 and 2.
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Figure 4
Statin-treated HFPEF patients (HFPEF stat) have higher myocardial PKG activity assessed by the ratio of vasodilatory-stimulated phosphoprotein (VASP) phosphorylated at
serine239 (pVASP) to total VASP (pVASP/VASP ratio) (A), lower myocardial nitrotyrosine content (B), smaller cardiomyocyte diameter (MyD) (C), and lower cardiomyocyte resting
tension (Fpassive) (D). Abbreviations as in Figure 1.
269
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endothelial dysfunction
heart failure